MCB II Block 4

  1. Dietary Lipases
  2. Plasma Lipoproteins
  3. Nitrogen Economy
  4. Degradation of Amino Acids
  5. Synthesis of Amino Acids
  6. Heme Metabolism
  7. Purines
  8. Pyrimidines
  9. Inorganic Nutrients
  10. Vitamins
  11. Fat-Soluble Vitamins
  12. Insulin and Glucagon
  13. Metabolism of Well-Fed State
  14. Obesity
  15. Diabetes and Starvation


Q: What do lipids dissolve in?
A: alcohol

Q: why are lipids vulnerable to oxidative damage by ROS?
A: because lipids are naturally reduced (have lot less O than C and H).

Q: What is the optimum pH for gastric lipase?
A: pH 4-6

Q: What is the primary target for gastric lipase?
A: Triacylglycerols with short or medium chain fatty acids (like milk fat)

Q: Gastric lipase is more important in neonates than in adults. Why?
A: Because the pH of the neonate’s stomach is near neutral, around gastric lipase’s optimum pH, so it is great for digesting milk fat. In adults, since the stomach has such a low pH, the lipids basically remain intact until it gets into the small intestines. In adults, low stomach pH is good because it is bacteriocidal and break down proteins.

Q: What are the two types of bile salts in the small intestine? What do they do?
A: glycocholic acid and taurocholic acid (“taurochenodeoxycholic acid”). They emulsify – surround triacylglycerols to form micelles.

Q: What is glycocholic acid made of? What is taurocholic acid made of?
A: glycocholic acid = cholic acid + glycine. Taurocholic acid = chenodeoxycholic acid + taurine

Q: Where do the carboxyl and hydroxyl groups point in bile salts?
A: towards the water.

Q: How do pancreatic lipases break down emulsified fats?
A: They attach to the micelles (bile acids + TAGs). Then they extract fatty acids one at a time.

Q: How many carboxyl and how many hydroxyl groups are in a bile salt?
A: 3 OH’s, 1 COO-

Q: Where is CCK produced? What does it do?
A: mucosa of jejunum and duodenum. It is triggered by dietary lipids and proteins in the gut. It causes gall bladder to expel bile and pancreatic enzymes. It also slows down gastric contractions, prolonging time of food in gut.

Q: What is secreted in duodenum in response of low pH of chyme from stomach?
A: secretin. They promote pancreas to release bicarbonate…. CO2 is so important to our body… not just waste! It’s important to have a neutral duodenum so that certain enzymes can work.

Q: Why can’t triacylglycerols be taken up from mucosa?
A: Because they’re too big! So you need pancreatic lipase to cleave it!

Q: How does pancreatic lipase cleave triacylglycerol?
A: it cleaves it into three pieces: two free fatty acids and one 2-monoacylglycerol (fatty acid + glycerol) because lipase can only reach the sides of the triacylglyceride.

Q: What kind of bond does pancreatic lipase cleave in triacylglycerol?
A: ester bonds.

Q: What does Orlistat do?
A: It’s used to treat obesity. It inhibits gastric and pancreatic lipases, so lipids aren’t digested.

Q: What does lipase need for it to work?
A: Co-lipase.

Q: How does colipase work?
A: acts as “hinge” for pancreatic lipase so it can do its job. Holds it between lipid and aqueous medium, exposes active site.

Q: How do you activate colipases?
A: by chymotrypsin, which cleaves the pre-colipase.

Q: What two enzymes do you use to break down phospholipids?
A: Phospholipase A2 cleaves fatty acid at C2 to become lysolecithin. Remaining fatty acid clipped by lysophospholipase, leaving glycerol-phosphoryl base.

Q: What enzyme do you need to hydrolyze cholesterol esters?
A: pancreatic cholesteryl ester hydrolase. Yields cholesterol and free fatty acids.

Q: What length fatty acids don’t need micelle to be absorbed?
A: short chain and medium chain. Others need to be broken down by lipases into smaller pieces within the micelle.

Q: After monoglycerides and free fatty acids are absorbed by jejunum, what happens to them?
A: They are reassembled into triacylglycerols in mucosal cell (esterified).

Q: Then what happens to the triacylglycerols?
A: They combine with cholesterol and phospholipids to form chylomicrons.

Q: What is the biggest class of lipoprotein?
A: Chylomicrons are the biggest class of lipoproteins. They transport triacylglycerol. Very short half life.

Q: What happens once the monoacylglycerols, fatty acids, cholesterol and fat-soluble vitamins get through the intestinal mucosal cell?
A: they get reassembled into cholesteryl ester (cholesterol + fatty acid), triacylglycerol (monoacylglycerol + 2 fatty acids), just like how they were in the micelle before breakdown by pancreatic lipase and cholesteryl ester hydrolase. Vitamins ADEK stay as they are. They all come together to form chylomicron.

Q: How do you activate free fatty acids in the mucosa so they can be assembled into triacylglycerol? What does it require?
A: fatty acyl-CoA synthetase. Irreversible reaction. Requires ATP.

Q: What else gets mixed in along with newly reformed-triglycerides and cholesteryl ester into the chylomicron?
A: Apolipoprotein B-48 (formed from amino acids) and phospholipids.

Q: What is the purpose of apolipoprotein B-48 and where does it get its name?
A: It is the “seed” in which chylomicrons are formed. It is called “B-48” because it has 48% of the amino acid content of another molecule called “B-100”

Q: What attaches two fatty acyl-CoAs onto monoacylglycerol to reform triglycerides in the mucosal cell (to be incorporated into chylomicron)?
A: Acyltransferase

Q: How are long-chain and medium/short-chain fatty acids different in terms of which ones are shipped out via chylomicrons?
A: long chain fatty acids are toxic inside the cell, so they must be esterified into triacylglycerol (a neutral lipid) and shipped out via chylomicrons. Short and medium-chain fatty acids on the other hand can just go straight to portal circulation without needing to be esterified.

Q: What does it mean for a fatty acid to be esterified?
A: when fatty acids are esterified, they are made into triacylglycerols.

Q: How are short and medium chain fatty acids transported directly into portal circulation into the liver?
A: via albumin.

Q: How many FFA molecules can albumin bind?
A: Ten. Albumin has 17SS bridges.

Q: What enzyme re-esterifies cholesterol back into cholesteryl ester in the mucosal cell?
A: Acyl CoA cholesterol acyltransferase.

Q: What is the difference between micelle and chylomicron?
A: micelle is formed in the intestine. Chylomicron is formed in the mucosa to be carried in the blood.

Q: What is the main cargo of chylomicrons?
A: Triacylglycerol

Q: Where are the chylomicrons assembled in a cell?
A: ER and Golgi

Q: What is the half-life of chylomicrons?
A: very very short! 30 minutes. Triacylglycerol half life is 5-10 min

Q: Where are the chylomicrons exocytosed into from the mucosal enterocyte?
A: into lacteals (lymphatic system)

Q: Once they go from the mucosal cell to lymphatics into the bloodstream, what enzyme disassembles chylomicrons?
A: Lipoprotein lipase (LPL). They are anchored to capillary walls. They degrade triglycerides.

Q: How are lipids released from liver into bloodstream?
A: via VLDL

Q: What do lipoprotein lipases use to disassemble chylomicrons?
A: Apo-C-II. Allosteric activator of LPL

Q: How is LPL (lipoprotein lipase) held on capillary inner wall so they don’t swim away in the blood stream?
A: via GPI anchor.

Q: Where do most of the dietary triacylglycerols go?
A: muscle, heart, kidney, adipose, but NOT RBC or nervous tissue. “the four biggest customers”

Q: Where is LPL NOT found?
A: liver and brain. Because liver dismantles lipids and brain does not use lipid.

Q: LPL deficiency can lead to what?
A: chylomicronemia, because can’t break down. Lots of fat in blood.

Q: What is the Km of myocardial LPL compared with adipose tissue LPL?
A: myocardial LPL’s Km is 10 times lower than adipose tissue (a lot more LPL in adipose tissue)

Q: What happens to the free floating middle and short chain fatty acids in blood circulation with albumin?
A: they go to either liver or adipocytes and are esterified into triacylglycerides where they are stored.

Q: In Adipocyte, where does the glycerol-3-phosphate used to make triacylglycerols come from?
A: from DHAP from glycolysis

Q: When triacylglycerol gets hydrolyzed (when they are released from adipocyte to bloodstream when you need it), what happens to the glycerol?
A: Since adipose tissue does not have any glycerokinase, the liver has to utilize the glycerol for glycolysis or gluconeogenesis.

Q: What is left over in the chylomicron after triacylglycerols are removed?
A: cholesteryl esters, phospholipids, protein, and a little bit of triacylglycerol.

Q: What happens to the chylomicron after all the triacylglycerides have been utilized and transferred?
A: The remnant chylomicron gets uptaken by the liver.

Q: What do you need for chylomicron remnants to be taken up by the liver?
A: apo E (E for endocytosis)… the components are reassembled, reused.


Q: What are the body’s four main avenues of lipid transport?
A: Fatty acids from adipose tissue to other tissues (via albumin), dietary lipids from intestine to other tissue, endogenously synthesized lipids from liver, and reverse transport of cholesterol from other tissue to liver. The last three involve lipoproteins.

Q: What is the structure of apoprotein?
A: amphipathic (makes sense, because it needs to stick to both the lipoprotein and the water), alpha-helix… so one side hydrophobic and the other side hydrophilic.

Q: How are lipoproteins uptaken by cells?
A: via receptor-mediated endocytosis.

Q: How are free cholesterol esters brought into the cell?
A: via LDL. The lipoprotein is endocytosed.

Q: What enzymes do cholesterol up- or down-regulate?
A: 1. Downregulate HMG-CoA reductase (which makes cholesterol, which you don’t need). 2. Upregulate acyl-CoA cholesterol acyl transferase (ACAT) (which re-esterifies cholesterol back into cholesteryl ester, which you need). 3. Reduce synthesis and accelerate degradation of LDL receptors

Q: What are two ways plasma lipoproteins are classified?
A: By Density or by electrophoretic mobility

Q: What are 4 types of plasma lipoproteins by density?
A: VLDL, IDL, LDL, and HDL (ordered from low to high density)

Q: How are chylomicrons different from other plasma lipoproteins?
A: chylomicrons proportionally have a lot more triacylglycerol than the other lipoproteins, and have a lot less cholesterol and apoproteins. Chylomicrons are also from intestinal mucosal cells while lipoproteins have origin from liver (VLDL).

Q: Which lipoproteins have Apoprotein B-100?

Q: Why are things like chylomicrons and VLDLs called “lipoproteins”?
A: because they carry lipids and apoproteins like B-100 or B-48

Q: Which lipoproteins (besides chylomicrons) have the most triglycerides?
A: VLDL (because it has the least density of cholesterol).

Q: 70% of total plasma cholesterol is from which lipoproteins?
A: LDL. So cholesterol level = LDL level

Q: What represents the cholesterol level vs. triglyceride level in the plasma?
A: VLDL level = triglyceride level. LDL level = cholesterol level.

Q: B-apoproteins are found in all lipoproteins but which one?
A: They are not found in HDL. Otherwise they transfer readily between different lipoprotein classes.

Q: What is the purpose of apoproteins (aka apolipoproteins)?
A: 1. regulate enzymes of lipoprotein metabolism (like lipoprotein lipase (LPL), and lecithin-cholesterol acyl transferase (LCAT)). 2. They facilitate lipid transfers between different lipoprotein classes and between cells. 3. They mediate cellular uptake of lipoproteins through cell surface receptors.

Q: Apoprotein B-48 is only found on which class of lipoproteins?
A: chylomicrons.

Q: Descript lipoprotein transport?
A: Liver makes VLDL, which go to capillaries. Remnants become IDL, which can become LDL, both of which can re-enter liver. LDL can go into muscles and organs as cholesterol. HDL come from muscles and organs and are picked up by liver (reverse transport) or go to endocrine glands for steroid hormone synthesis.

Q: What lipoprotein carries lipids of dietary origin?
A: Chylomicrons. They appear only after a meal.

Q: Through which lymphatic duct do chylomicrons reach general circulation?
A: Thoracic Duct. Contents reflect composition of meal.

Q: What apoproteins are chylomicrons formed with? What apoproteins do they end up with?
A: They are made with both apo B-48 (which is only found in chylomicron) and A-apolipoproteins. Later on, they get rid of A-apolipoproteins, and acquire ApoE and C-II in the bloodstream from HDL (which is an important reservoir of apoproteins). So they end up with apo B-48, E, and C-II.

Q: Which apoprotein activates LPL?
A: Apo C-II.

Q: After Apo C-II activates LPL which diassembles chylomicrons, what happens to the Apo C-II?
A: It returns to the HDL.

Q: What happens to the chylomicron remnants?
A: It gets endocytosed by the liver.

Q: What does LPL activity require?’
A: phospholipids and apoC-II

Q: Where are the chylomicron remnants endocytosed?
A: Space of Disse of the liver.

Q: Where do the chylomicron remnants bind to on the hepatocyte in the space of disse?
A: on heparan sulfate proteoglycans and lipoprotein receptors.

Q: What apoprotein is required for hepatocyte receptor binding of chylomicron remnants?
A: ApoE

Q: How long does it take for secretion of chylomicron remnants to reuptake by liver?
A: 1 hr.

Q: VLDL is the precursor to what lipoprotein?

Q: Where are VLDLs made?
A: in ER and Golgi in liver. They pass through the fenestrated capillary epithelium of liver.

Q: What apoproteins are VLDLs formed with?
A: apo B-100, some ApoE and C-II (later picks up even more ApoE and C from HDL).

Q: What apoproteins do HDL contain?
A: ApoE and C-II.

Q: What enzyme converts intermediate-density lipoproteins into low-density lipoproteins?
A: Hepatic Lipase.

Q: Is hepatic lipase activated by apoC-II?
A: No

Q: Besides converting IDL to LDL, what else does Hepatic Lipase do?
A: it converts HDL2 to HDL3 (more mature HDL) by removing triacylglycerol and phospholipids from it.

Q: Which lipoprotein has only ONE apoprotein? What apoprotein does it contain?
A: LDL, which has a single apoB-100.

Q: How long do LDLs circulate compared to VLDLs?
A: LDL circulate for 3 days, while VLDLs gone within minutes to hours.

Q: Where do LDL’s end up?
A: 2/3 go to liver. 1/3 go to muscles as source of cholesterol.

Q: When LDLs are taken up by liver, what binds to what?
A: apoB-100 binds to LDL.

Q: What does acyl-CoA cholesterol acyl transferase do?
A: It re-esterifies cholesterol back to cholesteryl ester.

Q: Not all LDL are cleared by LDL receptors on cells. Some are cleared by macrophages and other cells by what receptors?
A: Scavenger receptors.

Q: When are scavenger receptors the most useful?
A: When plasma LDL levels are the highest… have lots to scavenge. LDLs only bind to scavenger receptors secondarily because the receptors have a Km that is 7 to 8 times higher (lower affinity) than regular LDL receptors on hepatic cells.

Q: What type of LDLs are more avidly picked up by scavenger receptors?
A: chemically altered LDLs like on aberrant/aged lipoproteins. Protective function.

Q: What other things do scavenger receptors bind?
A: negatively-charged particles, like bacteria… so may be important for immune defense.

Q: In liver, adrenals, lungs and kidneys, most of LDL is taken up via LDL receptors. How about in the intestine and spleen?
A: most is taken up by scavenger receptors on macrophages.

Q: Cholesterol controls ACAT, HMG-CoA reductase, and LDL receptors to control how much cholesterol is available to the cell. However, it does not down-regulate scavenger receptors that much. What is the result of this?
A: macrophages can accumulate cholesterol more if the LDL receptors on other cells are reduced.

Q: What helps “reverse transport” cholesterol from extrahepatic cells to liver?

Q: What apoproteins do the nascent HDL (from liver and intestine) have?
A: Apo A-I, A-II, and C

Q: What are the two enzymes that HDL contain?
A: Lecithin-cholesterol acyl transferase (LCAT) and cholesterol ester transfer protein (CETP)

Q: What do LCAT and CETP do?
A: LCAT esterifies cholesterol into cholesteryl ester. CETP transfers the cholesteryl ester from HDL to other lipoproteins.

Q: What enzyme activates LCAT?
A: Apo A-I.

Q: What does LCAT catalyze?
A: cholesterol + phosphatidylcholine → cholesterol ester + 2-Lysophosphatidylcholine (aka lysolecithin)… so esterifies cholesterol.

Q: What enzyme esterifies cholesterol?

Q: What is the structure of lysolecithin?
A: phosphatidylcholine minus a fatty acyl group.

Q: What does CETP catalyze?
A: Transfers cholesterol esters from HDL to other lipoproteins, often (but not always) exchanging it for triglycerides from VLDL. Remember HDL goes to liver, so it controls how much cholesterol esters are in circulation and how much is in liver.

Q: What does ApoE do?
A: it enables HDLs to endocytose into the hepatocyte. Remember E for “Endocytosis.”

Q: What are the three ways that cholesterol can reach liver?
A: apoE-mediated endocytosis of remnant particles that have gotten cholesterol from HDL (via CETP), direct transfer of cholesterol esters from HDL, and endocytosis of large apoE-containing particles.

Q: What is the most important method of transfer of cholesterol into liver?
A: the first one… apoE-mediated endocytosis of remnant particles that have gotten cholesterol from HDL (via CETP).
Q: What are atheromas/xanthomatas?
A: yellowish plaques that contain cholesterol and other lipids.

Q: What causes plaque formation?
A: oxidized lipoproteins. Macrophages eat oxidized lipoproteins to become foam cells, which accumulate and cause smooth muscle cells to also become foam cells. Fatty streak forms as collagen deposits.

Q: What causes LDL to become oxidized?
A: superoxide, NO, H2O2, etc.

Q: What prevents LDL from becoming oxidized (which therefore prevents plaque formation)?
A: Vitamin E, C, beta carotene… “antioxidants.”

Q: Why is HDL the “good cholesterol”?
A: because it does “reverse transport” of cholesterol from muscles and organs to the liver.

Q: Why is LDL the “bad cholesterol”?
A: because in its oxidized form, it can cause plaques.

Q: Besides LDL, what special lipoprotein is another risk for atherosclerosis?
A: Lipoprotein a (LPa), which has apoprotein A disulfide bonded to apo B-100.

Q: Can you control the amount of LPa in your body through diet?
A: No… it is genetic.

Q: When do foam cells and fatty streaks form?
A: When there is not enough HDL to pick up all the excess cholesterol (in LDL) that macrophages carry.

Q: What happens in Abetalipoproteinemia?
A: you don’t have triacylglycerol transfer protein in ER of liver and intestines… so you can’t make triacylglycerol-rich lipoproteins like VLDL, LDL, and chylomicrons, and therefore can’t absorb fat or vitamins ADEK.

Q: There is an association between Alzheimer’s Disease and what apoprotein?
A: Apo E.

Q: What is deficient in Tangier’s Disease?
A: Apo A-I and A-II, both of which are needed for Nascent HDL… therefore you can’t make HDLs well. LDL also reduced too, but I don’t know why, since it only has Apo B-100. Patients have a risk for early atherosclerosis.

Q: What causes familial hypercholesterolemia?
A: Deficiency of LDL receptors in both liver and extrahepatic tissues.

Q: How is hypercholesterolemia inherited?
A: autosomal dominant.

Q: How many LDL receptors do patients homozygous for familial hypercholesterolemia have? When can they die?
A: almost complete absence of LDL receptors. They can die of coronary heart disease often by 20 years old.

Q: What are the symptoms of Familial LCAT deficiency?
A: high cholesterol/cholesteryl ester ratio (since it esterifies cholesterols), hypercholesterolemia, premature atherosclerosis.

Q: What happens in CETP deficiency?
A: cholesterol esters formed by LCAT cannot be transferred from HDL to other lipoproteins. Cholesteryl esters stay in HDL.

Q: Why is CETP deficiency benign?
A: because who can complain about too much cholesterol carried by HDL?

Q: How many types of hyperlipoproteinemias are there?
A: 5 – hyperchylomicronemia, hypercholesterolemia, dysbetalipoproteinemia, Type IV, and Type V.

Q: What causes hyperchylomicronemia (Type I hyperlipoproteinemia)?
A: impaired hydrolysis of triacylglycerol… most plasma cholesterol stays in VLDL, rather than LDL.

Q: What happens in hypercholesterolemia (Type II hyperlipoproteinemia)?
A: elevated LDL → diabetes mellitus II, obesity, etc.

Q: What causes dysbetalipoproteinemia (Type III hyperlipoproteinemia)?
A: Mutant ApoE cannot bind to hepatic apoE receptors → chylomicron remnants remain in blood and accumulates. Atherosclerosis develops.

Q: What is the difference between Type IV and Type V hyperlipoproteinemia?
A: Type IV has elevated VLDL. Type V has both elevated VLDL and chylomicrons.

Q: What does Lovastatin inhibit?
A: HMG-CoA Reductase → liver can’t synthesize cholesterol… so increased dependence on cholesterol from plasma lipoproteins → increased synthesis of LDL receptors… so not too much will be left over to be scavenged by the macrophages’ scavenger receptors to form fatty streak

Q: What does Cholestyramine do?
A: It binds bile salts in small intestines, preventing their absorption.


Q: What happens during melamine poisoning?
A: you get crystals in your urine and kidneys.

Q: What is the formula for Melamine?
A: C3H6N6.

Q: What do the crystals of melamine resemble?
A: Uric Acid.

Q: Why do people add Melamine to food?
A: Because it resembles “protein”

Q: How stable is O2, CO2, and N2?
A: O2 is unstable, CO2 is unstable, N2 is stable

Q: What are the end products of O2, CO2, and N2 in animal metabolism?
A: O2 becomes H2O to be stable. CO2 becomes CaCO3 to become stable. N2 become NH3 (ammonia) (toxic), Urea (neutral), and Uric Acid (harmful at high concentration)

Q: What does urease do?
A: Cleaves urea into 2 NH3 and CO2.

Q: Where is the highest level of enzymes for amino acid metabolism?
A: in liver.

Q: Where are most dietary glutamine and glutamate metabolized?
A: in intestinal mucosa. All others extracted from portal circulation by liver.

Q: Most branched chain amino acids are catabolized in liver except which ones? Where are they catabolized?
A: valine, leucine, and isoleucine, (VLI) catabolized in peripheral muscle.

Q: What is the first step in the catabolism of valine, leucine, and isoleucine?
A: they are first transaminated.

Q: When you are fasting, what are the main amino acids that the muscle gives off?
A: Alanine and Glycine. Alanine remember is an entrance into gluconeogenesis when it provides carbon. Its N is used for urea. Glycine metabolism would produce a lot of toxic NH3 (ammonia).

Q: What 6 amino acids do “all roads lead to pyruvate”?
A: Tryptophan, Alanine, Serine, Cysteine, Glycine, and Threonine

Q: What is the glucose-alanine cycle?
A: When muscle donates NH4+ of amino acids to pyruvate to make alanine, which travel in blood and goes to liver and converted back to pyruvate (leaving urea) for gluconeogenesis. The glucose made goes back to muscle for energy and work.

Q: What other cycle is glucose-alanine cycle most similar?
A: Cori cycle

Q: What enzyme is needed to transfer amino from amino acid in muscle and liver between alanine and pyruvate during the glucose-alanine cycle?
A: alanine aminotransferase

Q: How does the liver get rid of the NH4+ when it converts alanine back to pyruvate during the glucose-alanine cycle?
A: via urea cycle, producing urea.

Q: What are the four main pathways of NH3 in the body?
A: NH3 + CO2/ATP → Carbamoyl phosphate.
NH3 + Aspartate → Asparagine.
NH3 + a-ketoglutarate → Glutamate.
NH3 + Glutamate → Glutamine.

Q: Which three forms are interconvertible?
A: glutamate, a-ketoglutarate, and glutamine.

Q: What are most amino groups from amino acids converted to during catabolism?
A: mostly as NH2 or sometimes as NH3 then converted to urea.

Q: What are the lysosomal enzymes that continually degrade protein?
A: cathepsins

Q: With what do you tag a protein to degrade it?
A: calpains and ubiquitins.

Q: Half life of a protein depends on the N-terminal amino acid residue… true or false?
A: True. If serine is the N-terminal amino acid, then the half life is 20 hrs. If it is aspartate, then it’s 3 mins.

Q: Why is aspartate important in a protein?
A: because if it is used for its N-terminal residue, then it makes the protein readily catabolized (short half-life). Requires little long-term energy investment to be caatabolized.

Q: Proteins rich in what four amino acids have short half-lives?
A: PEST – proline, glutamate, serine, and threonine. i.e. HMG-CoA reductase (halflife = 4 hrs).

Q: what residue of ubiquitin binds to what residue of protein tagged to be destroyed?
A: glycine on ubiquitin covalently bound to lysine of protein.

Q: What recognizes polyubiquitinated proteins?
A: proteasomes. P for Poly and P for Proteasome. If it’s monoubiquitinated, then it is target for lysosome.

Q: How much does it cost to bind ubiquitin to a protein?
A: 2 ATPs

Q: How is calpain both a marker and a destroyer?
A: When calpain tags a protein to be destroyed, it autolyses, to become a proteolytic enzyme.

Q: What is the first step in protein degradation?
A: conversion of the amino acids to N-free product.

Q: What are the ketogenic amino acids (converted to Ketones i.e. acetone, acetoacetic acid, beta-hydroxybutyric acid)?
A: lysine and leucine (KL)

Q: What are amino acids are both ketogenic and glucogenic?
A: tryptophan, tyrosine, phenylalanine, and isoleucine (WYFI)

Q: What are the glucogenic amino acids (converted to TCA/glycolytic intermediates)?
A: all others (except alanine and valine).

Q: What fraction of protein is nitrogen?
A: 1/6

Q: Under what conditions does someone have a positive nitrogen balance (more N enter than exit)?
A: body builder, growing child, pregnancy. Basically any condition that requires lots of protein.

Q: Under what conditions does someone have negative nitrogen balance (more N exit than enter)?
A: Carcinoma, trauma, surgery, severe infections, burns… CORTISOL, EPINEPHRINE – degrades proteins to support gluconeogenesis, hence burns N.

Q: What is the only enzyme that deaminates an amino acid?
A: Glutamate Dehydrogenase (does oxidative deamination of glutamate). Produces ammonia and alpha-ketoglutarate

Q: what is our only amino acid that undergoes oxidative deamination?
A: Glutamate, via glutamate dehydrogenase, which can do both synthesis or degradation of glutamate (by adding or subtracting the ammonia) into alpha-ketoglutarate.

Q: What is the coenzyme of glutamate dehydrogenase?

Q: What two reactions do glutamate dehydrogenase do?
A: oxidative deamination (activated by ADP/GDP) and reductive amination (by ATP/GTP).

Q: Does it cost to make alpha-ketoglutarate or glutamate?
A: glutamate.

Q: What’s the difference between a deaminase and a transaminase?
A: deaminase like glutamate dehydrogenase removes the amino from the amino acid to form ammonia. Transaminase just transfers it to another molecule, an alpha-keto acid.

Q: What’s similar between deaminase and transaminase?
A: They are both reversible.

Q: What does transaminase require as a prosthetic group?
A: PLP (pyridoxal phosphate)

Q: What are the three types of alpha-keto acids used by transaminases to transfer the amino groups?
A: pyruvate, OAA, and alpha-ketoglutarate.

Q: How does the PLP attach to the transaminase?
A: via the enzyme’s lysine residue via a Schiff Base (N=C)

Q: How does the PLP work?
A: PLP (pyridoxal phosphate) accepts an amino group to become pyridoxamine phosphate.

Q: If you find a lot of bilirubin and alanine transaminase, what is that a sign of?
A: liver damage! Because transaminases very active in liver.

Q: D-amino acids cannot be used directly by our body for protein synthesis. How do we get around it?
A: by metabolizing them with D-amino acid oxidase. Deaminated D-amino acids then enter normal pathways as alpha-ketoacids.

Q: Where does most of our NH3 in our body come from?
A: deamination of glutamine in liver mitochondria.

Q: What is BUN?
A: Blood Urea Nitrogen.

Q: When is BUN low?
A: when liver is failing (L for Liver, L for Low). Because liver produces the N when it breaks down proteins, so a fall in urea means failure of liver.

Q: When is BUN high?
A: when kidneys fail, causing uremia (urea in blood). Because kidneys get rid of urea, so if you can’t get rid of it, then means you got kidney failure.

Q: What’s so great about memorizing the steps of Urea Cycle?
A: There are no coenzymes!

Q: What does the Urea cycle start with?
A: CO2, NH3 and 2 ATP

Q: What is the first step in the urea cycle?
A: CO2, NH3 and 2 ATP become Carbamoyl phosphate via Carbamoyl phosphate synthetase (CPS I) in the mitochondrial matrix

Q: What does Carbamoyl Phosphate do?
A: It turns Ornithine into Citrulline, which can then cross the mitochondrial membrane into the cytosol.

Q: Citrulline + Aspartate = ?
A: Arginosuccinate

Q: Arginosuccinate → ?
A: Fumarate + Arginine

Q: Arginine → ?
A: Urea + Ornithine

Q: What does arginase do?
A: Breaks down arginine into urea and ornithine.

Q: What crosses over back from cytosol to mitochondria?
A: Ornithine.

Q: What is needed to activate Carbamoyl Phosphate Synthetase I (CPS I)?
A: N-Acetylglutamate

Q: How does Arginine cause itself to proliferate?
A: It upregulates the synthesis of N-acetylglutamate (from Glutamate), which then activates the urea cycle, producing even more arginine.

Q: What’s the difference between CPS I and II?
A: I happens in the mitochondria, and II happens in the cytosol. CPS I makes carbamoyl phosphate in the urea cycle. CPS II is used to make pyrimidine nucleotides.

Q: What step makes the CPS I reaction irreversible?
A: first 2 ATPs

Q: Why is there a lot of CPS I?
A: to ensure that enzyme can remove lots of toxic ammonia quickly.

Q: What happens to the fumarate?
A: It is turned into Malate, crosses the mitochondrial membrane into the mito to enter the TCA cycle.

Q: How many ATPs is needed to make Urea?
A: 4 total (2 to start out).

Q: Does Urea cycle occur during transamination?
A: No, because transamination doesn’t produce free NH3.

Q: How does the actions of glutamate dehydrogenase tie into the actions of transaminase and the urea cycle?
A: glutamate dehydrogenase turns glutamate into alpha-ketoglutarate (+ free NH3). The alpha-ketoglutarate can then act as an alpha-keto acid that would collect the NH3 from the amino acid. The free NH3 goes into the urea cycle to become urea.

Q: What is the most common urea cycle enzyme deficiency?
A: OTC deficiency (X-linked). Leads to hyperammonemia and encephalopathy.

Q: What does liver disease do?
A: Disrupts carbon and nitrogen flow from amino acids… NH4 and aromatic amino acids accumulate in brain.

Q: What accumulates in blood plasma in kidney failure?
A: creatinine and urea, because can’t be disposed.

Q: How do you treat patients with urea cycle failure?
A: Treat with alpha-keto acid that will turn into essential amino acids. Treat with glycine and glutamine (because they are N-rich), which lets nitrogen excretion like benzoic acid, phenylacetate and phenylbutyrate become soluble and urinated out.

Q: Why is NH3 higher in portal circulation than systemic?
A: Because intestinal bacteria can release NH3 into the intestines, which go to the portal circulation.


Q: When do you do PKU test?
A: No less than 12 hours post-partum. Best within 1-7 days. Do Guthrie Test.

Q: What is an example of deamination and transamination working together to break down an amino acid?
A: asparagine deaminates to form aspartate, which transfers the nitrogen via alpha-ketoglutarate to glutamate, which forms oxaloacetate.

Q: How do you convert serine to pyruvate?
A: via serine dehydratase

Q: How do you convert serine to glycine?
A: via serine hydroxymethyltransferase – important source of one-carbon units tetrahydrofolate (THF)

Q: What coenzyme do you need if you want to make serine into a glycine?
A: Tetrahydrofolate (from folic acid).. It can accept the 1-C methylene group of serine.

Q: What vitamin is folic acid?
A: B-9

Q: how do you make folate into tetrahydrofolate?
A: via dihydrofolate reductase, which requires NADPH in 2 successive reductions

Q: What do you need to breakdown glycine?
A: tetrahydrofolate.

Q: What would happen if you are deficient in tetrahydrofolate?
A: non-ketotic hyperglycinemia, because you can’t break down glycine

Q: How do you degrade threonine?
A: via threonine dehydratase. Produces alpha-ketobutyrate, which converts to propionyl-CoA and NH3.

Q: How is histidine degraded?
A: histidase breaks it into Urocanic acid, forming NH3.

Q: FIGLU + Tetrahydrofolate → ?
A: Glutamate and 5-formiminotetrahydrate. Glutamate can then become alpha-ketoglutarate + NH3

Q: What is important about methionine degradation?
A: it is used to make S-adenosylmethioinine (SAM), which remember is a methyl-donor.

Q: How do you degrade methionine into SAM, cysteine or tetrahydrofolate (THF)?
A: Methionine → SAM → SAH → Homocysteine → cysteine; Homocysteine + Methyl THF → Methionine + THF.

Q: What cofactors do you need to degrade homocysteine into methionine?
A: folate and vitamine B12 (cobalamin)

Q: What cofactors do you need to degrade homocysteine into cysteine?
A: Pyridoxine (B6)

Q: THF acts as a carrier for what?
A: single carbon group.

Q: What does SAM become after it donates its methyl group?
A: SAH, which can be reconverted back to homocysteine and then methylated back into methionine.

Q: Where are the components of cysteine derived?
A: From the carbon skeleton of serine and sulfer of methionine.

Q: How do you make homocysteine into cysteine?
A: Cystathionine synthase condenses homocysteine and serine to form cystathionine, which is cleaved by cystathionine lyase to make cysteine and alpha-ketobutyrate.

Q: If you are deficient in cystathionine synthase, what do you have?
A: Homocystinuria (accumulationof methionine, homocysteine, and homocystine) → funnel chest.

Q: What are the effects of homocystinuria?
A: increased length but decreased thickness of long bones (spidery fingers), high arched feet, osteoporosis, blindness.

Q: How do you treat homocystinuria?
A: restrict methionine, intake more B6, B12 and folate.

Q: How are valine, leucine, and isoleucine degraded? (remember they are only ones catabolized in muscle)
A: Transaminated (to form alpha-keto-acids)→ Oxidative Decarboxylation → FAD-linked dehydrogenation to form TCA cycle intermediates.

Q: What happens if you can’t do the oxidative decarboxylation step in the breakdown of VLI (valine, leucine, isoleucine)?
A: you get maple syrup urine disease.

Q: Lysine is used to make what?
A: Carnitine (TML). Very costly (9 ATPs needed)

Q: What is the first step in tryptophan degradation?
A: tryptophan pyrrolase (oxidase) oxidizes tryptophan to N-formylkynurenine. Need NADPH.

Q: What does tryptophan degradation form?
A: alanine and acetoacetyl-CoA, nicotinic acid (→ niacin), and two wastes (kynurenate and xanthurenate, the “yellow” in urine).

Q: Is tyrosine essential?
A: No, because it is made from phenylalanine (via phenylalanine hydroxylase (PAH)). Requires O2 and Tetrahydrobiopterin (reduces O2 to OH, because remember tyrosine is just Phe with an OH).

Q: When is PAH active?
A: as a tetramer (dimer form is inactive) and with phosphorylation at critical serine.

Q: What all is tetrahydrobiopterin used for?
A: it is used to reduce phenylalanine to tyrosine, tyrosine to catecholamine, and tryptophan to serotonin.

Q: What does tetrahydrobiopterin (BH4) become after it reduces a molecule?
A: BH4 → BH2 (Dihydrobiopterin)

Q: How do you make tetrahydrobiopterin?
A: First use GTP to make BH2 (dihydrobiopterin) via Dihydrobiopterin Synthetase, then convert BH2 to BH4 via Dihydropteridine Reductase.

Q: What causes Alkaptonuria?
A: deficiency in homogentisate oxidase (used for tyrosine metabolism). Patient excretes homogentisic acid → black urine.

Q: What are the two causes of tyrosinemia?
A: Type I – deficiency in fumaryl-acetoacetate hydrolase (more common)
Type II – deficiency in tyrosine transaminase

Q: What do you have when you don’t have PAH?
A: Phenylketonuria.

Q: Instead of breaking down to tyrosine, what does phenylalanine become in patients with PKU?
A: Phenylalanine → phenylpyruvate → phenyllactate and phenylacetate (both abnormal and effect nervous and cardiac cells)

Q: Instead of breaking down to tyrosine, what does phenylalanine become in patients with PKU?
A: Phenylalanine → phenylpyruvate → phenyllactate and phenylacetate (both abnormal and effect nervous and cardiac cells)

Q: What is it called when PKU patients have too much phenylalanine?
A: hyperphenylalaninemia (HPA)

Q: Why is PKU not apparent at birth?
A: because Phe and its abberant metabolites (phenyllactate, phenylacetate) are easily transferred across placenta, so babies are born “clean” without those abberant metabolites.

Q: How does PKU cause MR?
A: high levels of Phe interfere with normal amino acid uptake in brain. Seizures are common too.

Q: Why do PKU patients have pale complexion?
A: Because synthesis of melanin from tyrosine is inhibited by too much phenylalanine (negative feedback → tyrosinase inhibition)

Q: How do you treat PKU?
A: don’t eat meat, nuts, legumes, and grains. Just eat fruit, veggies, and low protein. Don’t eat aspartame. Mothers of PKU fetuses should not eat Phe.


Q: What amino acids can alpha-ketoacids pyruvate, OAA, and a-KG become when they accept amino groups at their alpha-carbons (via transaminases)?
A: pyr → alanine, oAA → aspartate, a-KG → glutamate

Q: What is the only amino acid that can be synthesized via reductive amination?
A: glutamate, made from a-KG via glutamate dehydrogenase. Since it is reduction, it requires NADPH.

Q: What are two amino acids synthesized by amidation (creation of amide group)
A: Glutamine and Asparagine

Q: Where is the amide group on glutamine?
A: at the gamma-carbon. Glutamine is formed by glutamine synthetase and requires ATP.

Q: What is another function of glutamine synthetase?
A: removal of toxic NH3 from liver and brain.

Q: What two things do glutamine synthetase consume?
A: ATP and free ammonia

Q: Why is Glutamine needed for asparagine synthesis?
A: Because asparagine synthetase uses the NH3 donated by glutamine for asparagine synthesis.

Q: Asparagine is not an essential amino acid but why is it clinically significant?
A: Because it is needed in certain proportions for cells to divide. So you have a lot of asparagine if you have cancer. Sometimes you can treat cancer with asparginase to limit cancer growth.

Q: What is the intermediate when you convert glutamate to proline?
A: gamma-semialdehyde

Q: How do you make Serine?
A: 3PG (from glycolysis) → 3-phosphopyruvate → 3-phosphoserine → serine

Q: What is the key step in the interconversion between serine and glycine?
A: remove single carbon group from serine to yield glycine. The carbon group is transferred onto tetrahydrofolate.

Q: When you make methionine into cysteine, what are the three terminal products/
A: ammonia, alpha-ketobutyrate, and cysteine.

Q: “Demethylated methionine” is also known as what?
A: homocysteine, central in the conversion between methionine and cysteine and vice versa.

Q: What is alpha-ketobutyrate further broken down into?
A: propinonyl → methylmalonyl-CoA → Succinyl-CoA

Q: What is the risk of high homocysteine?
A: high risk for coronary heart disease and arterioscleriosis.

Q: What is a common cause of high homocysteine?
A: mutation in gene for cystathionine synthase.

Q: Where does Taurine come from? And don’t say Red Bull.
A: From Methionine in brain and liver via cysteine sulfinate decarboxylase, but the sulfur is from cysteine.

Q: Why is taurine (an amino acid) not incorporated into proteins?
A: because we have no codon for it!

Q: Where is epinephrine and dopamine from?
A: tyrosine → → → dopamine (add O2 and use Vitamin C) → norepinephrine (+methylation via SAM) → epinephrine

Q: What coenzyme is necessary for making dopamine into norepinephrine?
A: Vitamin C

Q: Tyrosine is precursor to what three things?
A: Catecholamines, thyroid hormones (MIT and DIT), and melanin.

Q: Errors in which amino acid metabolisms cause developmental problems (and therefore MR)?
A: all of them. This is because they are all “metabolic dead ends” that cannot be degraded so they accumulate in brain and stuff.

Q: What is the defect in Cystinosis?
A: Lysosomal transport defect. Cystine can’t be broken down into two cysteines.

Q: Where does cystinosis affect most?
A: cornea of eye and renal tubular epithelium. Causes Fanconi syndrome, blindness, glucosuria, diabetes, kidney damage.

Q: What is cystine?
A: 2 cysteines bound by disulfide bridge.

Q: What is the only amino acid disorder related to defect in membrane transport of stored material?
A: Cystinosis


Q: What is the body’s most common porphyrin?
A: Heme

Q: Where is heme synthesized?
A: Primarily in bone marrow, Secondarily in liver. All cells that conduct oxidative phosphorylation also produce heme (since they also require it).

Q: Where do most hepatic heme go to?
A: Cytochrome P450, Catalase, and Cytochrome B5

Q: Why do all tissues synthesize heme to their own needs?
A: Because there is no significant inter-organ transfer of intact heme. Any complete block in heme synthesis can be fatal.

Q: What are the starting ingredients of heme synthesis?
A: succinyl CoA and glycine.

Q: How does heme synthesis affect globin synthesis?
A: Increase heme → increase globin → to make hemoglobin

Q: How is heme synthesis regulated in liver vs. bone marrow?
A: in liver, negative feedback controls the first step. In bone marrow, negative feedback controls the last step (inhibit uptake of iron into heme).

Q: Heme is made mainly in liver during what stage in life? Bone marrow?
A: before birth = liver. afterbirth = bone marrow.

Q: What is the difference between heme and hematin?
A: heme binds Fe++. Hematin binds Fe+++

Q: How are the 4 pyrrole rings bridged in porphyrins?
A: methenyl bridges.

Q: Are the four pyrrhole rings in porphyrin (like heme) symmetrical?
A: No, because they all have different side chains.

Q: Why can’t RBC make heme?
A: Because it cannot do oxidative phosphorylation

Q: In the first step in heme synthesis, what condenses succinyl CoA and glycine?
A: ALA Synthase. (makes aminolevulinic acid)

Q: What does ALA Synthase require?
A: pyridoxal phosphate

Q: How does heme control ALA synthase activity?
A: low heme → stimulates the enzyme. High heme → blocks enzyme.

Q: What is another name for hematin?
A: Hemin

Q: What is the significance of heme’s turnover?
A: it places a significant part in the nitrogen balance of the organism

Q: What is the regulatory enzyme in hepatic heme synthesis?
A: ALA Synthase

Q: What can Hematin do to ALA synthase?
A: It can inhibit it, thus reducing heme synthesis and levels of porphyrin precursors.

Q: What are some drugs that affect ALA Synthase?
A: phenobarbitals, hydantoins, griseofulvin. These indirectly cause increase in the enzyme level and activity. This is because they are destroyed by Cyt P450, which need heme as prosthetic group. You keep consuming these hemes, leading to loss of feedback inhibition and more heme production.

Q: After you make ALA in the heme synthesis pathway, what happens next?
A: two ALAs (delta-aminolevulinates) condense to form Porphobilinogen via ALA Dehydratase (so water is taken out)

Q: What does ALA Dehydratase require to make porphobilinogen?
A: Zinc

Q: What is ALA Dehydratase very sensitive to (poisoning)?
A: Pb (lead), causing Plumbism

Q: In the heme synthesis pathway, what happens after you make porphobilinogen?
A: You take 4 porphobilinogens to make uroporphyrinogen III (asymmetric) via two enyzmes – Hydroxymethylbilane synthase and uroporphyrinogen III synthase.

Q: What is the difference between hydroxymethylbilane synthase and uroporphyrinogen III synthase?
A: Hydroxymethylbilane synthase acts first to make a chain of 4 porphobilinogens. Uroporphyrinogen III synthase acts second to create ring from this chain and isomerizes it.

Q: What happens if you are missing uroporphyrinogen III synthase?
A: then you accumulate so much hydroxymethylbilane (phototoxic metabolite), causing congenital erythropoietic porphyria.

Q: During the heme synthesis pathway, after you form uroporphyrinogen III, what happens?
A: A series of decarboxylation steps make it into coproporphyrinogen to enter cross over from cytosol to mitochondria, then become protoporphyrin IX.

Q: During the heme synthesis pathway, after you get protoporphyrin IX, what happens?
A: Ferrochelatase inserts Fe++ (notice this is ferrous state) into the ring center. This is now called heme.

Q: What is the regulatory step in heme synthesis in bone marrow?
A: ferrochelatase.

Q: What is ferrochelatase very sensitive to?
A: Pb poisoning (Plumbism). Remember ALA Dehydratase is also sensitive to Pb.

Q: What is deficient in these porphyrias?
A: Acute Intermittent Porphyria = hydroxymethylbilane synthase, so porphobilinogen and ALA accumulate and porphyrin ring can’t be made. This is the only porphyria where patients are NOT photosensitive!
Congenital erythropoietic Porphyria (Gunther’s Disease) = uroporphyrinogen III synthase, so uroporphyrinogen I and coproporphyrinogen I accumulate (shunted products of accumulated hydroxymethylbilane)
Porphyria Cutanea Tarda = Uroporphyrinogen decarboxylase, so uroporphyrin accumulates
Hereditary Coproporphyria = Coproporphyrinogen Oxidase, so coproporphyrinogen III accumulates
Varigate Porphyria = Protoporphyrinogen Oxidase, so protoporphyrinogen IX accumulates.
Erythropoietic Protoporphyria = Ferrochelatase, so protoporphyrin accumulates

Q: How is heme held in place in the hemoglobin?
A: By proximal histidine. It has to be a relatively hydrophobic amino acid.

Q: What affects the succession of globin chain developmenet?
A: O2 availability

Q: What is the succession of globin chain development?
A: zeta → alpha; epsilon → gamma → beta. (z→a) (e→g→b)

Q: What is the only porphyria that is autosomal recessive?
A: Congenital Erythropoietic Porphyria (CEP).

Q: What are the only two porphyrias that happen in bone marrow (and not in liver)?
A: Erythropoietic Protoporphyria and Congenital Erythropoietic Porphyria.

Q: What is the only porphyria where patients are NOT photosensitive?
A: Acute Intermittent Porphyria, because the accumulated products are easily removed.

Q: How do you treat hepatic porphyria?
A: administration of hemin, which inhibits hepatic ALA synthase and reduces accumulation of products. Also avoid direct sunlight, and make up for it by eating beta-carotene.

Q: What did Petry have?
A: Congenital Erythropoietic Porphyria.

Q: What is the life span of RBC?
A: 120 days

Q: Where is heme degraded?
A: in spleen then in liver. (travel through blood to get there)

Q: What is first produced during heme degradation?
A: biliverdin, via heme oxygenase, which breaks down a methenyl bridge between two pyrrole rings by adding oxygen and forming carbon monoxide as well. Also oxidizes Fe++ to Fe+++

Q: What does heme oxygenase require?
A: NADPH and O2

Q: What is the step after degradation of heme to biliverdin?
A: Reduction to bilirubin, which is insoluble.

Q: What transports bilirubin from spleen to liver via blood?
A: Albumin.

Q: After bilirubin arrives in hepatic circulation, it leaves albumin and binds to what to enter hepatocyte?
A: Ligandin, which has glutathione-S-transferase activity.

Q: What is kernicterus?
A: when too much unconjugated bilirubin (not conjugated with albumin) accumulates in the brain and cause neural damage.

Q: In order for bilirubin to be excreted from the liver, it needs to be more soluble. What does this?
A: Bilirubin glucuronyltransferase transfers two molecules of glucuronic acid from UDP-glucuronic acid to the bilirubin to become bilirubin diglucuronide. This is then removed via bile.

Q: Once bilirubin diglucuronide gets excreted, what happens to it in gut?
A: gets reduced by bacteria in gut to become urobilinogen (colorless).

Q: What happens to urobilinogen?
A: It goes to kidney to become urobilin, making pee yellow, and it also goes to large intestine to become stercobilin, making doo doo brown.

Q: What causes hemolytic jaundice?
A: When massive lysis of RBC produces bilirubin at a rate that exceeds the capacity of liver to degrade it. Unconjugated bilirubin accumulate in blood.

Q: What’s the difference between hemolytic jaundice and neonatal jaundice?
A: They both involve accumulation of unconjugated bilirubin that cannot go through the liver step to become conjugated. In the case of hemolytic jaundice, it is due to the liver not being able to handle the sheer amount of hemolysis that took place. In neonatal jaundice, it is due to a decrease in bilirubin glucuronyl transferase, decreasing the amount of conjugation.

Q: What causes obstructive jaundice?
A: obstruction of bile duct (cholestasis)

Q: What causes hepatocellular jaundice?
A: damage to liver cells, like cirrhosis, hepatitis, toxicosis, etc. → clay-like stool and dark urine

Q: Describe the serum bilirubin levels of premature infants?
A: it rises to toxic levels. UDP-Glucuronyl transferase activity is also low, preventing it from adding glucuronic acid to bilirubin. All of this causes neonatal jaundice, especially in premature babies.

Q: When does bilirubin glucuronyl transferase activity in liver reach adult levels in newborns?
A: in about 2 weeks after birth.

Q: What are two main reasons for neonatal jaundice?
A: low levels of UDP-Glucuronyl transferase and high levels of bilirubin. Also remember babies are born with a lot of fetal Hb, which starts to be degraded as soon as baby is born, to be replaced by HbA.

Q: How are newborns with jaundice treated?
A: with fluorescent lighting. This makes bilirubin water-soluble, making it easier to excrete. But since riboflavin is also destroyed by light, need to routinely supplement with riboflavin during treatment.

Q: What is the precursor to Creatine and Creatine Phosphate?
A: Arginine

Q: Why is Creatine Phosphate such a great energy source?
A: Because it can donate a phosphate to ADP to yield ATP and Creatine. It yields -10KCal/mol! Compare this with ATP hydrolysis which yields -7.5 and G6P yields -4KCal/mol.

Q: What is the main energy source in muscle then?
A: Creaetine Phosphate, which is 10x more concentrated than ATP in muscle.

Q: Where is creatine synthesized and used?
A: Synthesized in liver and pancreas but used in the muscle and brain.

Q: What are the starting materials for creatine?
A: Glycine and the guanidino group of arginine and methyl group of SAM. Arginine transfers its guanidino group (3 nitrogens) to Glycine and tosses out ornithine to form Guanidinoacetate, and then SAM adds a methyl group to form Creatine. Creatine Kinase adds a Pi to form Creatine Phosphate.

Q: What is creatine degraded (cyclized) to?
A: Creatinine. Amount of creatinine = muscle mass lost.

Q: Tell me about synthesis of NO.
A: NO synthase converts Arginine and O2 into Citrulline and NO. It requires two NADPH reactions and is strongly activated by increased calcium levels.

Q: How do you make Histamine?
A: You make it from Histidine via Histidine decarboxylase, which requires PLP

Q: How do you make Serotonin?
A: Tryptophan is hydroxylated (and also uses BH4 → BH2) to form 5-Hydroxytryptophan. Then decarboxylate this (PLP-dependent) to form 5-Hydroxytryptamine (aka “serotonin”).

Q: How do you convert BH2 (dihydrobiopterin) to BH4 (tetrahydrobiopterin)?
A: Donate an electron (reduce) via NADPH

Q: What are the catecholamines?
A: Dopamine, Norepi, and epi. They are called so because they all have Catechol group (phenol + 2 OH’s) and are derived from tyrosine. They are al synthesized in the adrenal medulla.

Q: Describe the chain of reactions from tyrosine to make DOPA, Dopamine, Norepi, and Epi.
A: Tyrosine is converted to L-DOPA via Tyrosine Hydroxylase (which adds O2 → H2O, BH4 → BH2).
L-DOPA is converted to Dopamine via DOPA Decarboxylase (PLP-Dependent).
Dopamine is converted to Norepi via Dopamine hydroxylase and Vitamin C!
Norepi is converted to Epi via PNMT which requires SAM→SAH for methyl group.

Q: How is SAM made?
A: Spend 3 ATPs on methionine.

Q: What is one cause of Parkinson’s Disease? What is one way you can treat this?
A: premature degeneration of the CNS cells that make dopamine in substantia nigra and locus caeruleus. Let DOPA enter brain via blood (which dopamine cannot do), then let it be decarboxylated into dopamine.

Q: How do you degrade catecholamines?
A: via COMT and MAO. (Extra Info: Degrade Epi and Norepi into 3-methoxy 4-hydroxymandelic acid, and dopamine into homovanillic acid.)

Q: Where is MAO active and why?
A: It is active in the mitochondria of neural tissue, gut, and liver and mops up any excess neurotransmitter through its inactivation. Too much could cause depression, so treat depression with MAO inhibitors.

Q: How do you form T3 and T4?
A: add iodine to tyrosine to form thyroglobulin. Require H2O2 to add iodine. Then release T3 and T4 by proteolytic degradation. This is why thyroid needs iodine.

Q: How does hypothyroidism (lack of iodine) cause goiter?
A: Because your thyroid is trying to salvage all available iodine so it grows bigger.

Q: How do you make GABA?
A: from glutamate via glutamate decarboxylase (so need PLP)

Q: How do you make melanin?
A: From tyrosine via tyrosinase (which has copper, and uses DOPA as cofactor). Lack of tyrosinase can cause albinism.

Q: What causes the depth of color in melanin?
A: The number of conjugated double bonds.


Q: What is a nucleoside?
A: Nucleoside = nucleotide without the triphosphate

Q: What are the four ingredients that form purines?
A: Aspartate and Glutamine donate N’s. CO2 and Formyl-THF donate C’s. Glycine donates itself.

Q: What is the scaffold that purines form on?

Q: How do you make the scaffold on which purines are built? (FIRST STEP)
A: Convert Ribose-5-Phosphate into PRPP via PRPP synthetase (spend ATP, and activated by Pi)

Q: After PRPP is formed, what do you do? (SECOND STEP)
A: Remove Pyrophosphate from C-1, then add amide group from glutamine → becomes 5’-phosphoribosylamine. This is done by Glutamine-PRPP-amido-transferase, which is regulatory. Inhibited by its end products AMP, GMP, and IMP.

Q: After you make 5-phosphoribosylamine, what next? (THIRD STEP)
A: 9 steps that follow turn it into inosine monophosphate (IMP). THF is needed in two key reactions that transfer 1-C groups. SO YOU NEED THF, SO YOU NEED FOLATE BECAUSE OF THIS!!!

Q: Where is THF derived from?
A: Vitamin B9 aka “folic acid”

Q: Where does the Formyl group of Formyl-THF come from?
A: from serine-glycine interconversion → 5,10-methylene-THF (+NADPH) → 5,10-methenyl-THF → 10-Formyl THF

Q: What is the function of THF?
A: to carry single carbon groups

Q: What’s another way that Formyl-THF can get its formyl?
A: from Formate.

Q: After you make IMP, what next? (FOURTH STEP)
A: IMP is converted to GMP (via IMP dehydrogenase) and AMP (extra: via adenylosuccinate synthetase). 2 steps. The first step is regulated (by products GMP or AMP).

Q: What does the drug mycophenolate do?
A: it is an uncompetitive inhhibitor of IMP dehydrogenase. So GMP is not made. Used to prevent graft rejection.

Q: After you get AMP and GMP, what now? (FIFTH STEP)
A: convert to ATP and GTP via (base-specific or not) nucleoside mono- or di-phosphate kinases. “Upgrading”
Base-Specific: ATP + AMP → 2 ADP
Not Base-Specific: ATP + GDP → ADP + GTP

Q: You get a lot of turnover nucleic acids, either from yourself or from eating. What happens to these/
A: they can either be converted to nucleotides for use in energy metabolism or reused in nucleic acid synthesis (SALVAGE PATHWAY).

Q: What are the two enzymes that do the SALVAGE PATHWAY? What do they all require?
A: HGPRT and APRT. They both require PRPP. HGPRT converts Hypoxanthine into IMP or GMP. APRT converts Adenine into AMP.

Q: What happens to purines when you degrade them?
A: They become uric acid/urate, which can cause Gout (deposition of uric acid crystals in synovial fluid in joints)

Q: What is urate?
A: It’s ionized uric acid. 4 hydrogens on uric acid is ionizable: 1,3,7,9. Only NH #9 ionizes at normal plasma pH!!! Therefore it is a great antioxidant. Ionizing makes it more soluble (but still poor)

Q: What’s good about uric acid though?
A: It is a great antioxidant, 50% of our antioxidant capacity in plasma!! It is oxidized, then excreted (-ish).

Q: How is purine broken down into uric acid?
A: After a few steps, it eventually gets converted into Hypoxanthine.
Hypoxanthine + O2 → xanthine + H2O2 via XO (xanthine oxidase)
Xanthine + O2 → uric acid + H2O2 via XO

Q: How does allopurinol combat gout?
A: it is a competitive inhibitor of XO, preventing hypoxanthine from eventually becoming uric acid.

Q: What causes Lesch-Nyhan Syndrome?
A: Deficiency in HGPRT → you can’t salvage hypoxanthine back into IMP or GMP. Instead, it gets degraded into uric acid. Excessive uric acid → self-mutilation.

Q: What is one sign of Lesch-Nyhan disease?
A: pink or orange color in wet diaper – shows uric crystals in urine.

Q: What is one cause of diabetes mellitus due to uric acid?
A: oxidation of uric acid forms alloxan → toxic to beta cells of pancreas.

Q: What happens with ADA (adenosine deaminase) deficiency?
A: SCID (bubble boy syndrome). Prevents sufficient production of DNA.

Q: How does your body digest DNA?
A: phosphodiesterases break phosphodiester bonds. Nucleotidases break nucleotides into nucleosides + Pi. Nucleosidases break nucleosides into pyrimidines and purines, which then either go into circulation or excreted as uric acid.


Q: What is the big difference between purine and pyrimidine synthesis?
A: In purine synthesis, the ring is made little by little onto the PRPP scaffold. In pyrimidine synthesis, the ring is completely fabricated first, then added to the PRPP scaffold once it’s done.

Q: What are the ingredients to making pyrimidines?
A: Glutamine donates N. CO2 donates C. Aspartic acid donates itself

Q: What is the commited step in making pyrimidines? (FIRST STEP)
A: Carbamoyl Phosphate Synthetase II (CPS II). Inhibited by UTP, activated by ATP and PRPP.

Q: What is the first step in the urea cycle?
A: CO2, NH3 and 2 ATP become Carbamoyl phosphate via Carbamoyl phosphate synthetase (CPS I) in the mitochondrial matrix

Q: What’s the difference between CPS II in pyrimidine synthesis pathwya and CPS I in urea cycle pathway?
A: CPS I uses free NH3 as nitrogen source. CPS II uses glutamine’s amido group as nitrogen source.

Q: After you get Carbamoyl Phosphate, what’s next? (SECOND STEP)
A: Make carbamoyl aspartate via aspartate transcarbamoylase (ATCase)

Q: After you get a complete ring, what’s next? (THIRD STEP)
A :You transfer on a PRPP to form OMP (orotidine monophosphate).

Q: After you get OMP, what’s next? (FOURTH STEP)
A: You make decarboxylate it to form UMP.

Q: After you get UMP, what’s next? (FIFTH STEP)
A: Upgrade it to UTP (by adding 2 Pi’s from ATP)

Q: After you get UTP, what’s next? (FINAL STEP)
A: aminate it with Glutamine → Glutamate to form CTP, via CTP synthetase.

Q: What do you get when you degrade pyrimidines?
A: beta-alanine and beta-succinobutyrate, which can convert to acetyl-CoA nd Succinyl-CoA. NO SALVAGE PATHWAY!!

Q: What reduces ribonucleoside to deoxyribonucleoside?
A: NADPH→NADP, which reduces Thioredoxin, which reduces ribonucleoside to deoxyribonucleoside via ribonucleoside reductase.

Q: What are the two sites on the ribonucleoside reductase that control the reduction of ribonucleosides?
A: Activity Site and Substrate Specificity Site

Q: What inhibits the reduction of ribonucleoside to deoxyribonucleoside?
A: dATP binding to Activity Site of the nucleoside reductase.

Q: How is the reduction of ribonucleosides controlled on the Substrate Specificity Site?
A: ATP tells enzyme that ADP needs to be reduced to dADP. CTP tells enzyme that CDP needs to be reduced to dCDP, etc.

Q: How do you make dTTP?
A: dUTP → de-P’d to dUMP → methylated to dTMP → upgraded to dTDP → upgraded to dTTP. NOTICE THAT THE NUCLEOSIDE HAS TO BE IN THE MONOPHOSPHATE STATE TO CONVERT.

Q: how do you convert dUMP to dTMP?
A: via Thymidylate Synthase (no ATP needed), which adds methyl group from methylene-THF and tosses out dihydrofolate (DHF), which you need dihydrofolate reductase (+NADPH) to recycle back to THF.

Q: Which 2 enzymes is required to convert dUMP to dTMP?
A: Thymidylate Synthase and Dihydrofolate reductase.

Q: What does methotrexate do?
A: It inhibits dihydrofolate reductase, preventing formation of dTTP and therefore DNA.

Q: How do you convert folate into tetrahydrofolate?
A: Folate → Dihydrofolate → Tetrahydrofolate (THF). Requires 2 NADPH’s.

Q: What does 5-Fluorouracil do?
A: It binds to thymidylate synthase and inhibits it, and therefore inhibits synthesis of dTMP and DNA.

Q: What can UV do to pyrimidines?
A: Pyrimidine dimerization, which prevents DNA polymerase from replicating past dimerization point. Fix with UV-specific endonuclease (uvrABC exinuclease)

Q: What group on nucleotides does the H-bonding?
A: NH2 groups!

Q: What is the function of CH3 in thymine on DNA?
A: makes sure AT pairings are weaker than GC pairing.


Q: What’s the difference between Calcium Phosphate and Ca++?
A: Calcium Phosphate is what you find in bones and teeth. Ca++ is what you find in signalling cascades.

Q: How do you control Ca++ levels?A
A: Low plasma Ca++ → PTH released → Ca liberated from bones → reabsorbed by gut and kidney.
High plasma Ca++ → Calcitonin released from thyroid → deposit Ca in bone and lower reabsorption in kdiney. Calcitonin tones down blood calcium.

Q: What are trace elements used as?
A: Co-factors for selected enzymes.

Q: What is urease’s cofactor?
A: Nickel

Q: What is the deal with trace elements?
A: It’s bad to have too little (deficiency) and it’s bad to have too much (toxicity)

Q: What’s the deal with violence and nutrient deficiencies?
A: They seem to be strongly correlated!

Q: Menke’s Disease (kinky hair syndrome/growth retardation/MR) is caused by deficiency in what?
A: ATP-dependent copper transporter, so you don’t get copper. Treat with absorbable copper-histidine complex

Q: What causes Wilson’s Disease?
A: deficient in another type of copper transporter that prevents copper from being excreted, so accumulation causes liver and brain damage. Treat with a copper chelator that binds to the copper and allows it to be excreted through urine.

Q: How is Zinc stored?
A: with metallothionein, which protects cell from toxic effects of free, unbound metal ions.

Q: What does zinc deficiency cause?
A: delayed development, poor wound healing, dermatitis, and acrodermatitis enteropathica (dermatitis, hair loss, diarrhea). Common with alcoholics.

Q: Manganese is a cofactor for what?
A: mitochondrial SOD.

Q: Toxicity of manganese is what?
A: “manganese madness” like Parkinson’s Disease

Q: Molybdenum is found in what?
A: Xanthine Oxidase

Q: Selenium is found in what?

Q: Keshan Disease is caused by deficiency of what?
A: Selenium (low selenium in soil, crops)

Q: Chromium is found in what?
A: “Glucose Tolerance Factor” – facilitates action of insulin.

Q: How much Iron do you need?
A: 3-4g for adults.

Q: Where is the iron in our bodies?
A: 2/3 in Hb. Rest in ferritin and hemosiderin. Free iron is very toxic, because it can bind to proteins, disrupting structure and function.

Q: What’s the difference between H-Ferritin and L-Ferritin?
A: H is found in heart and NUCLEATED blood cells. L is found in liver and spleen.

Q: When iron stores are low, what is the most abundant storage?
A: Ferritin.

Q: When iron stores are high, what is the most abundant storage?
A: Hemosiderin. Otherwise Fe most commonly stored in Hb.

Q: How do you digest Fe?
A: As an Fe-transferrin complex. Once endocytosed, low pH dissociates Fe from apotransferrin.

Q: Is Fe+++ absorbed?
A: No! Only Fe++ is absorbed by duodenum, so need to reduce Fe+++ to Fe++.

Q: What kind of Fe does transferrin bind?
A: Fe+++!! So must convert to Fe++ once dissociates to be absorbed by cell.

Q: What is the most common nutritional deficiency in the world?
A: Iron deficiency (microcytic anemia).

Q: How much iron is absorbed per day in adult male?
A: 1mg/day. 1.5 in pre-menopausal woman.

Q: Fe deficiency in an adult male can be a sign of what?
A: cancer.

Q: What is Fe Toxicity called?
A: hemosiderosis – promotes free radicals. Non-pathogenic Fe-dependent bacteria can grow out of control, like vibrio vulnificus from eating shellfish. If you have hemosiderosis and eat infected shell fish, you could die within 24 hrs!

Q: What is Hemochromatosis?
A: Genetic hemosiderosis. 10% of white americans are heterozygous for it.


Q: Vitamin B-1 is also known as what?
A: Thiamin – precursor to TPP. Used to transfer 2-carbon keto-groups.

Q: An advanced deficiency in B-1 (thiamin) causes what?
A: Beriberi

Q: An Acute deficiency in B-1 (thiamin) causes what?
A: Wernicke-Korsakoff syndrome → amnesia

Q: Vitamin B-2 is what?
A: Riboflavin – precursor to FAD and FMN.

Q: Vitamin B-2 is what?
A: Riboflavin – precursor to FAD and FMN.

Q: Deficiency in B-2 (riboflavin) causes what?
A: hyperbilirubinemia (neonatal jaundice)

Q: Vitamin B-3 is what?
A: Niacin – Precursor to NAD and NADP. Can be made from Tryptophan.

Q: Vitamin B-6 is what?
A: pyridoxine pyridoxal, pyridoxamine – precursor to PLP

Q: What is unique about Pyridoxamine in terms of toxicity?
A: unlike the other water-soluble vitamins, Pyridoxamine is toxic at high levels. Too much can cause peripheral neuropathy.

Q: What is vitamin B-5?
A: Pantothenic Acid.

Q: What are two things that contain B-5?
A: Acyl Carrier Protein, Coenzyme-ASH.

Q: What do B-5 form in multi-enzyme peptides (that have thiol group)?
A: Forms thioesters.

Q: What is Vitamin B-9?
A: Folic Acid.

Q: Describe the structure of B-9.
A: It is a conjugate of PABA and Glutamate. (conjugated in microorganisms but not in humans, that’s why humans have to eat folate)

Q: Folic Acid is reduced to form what in body?
A: tetrahydrofolate (via dihydrofolate reductase + NADPH)

Q: What are the two antagonists of THF?
A: Sulfanilamide (blocks PABA →Folic Acid, which only happens in microbes so this is an antimicrobial drug) and Methotrexate (blocks Folic Acid → THF, so this is used for leukemia treatments, since blocking THF acid blocks purine synthesis, amino acid and thymidine synthesis.)

Q: What is Vitamin B12?
A: Cobalamine.

Q: What does Cobalamine do?
A: It helps Methyl-THF donate its methyl group to homocysteine to make methionine.

Q: What is folate trap?
A: When you are deficient in B12 and so Methyl-THF can’t donate it’s methyl group.

Q: What is megaloblastic anemia?
A: When a pregnant woman is on a diet low in folate or cobalamin, DNA of RBC can’t be synthesized, so they get anemia.

Q: What kind of damage does folic acid deficiency cause?
A: Impaired DNA replication, because you can’t make purine nucleotides or dTTP.

Q: How much folate should women eat?
A: 400mg/day

Q: Describe the structure of cobalamin.
A: Cobalt in center of corrin ring, which looks like porphyrin except two pyrrole groups are linked directly while other two held together by methene bridges.

Q: What is cyanocobalamin? Where do you get it?
A: Cobalamin (B12) with Cyanide group. You can only get it from animal products.

Q: What do you need to absorb B12?
A: Intrinsic Factor. Binds to Transcobalamin II to be endocytosed.

Q: What are the only two reactions known to require cobalamin in mammals?
A: 1. Methylation of homocysteine to methionine. 2. Methylmalonyl CoA mutase reaction (methylmalonyl CoA → succinyl CoA)

Q: What causes Pernicious Anemia?
A: atrophic gastritis (autoimmune loss of stomach lining) → loss of intrinsic factor (made in lining of stomach) → can’t absorb B12

Q: What pathway makes Vitamin C?
A: glucuronate pathway.

Q: Why can’t humans make Vitamin C?
A: Because we are missing the last step in the glucuronate pathway: gulonolactone oxidase (GULO)

Q: What regulates uptake of Vitamin C?
A: glucose and insulin. Vitamin C gets uptaken by GLUT transporters.

Q: How is Vitamin C recycled?
A: take the breakdown product dehydroascorbate, and reduce it with glutathione transferase into ascorbate (Vit C)

Q: What Four Critical Reactions are Ascorbate (Vitamin C) responsible for?
A: 1. Hydroxylation of Prolyl and Lysyl residues in Procollagen (so if deficient in Vit C → can’t make collagen → scurvy)
2. Carnitine Synthesis
3. Synthesis of norepi from dopamine
4: 7alpha hydroxylase reaction (first step in converting cholesterol to bile acids in liver)

Q: What is Vitamin H (or B-7)?
A: Biotin.

Q: Biotin is the prosthetic group of what enzymes?
A: ATP-Dependent carboxylases EXCEPT purine nucleotide synthesis carboxylase.

Q: What do raw eggs have?
A: Avidin, which binds biotin, causing deficiency.

Q: Proteolysiis of Biotin-containing enzymes releases what?
A: biocytin, via Biotinidase, releasing biotin for re-use

Q: What common food item has a lot of biotin?
A: Chocolate.


Q: What is the grandmother of all the fat-soluble vitamins, cholesterol including steroids and bile acids, and dolichol?
A: isopentenyl pyrophosphate

Q: How is Vitamin A incorporated into chylomicrons?
A: The retinol is attached to a long chain fatty acid via an ester.

Q: What turns beta carotene into Vitamin A? How much is turned into Vitamin A?
A: beta-carotene dioxygenase. Only half is converted.

Q: What’s the difference between Retinol and Retinal?
A: Retinol is Vitamin A. If you oxidize this at C-15, it becomes Retinal, the prosthetic group of rhodopsin along with opsin (in eyes). If you oxidize again you get Retinoic Acid, used in hormone signaling.

Q: How do you make Beta Carotene in Vitamin A?
A: cleave it in the middle.

Q: What carries retinol from liver (where they are stored) to their target tissues?
A: Retinol Binding Protein (RBP)

Q: Is retinal originally in cis or trans form?
A: cis. But changes to trans when light hits it, triggering action potential to brain.

Q: Deficiency of Vitamin A causes what?
A: night blindness.

Q: What does retinoic acid do?
A: binds nuclear receptor proteins, which then binds to Response Elements on DNA, like steroid hormone.

Q: Is retinoic acid essential for vision?
A: NO! It’s not the same as retinal! However, deficiency of Retinoic acid can lead to vision due to loss of glycoprotein content of tears leading to dry eyes and eventual blindness.

Q: beta-carotene can be used to treat what type of porphyria?
A: Erythropoietic Protoporphyria (EPP)

Q: What are the best sources of active Vitamin A?
A: Liver, meat, fish liver oil (basically anything with fat)

Q: What are the best sources of provitamin?
A: orange fruits, leafy veggies.

Q: What is the first step in Vitamin D Synthesis?
A: UV light causes 7-dehydrocholesterol → cholcalciferol (Vitamin D3)

Q: What happens after cholecalciferol is formed?
A: It goes to liver and kidney to become Calcitriol via 2 hydroxylations.
Q: What is the major circulating form of Vitamin D?
A: 1, 25-dihydroxycholecalciferol. The C-1 hydroxy was added in Kidney. The C-25 hydroxy was added by Liver.

Q: What is the regulatory step in synthesis of Vitamin D?
A: The last step – 1-alpha-hydroxylase, controlled by PTH.

Q: What does Calcitriol do?
A: Acts on kidney (Ca Absorption) and intestine (absorb dietary Calcium and Phosphate) and bone (stimulate osteoclast) to raise Calcium levels. Has Aid of PTH in bone and kidney but not in intestine (because dietary).

Q: What happens when you have low plasma Calcium?
A: you release PTH, which then stimulate Calcitriol synthesis in bone and kidney, which then raises plasma calcium.

Q: What causes rickets?
A: Vitamin D deficiency → Deficiency in Calcitriol → can’t absorb dietary calcium → soft bones → rickets.

Q: What happens if you have hypervitaminosis D (too much Vit D)?
A: hypercalciuria, hypercalcemia, metastatic calcification → cardiovascular and renal damage.

Q: What is another name for Vitamin E?
A: alpha-Tocopherol

Q: What is the only known biological function of Vitamin E?
A: as antioxidant

Q: What is a sign of vitamin E deficiency?
A: Sensitivity of RBC to peroxide. So far, we haven’t seen if having too much Vit E is bad or not.

Q: What is the only known role of Vitamin K?
A: “Koagulation,” more specifically the post-translational processing of some clotting factors.

Q: Where do we get Vitamin K?
A: from Phylloquinone from plants, or Menaquinone from gut bacteria, or Menadione.

Q: If you have acute fat malabsorption, when is the first vitamin to be deficient?
A: Vitamin K

Q: What specifically does Vitamin K do in liver?
A: acts as cofactor in the carboxylation of glutamyl residue on precursors of II, VII, IX, X and prothrombin to become gamma-carboxyglutamate residue.

Q: While Vitamin K aids in the carboxylation of glutamyl residue (on clotting factors 2,7,9,10) to become gamma-carboxyglutamyl residue, what inhibits it?
A: Warfarin and dicumarol.

Q: What four steps of the blood clotting cascade require Calcium?
A: activation of Factor IX, X, Prothrombin, and conversion of prothrombin to thrombin.

Q: What is the feature of having a gamma-carboxyglutamyl residue?
A: it makes the molecule have affinity to calcium.

Q: What is the only known deficiency of Vitamin K?
A: Hemorrhagic disease of the newborn, the most common disease of the neonate. This is because their guts are still sterile (remember we get a lot of Vitamin K from bacteria in our gut), and maternal milk is insufficient in Vitamin K.

Q: If you kill off all flora in the GI tract and don’t eat a lot of leafy vegetables, what deficiency are you more likely to develop?
A: Vitamin K deficiency, causing prolonged blood clotting time.


Q: Which pancreatic cells produce glucagon? Insulin? Somatostatin?
A: α cells – glucagon. β cell – insulin. δ cells – somatostatin. MNEMONIC: “Agbids”

Q: What regulates the pancreatic hormones?
A: NOT CNS!! Blood glucose levels.

Q: What is clipped off preproinsulin to form proinsulin?
A: signal sequence.

Q: What is clipped off proinsulin to form insulin?
A: C peptide

Q: The A and B chains of insulin are held together by what?
A: 3 Disulfide bridges.

Q: What is hyperproinsulinemia?
A: When there is a deficiency of β-cell’s proinsulin-cleaving enzyme. Lots of proinsulin accumulate. More frequent in Type II Diabetics. Asymptomatic.

Q: What increases secretion of insulin?
A: Glucose, Amino Acids, Secretin, Glucagon (why??)

Q: What inhibits insulin secretion?
A: Trauma, strenuous exercise, epinephrine.

Q: Describe the structure of insulin receptor (CD220).
A: one insulin molecule binds to alpha subunits. Beta subunits stick in cell membrane.

Q: Insulin causes which GLUT to increase in activity?
A: GLUT4, found in muscle, adipocytes, (and heart sometimes). Glucose enters these tissue and gets stored.

Q: Which GLUT is found in pancreatic beta-cells?
A: GLUT2. It is insulin-independent.

Q: What events in the pancreatic beta-cell trigger it to release insulin?
A: glucose that enters through the Glut-2.

Q: Tell me the story about GLUT2 and GLUT4 and their roles in glucose storage.
A: dietary glucose enters through GLUT2 into pancreatic beta cell, triggering insulin to be released. Insulin binds to insulin receptors of peripheral cells (muscle, adipocytes), triggering GLUT4 to come to the surface of the cell, intaking glucose to get stored.

Q: What does elevated levels of insulin do to the number of insulin receptors?
A: It downregulates the population, so you get less – causing insensitivity to insulin.

Q: What regulates (inhibits) the synthesis and release of glucagon?
A: insulin.

Q: What does glucagon do to glycogenolysis and glycolysis?
A: It promotes glycogenolysis (so break down glycogen) and inhibits glycolysis (so can’t break down glucose for energy… the purpose is to raise blood-glucose level anyway, not to get more energy). This activates gluconeogenesis.

Q: What amino acid does glucagon NOT have?

Q: What stimulates Glucagon Release?
A: Fall in plasma glucose, high catecholamines, increased amino acid (to prevent hypoglycemia after all-protein meal), Ach (parasympathetic), and CCK (after a fat-rich meal?)

Q: What inhibits Glucagon Secretion?
A: Somatostatin (don’t need to grow, so don’t need more glucose in blood), Insulin

Q: What are the two primary targets of glucagon?
A: Liver (glycogenolysis) and Adipocytes (release free fatty acids and glycerol, which can be converted to glucose via certain pathways)

Q: What does glucagon do in Liver and adipocytes?
A: elevates cAMP

Q: What is glucagonoma?
A: pancreatic tumor, causing too much glucagon → hyperglycemia and elevated amino acids.


Q: What tissues synthesize glucose?
A: Liver and Kidney Cortex

Q: What tissues use glucose as primary energy source?
A: Muscles, Testes, RBCs, Kidney medulla, Brain and nervous tissue.

Q: When is glucose the preferred energy source in all tissue?
A: During periods of raised insulin/glucagon ratio.

Q: What is Specific Dynamic Action (SDA)?
A: Also known as Thermic Effect of Food. It is the amount of energy (in addition to resting metabolic rate) that is required to burn all the food you eat. It is expressed as a percentage of your metabolic energy requirements.

Q: What is Respiratory Quotient (RQ)?
A: It is the ratio of CO2 production to O2 uptake. (CO2/O2)

Q: What is the Respiratory Quotient for Carbs, Fat, and Proteins?
A: Carbs: 1.0, so the same amount of CO2 is produced compared with the O2 needed to break down carbs. Fat: 0.7. Protein 0.8. For these two, less CO2 is produced compared with O2 needed.

Q: In glycolysis, insulin stimulates what and glucagon inhibits what?
A: glucokinase (G → G6P), Phosphofructokinase (F6P → F16bP), Pyruvate Kinase (PEP → Pyruvate)

Q: What does excessive alcohol do to liver’s gluconeogenic capacity?
A: it impairs it.

Q: Why does excessive alcohol intake impair gluconeogenesis in liver?
A: Because breaking down ethanol to acetaldehyde then to acetate create a lot of NADH, which causes pyruvate to turn into lactate, and oxaloacetate into malate. Pyruvate and oxaloacetate are the precursors to gluconeogenesis! NO PRECURSORS LEFT! Lots of Malate → increase in NADPH (used in fatty acid elongation) → fatty liver. DIVERTED!!

Q: What is Microsomal Ethanol Oxidizing System?
A: A CytP450 enzyme that oxidizes ethanol using NADPH. It is activated with 1-2 drinks and is an alternative to alcohol dehydrogenase.

Q: What are the consequences of alcohol dehydrogenase reaction?
A: NAD/NADH ratio falls (NADH created). This causes hyperlacticacidemia, because NADH keeps converting Pyruvate into Lactate. Lactate competes with urate in kidney for excretion, and so plasma urate rises.

Q: How does making too much malate (because of NADH from ethanol metabolism) cause fatty liver?
A: Malate + NADP → Pyruvate + CO2 + NADPH + H. the NADPH is an essential reducer in lipid synthesis.

Q: How does eating too much glucose cause fat storage?
A: Insulin-dependent GLUT4 transports glucose into the adipocyte, where it goes through glycolysis to become acetyl CoA. The acetyl CoA along with VLDL from liver and other stuff from chylomicron together build triacylglycerol in the adipocyte.

Q: How does eating a meal cause hydrolysis of triacylglycerol to be inhibited?
A: high insulin/glucagon ratio favors dephosphorylation (inactivation) of PFK-2 and PyK. They are hormone-sensitive lipases.

Q: Is pepsin secreted by pancreas or stomach? What does it do?
A: stomach! It is an endopeptidase, so it cleaves polypeptides in the middle.

Q: Where does trypsin cut?
A: Carboxyl side of RK (nitrogen)

Q: Where does chymotrypsin cut?
A: Carboxyl side of FLY MW (aromatic rings)

Q: Where does elastase cut?
A: Carboxyl side of GAS (simple side chains)

Q: Where does carboxypeptidase A cut?
A: Amino side of VAIL (hydrocarbons)

Q: Where does carboxypeptidase B cut?
A: Amino side of RK (nitrogen)

Q: What activates trypsinogen to become trypsin?
A: Enteropeptidase, produced from mucosal surface of intestine’s brush border. Trypsin can now attack trypsinogen, making more trypsin.

Q: Trypsin, Chymotrypsin, and elastase are active only at what kind of pH?
A: neutral pH!

Q: Peptides are first chopped up by trypsin, chymotrypsin, and elastase. What happens next?
A: The peptides are further degraded by carboxypeptidases A and B (the Zn metalloenzymes)

Q: After carboxypeptidases come in and degrade polypeptides, what comes next?
A: digestion continues at surface of intestines via aminopeptidases, making free amino acids and dipeptides. So total you got: trypsin/chymotrypsin/elastase → carboxypeptidases A and B → aminopeptidases.

Q: What happens to the free amino acids?
A: They enter muscle and gets resynthesized into protein. Glycogen also gets stored in muscle.

Q: What happens when glucose enters the muscle?
A: Hexokinase turns it into G6P, which goes through glycolysis. But if glycogen is depleted, the G6P gets turned into glycogen by glycogen synthase.

Q: Glycogen phosphorylase and glycogen synthase are both dephosphorylated. What happens?
A: Glycogen phosphorylase is inactive and glycogen synthase is active.

Q: What is the only fuel that can cross the blood-brain barrier?
A: glucose, via GLUT-3. Glucose is only fuel for brain, and glycolysis/TCA are the major pathways in brain during absorptive state, unlike adipocytes and muscle.

Q: What happens to all the glucose that goes to the brain?
A: They all get oxidized into CO2 and water. There is no glycogenesis. Because glucose is the only fuel for brain, brain is the predominant consumer of glucose in the body.

Q: Where are glucose transporters insulin-independent?
A: Liver, RBC, and Brain

Q: Where are glucose transporters insulin-dependent?
A: muscle and adipocytes – so glucose can’t go into muscle and adipocytes in diabetics?

Q: The Lipostatic model describes regulation of body weight in what way?
A: with leptin and resistin. Leptin is produced bya dipocytes and promotes feeling of satiation. Resistin is produced by adipocytes and promotes resistance to insulin, preventing adipocytes from storing fatty acid.


Q: What is the leptin content like in lean vs. obese people?
A: In Lean people, 80% of leptin is bound to carrier protein. In obese people, 80% of leptin circulates in free state

Q: What does Leptin do?
A: It inhibits fat synthesis and stimulates beta oxidation of fats.

Q: What are anorexigenic hormones?
A: hormones that suppress appetite

Q: How does leptin affect insulin?
A: It increases liver, muscle, and fat’s sensitivity to insulin to bring the blood glucose levels down during a meal, but also inhibits insulin secretion as well, to prevent fat storage.

Q: What are two mechanisms that cause obesity that has to do with leptin?
A: 1. Deficiency of leptin production. 2. Deficiency of leptin receptor

Q: What is Ghrelin?
A: appetite-stimulating hormone released from stomach that causes release of orixogenic (appetite-stimulating) hormones.

Q: What is PYY?
A: appetite-reducing hormone (like leptin) except from intestine and colon (instead of adipocyte).

Q: What is Adiponectin?
A: a hormone that catabolizes fat. It increases beta-oxidation (breakdown fatty acids) and decreases lipogenesis and gluconeogenesis.

Q: How does adiponectin cause adipose catabolism?
A: via AMPK (AMP-activated protein kinase). It inhibits all biosynthetic (anabolic) processes. Basically if you have low energy (AMP), AMPK comes in and increases catabolism of fats.

Q: In what syndrome do you find high ghrelin levels, leading to extreme obesity?
A: Prader-Willi syndrome.


Q: When does Fasting begin? When does starvation begin?
A: Fasting begins 24hr-36hr of not eating. Starvation begins 36-38 hrs of not eating.

Q: What differentiates between fasting and starvation?
A: Fasting is when your body taps into stored glycogen in liver for blood glucose. Starvation is when your body starts tapping into your deep stores of fat and proteins.

Q: What are the major substrates of hepatic gluconeogenesis?
A: alanine, pyruvate (from muscle), and lactate (from muscle and RBC)

Q: In what phase in starvation is glucose use the highest?
A: Phase I (hours)

Q: In what phase is glycogen use the highest?
A: Phase II (hours)

Q: In what phase is Gluconeogenesis the highest?
A: Phase III (hours)

Q: In what phase does all tissues (but RBC and renal medulla) use alternate fuels?
A: Beginning of phase IV (measured in days)

Q: What happens to Liver during starvation?
A: 1. First all the liver glycogen is degraded. 2. Then non-carb precursors are converted into glucose. 3. Then liver does beta oxidation on fatty acids, turning them into acetyl CoA, and into ketones.

Q: What happens to Adipose Tissue during starvation?
A: triglycerides are degraded into fatty acids and glycerol, which are both released. Acetyl CoA is kept to do TCA cycle.

Q: What happens to muscle during starvation?
A: Proteins are degraded into amino acids and turned into gluconeogenic precursors. Fatty acids and ketone bodies (fatty acids first, then ketone bodies) are imported and made into Acetyl CoA to do TCA Cycle.

Q: What are the major glucogenic amino acids that are first broken down from muscle proteins?
A: Glutamine and Alanine.

Q: What is the muscle’s major fuel source the first two weeks of starvation? After two weeks?
A: First two weeks: Fatty acids. After two weeks: Ketones.

Q: At what phases of glucose homeostasis does ketones start becoming a brain fuel?
A: IV, V (5 stages total). Ketone’s don’t completely replace glucose, however.

Q: Chronic semi-starvation leads to what?
A: Kwashiorkor and Marasmus.

Q: What is kwashiorkor?
A: normal caloric intake, but diminished protein intake. This causes a decrease in serum albumin, leading to EDEMA!! (plump belly) Think vegans.

Q: What is Marasmus?
A: not enough caloric intake, but all nutrients in normal proportions.

Q: One cause of IDDM (Type I Diabetes) is insulitis. What is it?
A: When virus infects beta-cells of pancreas, causing T-cells to come in and destroy them.

Q: On what chromosome is there a major locus of IDDM (Insulin Dependent Diabetes)?
A: Chromosome 6, which is also where the HLA loci for MHC molecules are located. So perhaps IDDM is an autoimmune disease in which beta cells are presented as foreign.

Q: If you find a really high glucagon levels, what does it mean?
A: no insulin

Q: What causes weight loss in Diabetes?
A: excessive fat consumption (due to high glucagon), and loss of muscle protein to support gluconeogenesis.

Q: What is glucosuria?
A: When plasma glucose exceeds renal ability to reabsorb it. You pee out glucose.

Q: How do glucose levels look in a person who is starving and someone who has diabetes?
A: In the diabetic, glucose levels are too high. In the starving, the glucose levels are normal (because your body does gluconeogensis, glycogenolysis and other processes to keep glucose levels around normal).

Q: How do ketone production look production look in a starving patient vs. diabetic?
A: ketone production much greater in diabetic (ketoacidosis). The starving patient just has physiological ketosis, not ketoacidosis.

Q: A diabetic patient starts experiencing seizures, intense sweating, and hypothermia. What happened?
A: He had too much insulin dose, causing hypoglycemia.

Q: What is MODY?
A: Mature Onset Diabetes of the Young. It is Type II. It is autosomal dominant.

Q: If you have diabetes, how can you recover insulin sensitivity?
A: lose weight! It can almost always bring back some recovery of insulin sensitivity.

Q: What are microvascular complications of NIDDM? Macrovascular complications?
A: Micro: retinopathy, nephropathy. Macro: Cardiovascular Disease

Q: What are the chronic effects of Diabetes II?
A: vascular deposits of carb-rich plasma proteins → thickening of capillary basement membranes → deposition of collagen → narrow vessel lumen → cellular hypertrophy and hyperplasia. → high blood pressure, stroke, aneurysm.

Q: What causes diabetics to become blind?
A: Diabetic retinopathy – micro-aneurysms of terminal retinal capillaries → blindness.

Q: What causes diabetic neuropathy?
A: Again, deposition of glycosylated plasma proteins deposit (because can’t be stored, just linger around blood), causing aneurysms to nerves → lose sensation to lower extremities → gangrene and amputations

Q: Why do diabetics tend to develop cardiovascular disease earlier?
A: We don’t know.

Q: What is diabetic nephropathy?
A: It’s the most common end-stage renal disease (ESRD), from long-time patients.