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193 Cards in this Set
- Front
- Back
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What are the three cofactors in amino acid and nitrogen metabolism
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What are the nutritionally essential amino acids?
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Phenylalanine; Valine; threonine ; tryptophan ; isoleucine ; methionine ; histidine ; arginine ; leucine ; lysine
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What two amino acids are essential only if their precursors are not taken in in proper amounts?
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cysteine (methionine) and tyrosine (phenylalanine)
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Which amino acids are synthesized from intermediates of glycolysis?
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serine, glycine (from serine), cysteine (serine + methionine), and alanine from pyruvate
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Which amino acid is the major source of carbon for the "one carbon" pool?
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serine (serine hydroxymethyl transferase)
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What is the enzyme that takes serine to glycine?
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serine hydroxymethyl transferase; requires PLP and FH4
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Which four TCA intermediates are amino acids converted to during degradation?
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Fumurate (Phe/Tyr) ; OXA (Asn > Asp) ; aKG (Arg, His, Pro, Glu, Gln); Succinyl CoA (Ile, Met, Thr, Val)
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Which amino acids are only ketogenic?
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Leucine and Lysine
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What is the enzyme that takes phenylalanine to tyrosine?
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phenylalanine hydroxylase
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What enzyme defecit results in tyrosenemia 2?
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tyrosine aminotransferase
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What enzyme defecit results in alcaptonuria?
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homogentisate oxidase
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What enzyme defecit results in tyrosenimia 1?
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fumarylacetate hydrolase
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What enzyme defecit results in PKU?
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Phenylalanine hydroxylase
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What cofactor is required for the hydroxylation of phenylalanine?
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BH4
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What enzyme reduces the BH2 back to BH4 after it is used to hydroxylate phenylalanine?
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Dihydropteridine reductase
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What is the main reason to form urea in the body?
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Reduce the level of toxic ammonia
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Which form of ammonia does physiological pH favor the formation of?
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NH4 (NH3 is the form which crosses membranes)
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Describe the basic transition of Nitrogen from Amino Acids to urea that occurs in the liver?
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AA transfers Nitrogen to Alpha-KG via TA to form gltamate; Glutamate can either give up Ammonia directyl (via GDH) or transfer its nitrogen to OXA to form aspartate via TA
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What two forms of nitrogen enter the urea cycle?
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Aspartate and Ammonia
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What cofactor is involved in transamination reactions?
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PLP (pyridoxal phosphate)
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Oxidative or reductive deamination? For glutamate to alpha-KG?
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Oxidative deamination
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Name five reactions that produce ammonia?
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GDH; Histidase (histidine > urocanate); Serine dehydratase (serine > pyruvate and threonine > 2-ketobutyrate); glutaminase; aspariginase
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What does histidase do?
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removes ammonia from histidin to form urocanate
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What does the removal of ammonia from serine produce?
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pyruvate
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How can you go from glutamate to glutamine?
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use glutamine synthetase to add ammonia to glutamate (reaction invovles the cleavage of ATP to form AMP and Ppi)
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What are the two main non-toxic carriers of nitrogen ?
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alanine and glutamine
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Describe the glucose-alanine cycle
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muscle breakdown produces amino acids which are TA to form glutamate (from a-KG), glutamate then Tas to pyruvate to form alanine which is transported to the liver; in the liver alanine is used to make up glucose and its nitrogen is removed to form urea; glucose is taken back to the muscle and glycolysis reforms pyruvate
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Describe the pathway for glutamine transport of nitrogen
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In peripheral tissue; a-KG is converted to glutamate (addition of ammona) via GDH; then glutamate is converted to glutamine (addition of NH4) via Gln synthetase; Gln is transported to the liver and glutaminase removes the nitrogen to form glutamate > GDH removes another nitrogen (2 ammonias are transported and removed to form urea)
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Does glutamine synthetase require energy?
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Yes….ATP is converted to AMP and Ppi
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What is the enzyme pathway of the urea cycle?
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CPS1 > ornithine transcarbamolase > arginosuccinate synthetase > arginosuccinase > arginase
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CPS1
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bicarbonate + C02 + NH4 + 2 ATP = Carbamoyl Phosphate
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Ornithine transcarbamolase
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attaches a carbamoyl group to the amino terminal of ornithine to form citrulline
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arginosuccinate synthetase
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attaches aspartate to citrulline (ATP) to form arginosuccinate
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Arginosuccinase
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removes fumarate from arginosuccinate to form arginine
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Arginase
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removes urea from arginine to form ornithine
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which steps of the urea cycle are in the mitochondria?
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steps 1 (CPS1) and step 2 (ornithine transcarbamolase)
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How many ATP are needed for the production of urea?
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4
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What regulates the formation of urea?
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"feed forward" availaility of substrate; Induction of enzymes via high protein diet; N-acetyl glutamate
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What activates the syntehsis of N-acteyl glutamate?
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arginine
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N-acetylglutamate synthetase
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glutamate + acetyl coA = N-acetyl glutamate (activates CPS1)
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What are the fates of fumarate?
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can be recycled to aspartate (only option in well fed state) and can be converted to glucose (50% in fasting)
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What must fumarate be converted to in order to either go to glucose or aspartate?
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Malate
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If ammonia is in excess what happens?
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ammonia is TA'd to aKG to form glutamate which donates the nitrogen to OXA to form Aspartate
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If Aspartate is in excess what happens?
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Aspartate is TA'd to OXA and transfers its ammine to aKG to form glutamate which GDH then releases ammonia
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What is CPS2 involved in
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formation of orotic acid from carbamoyl phosphate and aspartate in the cytosol
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What are the three common lab results for all urea disorders?
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High glutamine; Low urea : High Ammonia
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What is the treatment option for urea disorders?
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low-protein diet; use drugs that conjugate glycine or glutamine to remove nitrogen from the blood
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What is the most common precursor of eiconasoids?
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Arachodonic acid (5,8,11,14) 20 carbons long
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What essential fatty acid is needed for the synthesis of arachodonic acid?
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Linoleate (linoleic acid)
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Which cells in the body cannot synthesize eicosanoids?
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RBC
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What are the functions of eicosanoids (7 of them)
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Inflammatory (leukotrienes); Pain/fever (PGI, PGF); Blood clotting (thromboxane A2); lowers platelet agg, vaso and bronchodilation (Prostacyclyn PGI2); Sleep wake cycle (HPETE, PGD2); Smooth muscle contraction (PGF2a); paracrine/autocrine via interactions with GPCRs
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What two phospholipases remove arachodonic acid from the membrane?
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PLA2 and PLC (removes DAG and IP3>>> DAG has the arachodonic acid on it)
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What enzyme removes arachidonic acid from DAG?
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Diacylglycerol lipase
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What are the three pathways for arachidonic acid metabolism?
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cyclo-oxygenase (prostaglandins and thromboxanes); lipoxygenase (leukotrienes, HETE, lipoxins); Cytochrome P450 (epoxides)
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What is the rate-determining step of the pathway for prostaglandin and thromboxane synthesis?
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cyclo-oxygenase
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What drug inhibits cyclo-oxygenase?
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Aspirin and NSAID
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What are the two domains of prostaglandin-endoperoxide synthase?
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COX and Peroxidase (COX cyclizes arachidonic acid and inserts an unstable peroxy group; Peroxidase removes the group on carbon 15)
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What are the two isoforms of COX and where do they work?
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COX 1 (stimulaties mucin production in gut; constitutive) and COX 2 (controls inflammation, pain and fever and is inducible)
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What organelles surface is the site of synthesis of PGH2?
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ER
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What is the product of the combined activites of COX and peroxidase found in the Prostaglandin-endoperoxidase synthase complex?
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PGH2
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Wat amino acid inside the hydrophobic channel is targeted by NSAIDS?
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Ser 530
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Which drugs are reversible and inrreverible inhibitors of COX?
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NSAIDS are reversible; Aspirin is irreversible
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What are some long-term health problems of nonspecifically inhibiting COX?
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peptic ulceration; Dyspepsia; Kidney damage
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Which COX isoforms are celebrex and vioxx more specific for?
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COX 2 due to steric hinderence
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What property or difference between the two isoforms of COX have drug companies taken advantage of in order to make a COX 2 specific drug?
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The size of the hydrophobic channel; COX 1 has a larger side chain than COX 2; COX 2 can accompany a bulkier molecule (hence vioxx is a larger molecule than previous NSAIDs
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What may be a detrimental effect of COX 2 specific inhibition?
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heart attack and stroke
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What structural features are shared by all prostaglandins?
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Carbon 15 hydroxyl group; double bond on 13-14; 5 carbon ring
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What structural features are seen in thromboxane-2
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Six carbon ring; 15-OH; oxy bridge (oxigen linked to two carbons of the six member ring)
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How are prostaglandins broken down?
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Oxidation of the 15-OH into a ketone; and B and Omega oxidation of the non ring ends of the structure produces a dicarboxylic acid which is excreted into the urine
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How are Thromboxanes broken down?
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TXA2 is metabolized non-enzymatically into TXB which is the more stable form. It is then excreted
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What are the three carbon positions of arachodonic acid which lypoxygenase may add a peroxy group to?
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5, 12, 15
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Briefly go through the steps of leukotriene synthesis?
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Arachidonic acid to 5-HPETE (5-LOX); 5-HPETE to LTA4; LTA4 to LTC4 (LTC4 synthase by addition of reduced glutathione); LTC4 to LTD4 by removal of glutamate (gamma-glutamyl transpeptidase); LTD4 to LTE4 by removal of glycine (dipeptidase)
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What do the leuokotrienes LTC4 and LTD4 do in the body?
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increase bronchoconstriction
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What effects do PGI2 have on the cardiovascular system?
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relaxes vascular smooth muscle, hypotension
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TXA2 on cardiovascular?
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Vasoconstrictor
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What is the relationship between PGI2 and TXA2 on platelet aggregation?
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Opposite effects; PGI2 inhibits aggregation; TXA2 stimulates aggregation by activating thrombin
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As far as bronchoconstriction and bronchodilation, which does what (PGI2 and LT)
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LT constrict; PGI2 dilate
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How does aspirin induce asthma?
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10% of people; inhibits COX and reduces PGI2 which shifts the balance to LTs which are constricters
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How do glucocorticoids reduce the inflammatory response?
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Induce the synthesis of Annexin/lipcortin which decreases PLA2 which prevents arachidonic acid sequesterization and decreases the precursors for leukotriene and prostaglandin synthesis
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What kind of linkage is found in plasmologens?
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Ether linked phospholipids
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Position 1 of plamologens contains what?
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long chain unsaturated (double bond) fatty acid (alkenyl group)
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How are ehter lipids synthesized?
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DHAP + FACoA condense; a FACoA is double reduced to an alcohol which is then added to the previous product at the 1 position thereby forming an ether linkage; C2 is reduced, FAcoA added and dephosphorylation of C3; addition of activated head group (phosphatidylcholine); MFO inserts a double bond in saturated C1 group
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What kind of plamologen is found in myelin and heart muscle?
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ethanolamine in myelin and choline in heart muscle
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What is platelet activating factor?
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Fatty acyl group of C2 (plasmologen) is replaced by acetyl group; C1 is saturated; It has a higher solubility then plasmologens and functions in platelet aggregation and inflammation
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What enzyme is the RDS in PAF formaiton?
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Acetyl CoA: Lyso-PAF acetyltransferase
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Why does plasmologen synthesis suffer in Zellweger syndrome?
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Because peroxisome biogenesis is defective; Plasmologen synthesis occurs in peroxisomes
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What does mutations in peroxins lead to?
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defective peroxisome biogenesis and zellwegers
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What amino acid is sphingosine derived from?
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Serine
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Where are ceramides made?
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ER
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Where is sphingomyelin and cerebrosides made?
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Golgi
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What key cofactor is needed for ceramide synthesis and why?
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pyridoxal phosphate; it activates serine though a "schiff base" which decarboxylates it and allows it to displace CoA from palmitoyl CoA
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Briefly describe the process of ceramide synthesis
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serine + palmitoyl coA (PLP); reduction of ketone to alcohol (NADPH); addition of VLCFA to amino which creates an amide linkage; then oxidation (FAD) to create a double bond (at the C1 position)
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What is addded to ceramide to create sphingomyelin?
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phosphatidylcholine (DAG is displaced)
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Sphingomyelin synthase?
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ceramide + phosphatidylcholine = sphingomyelin and DAG
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How are cerebrosides created?
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addition of activated (UDP) sugars to ceramides; they are monosaccharides
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Galactocerebroside
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Major glycolipid found in myelin; neutral at physiological pH
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Globosides
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ceramide oligosacharrides; neutral at physio pH
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Gangliosides
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Negatively charged; addition of activated sugars and sialic acid (NANA) onto glucocerebroside; GM2 builds up in Tay Sachs
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What donates sulfate to galactocerebroside to create sulfatide?
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PAPS (sulfotransferease)
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Sulfatide
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only brain sulfolipid (15% of white matter)
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Where are lipids broken down?
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lysosomes and membranes
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Where does phospholipase C cleave
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At the phosphoester bond to the backbone (releases both the head group and the phosphate)
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Where does phospholipase D cleave?
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At the phosphoester bond to the head group (releases just the head)
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Which phospholipase is activated by vasopressin?
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PLC (releases IP3)
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What is PLA2 involved in
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repair of oxidized FA; release of arachidonate in response to need for ecosanoids
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What role does ceramide play as a second messenger?
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apoptotic pathway
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What releases ceramide from the membrane?
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sphingomyelinase
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Decribe how cholera toxin uses sphingolipids
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B subunit attaches to the surface sphingolipid and is endocytosed; A subunit constituitively activates G protien > increases cAMP and leads to electrolyte and water loss = diarrhea
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What can block the release of new virions which are attached to the NANA of surface gangliosides?
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neuroamidase inhibitors
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Where is fatty acid synthesis located in (cytosol or mitochondria)?
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Cytosol
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If acetyl Coa has nor transporters within the mitochondria, how can it be used in a cytosolic reaction?
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Transported out via citrate; PDH makes acetyl coA; pyruvate carboxylase makes OXA; citrate synthase creates citrate; isocitrate DH is inhibited by well fed state (high energy); citrate accumulates and is transported out of the mitochondria
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What cleaves citrate in the cytosol?
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citrate lyase (acetyl coA and OXA)
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How is OXA recylceld in the cytosol?
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cytosolic malate DH ( into malate); Malic enzyme (into pyruvate; producinh NADPH)
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What two processes produce the NADPH needed for fatty acid synthesis?
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Pentose pathway and citrate-pyruvate cycle (malic enzyme)
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What is the commited step in FA biosynthesis?
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Acetyl CoA Carboxylase (create malonyl coA)
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Is Acetyl coA carboxylase activated by phosphorylation or dephosphorylation?
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Dephosphorylation (insulin)
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What activates Acetyl coA carboxylase?
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insulin (dephosphorylation); citrate; induction
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What inactivates acetyl coA carboxylase?
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Glucagon/epinephrine; phosphorylation; repression (feedback inhibition by palmitoyl coA)
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How many ATP and NADPH are required to synthesize palmitate (C16)?
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7 ATP and 14 NADPH
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What are the general steps of synthesis or elongation of FA?
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Condense (malonyl coA is ADDED); Reduction (NADPH creates an alcohol); dehydration (turns into double bond); Reduction (NADPH turns into single bond)
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What enzyme catalyzes the desaturation of a Fatty Acyl CoA and what is the normal carbon that is desaturated?
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Fatty acyl coA desaturase (carbon 9)
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How does the MFO, fatty acyl coA desaturase insert a double bond into a FA?
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It first inserts an oxygen between the carbon hydrogen bond, then dehydration creates a doubler bond
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Where does the process of desaturation of fatty acids occur?
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ER
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Briefly explain how linoleic acid is converted to arachodonic acid in the membrane?
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First it(omega 6) is desaturated at carbon 6; elongated once; desaturated at carbon 5
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Why can't adipose use glycerol to make triacylglycerol?
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does not contain glycerol kinase; uses glucose (via DHAP to form glycerol 3 phosphate)
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What does a nascent VLDL molecule need in order to be mature?
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apoC2 and apoE
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What is perilipin and why must it be inactive in order to mobilize fatty acids from adipose tissue?
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It is a protein coat that protects a fat droplet from lipase (phosphorylation inactivates it)
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What is the driving force of lipid droplet formation?
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hydrophobic effect
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what produces lung surfactant and what is the major lipid component?
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type 2 pneumocytes; phosphatidylcholine
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How are isoprostanes formed, and why are they useful?
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in vivo by the free radical-catalyzed peroxidation of arachodonic acid; provide markers for oxidative stress
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What enzyme takes you from glycerol 3 phosphate to phosphatidic acid?
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FA coA transferase (need 2 activated FA)
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What enzyme takes you from phosphatidic acid to DAG?
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Phosphatidic acid phosphatase
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What is CTP and why must it be used for glycerophospholipid synthesis?
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it is cytodine triphosphate; it increases the nucleophilic reactivity of the substrate allowing attachment of a head group onto DAG
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What is the regulated step in glycerophospholipid synthesis?
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cytidyl transfer (CTP attaching onto the head group or DAG to activate) catalyzed by cytidyl transferase
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Describe the interconversion of phosphatidylethanolamine and phosphatidylserine?
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PS can be decarboxylated to PE (PS decarboxylase); PE can be changed to PS by PS synthase and Serine
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How is it possible to produce phosphatidylcholine if your diet is lacking in choline?
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Indirectly produce it from Phosphatidylethanolamine using 3 SAM (methylation) and a transferase (PEMT)
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How do you synthesize cardiolipin?
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activate DAG with CTP; then attack with phospatidylglycerol
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Where does synthesis of cardiolipin occur?
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in mitochondria
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What is Neonatal respiratory distress syndrome?
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deficiency of lung surfactant; deficiency in dipalmitoylphosphatidylcholine
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Barth Syndrome?
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X-linked recessive; cardiolipin defiecency; mutations in the gene encoding Tafazzin, which is responsible for symmetricalcardiolipin molecules
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Where is cardiolipin located?
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inner mitochondrial membrane
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What does a deficiency of cardiolipin lead to ?
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poor oxidative phosphorylation; abnormally shaped mitochondria in cardiac muscle, and others; release of cytochrome c (apoptosis)
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How can the lack of phosphatidylcholine lead to fatty liver?
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lack of this can cause problems in VLDL synthesis and Fatty acids and cholesterol would build up in the liver
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What organelle is the site of cholesterol homeostatic machinery?
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ER
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What are prenyl groups?
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C15 and C20 intermediates of cholesterol synthesis; tether protiens to membranes
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What transporter is responsible for enterocyte absorbtion of cholesterol?
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Niemann Pick C1 like - 1 protein
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What does ezetimibe do?
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reduces cholesterol by inhibiting the absorbtion receptor on enterocytes (nieman pick c1 like 1 protien)
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what transporters are responsible for excretion of sterols from enterocytes?
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ABC (ATP binding cassette protiens)
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Sitosterolemia
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A deficiency in enterocyte excretion of sterols; affects the ABC transporter family; can lead to a high risk of coronary heart disease
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Where in the cell is cholesterol synthesized?
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Cytosol near the ER
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What important biomolecule is the carbon donor for all the carbons of cholesterol?
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acetyl CoA
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What is the commited and RDS of cholesterol synthesis?
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HMG-reductase (HMG-CoA > Mevalonate)
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What are the steps to synthesize cholesterol
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2 acetyl coA (thiolase) condense to form acetoacetyl-CoA; Another acetyl CoA is added (HMG-CoA synthase) to form HMG-CoA; HMG CoA reductase creates mevalonate> Mevalonate kinase leads to isoprenes; 3 isoprenes form farnesyl pyrophosphate; two farnesyls form squalene; squalene is MFO to create cholesterol
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What step in cholesterol synthesis is targeted by statins like lipitor?
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HMG-CoA Reductase
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How many phosphates are added to mevalonate by mevalonate kinase?
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3 (it activates the product for decarboxylation)
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What are the 3 ways of regulating HMG-CoA reductase?
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transcriptional (SCAP-SREBP); Allosteric regulation; Phosphorylation/inactivation
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How does the decrease of sterols result in an increase of HMG-CoA reductase transcription?
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Sterols released from SCAP allow SCAP-SREBP to move to the golgi from the ER; there the DNA binding domain is cleaved and migrates into the nucleus where it promotes HMG-CoA reductase mRNA transcription
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Descirbe allosteric regulation of HMG-CoA reductase?
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sterols induce binding of the enzyme to Insig proteins that recruit E3 ligase; this results in ubiquiting labeling and targeting for destruction
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What phosphorylation state is HMG-CoA active?
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depohosphorylated (insulin activates the enzyme via phosphatases)
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What role do LDL receptors play in circulating cholesterol levels?
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Decreased LDL receptors will result in an increase of circulating LDL and cholesterol increase (BAD); increasing LDL receptors is a clinically good method of decreasing cholesterol
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What controls LDL receptor expression in peripheral tissue?
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intracellular sterol levels (inversely; high levels will decrease expression of receptor)
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What are the two mechanisms of increasing LDL receptors?
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Statins (HMG-CoA reductase inhibitors) will decrease intracellular levels of sterols; Bile Salt sequesterants
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How can Bile Salt Sequesterents increase LDL receptor expression?
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Prevention of reabsorbtion in the ileum of bile salts will upregulate bile production; hepatic cholesterol will be used up in bile synthesis thereby decreasing the intracellular cholesterol levels; increased excretion of bile and cholesterol.
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What is the rate determining step of bile acid synthesis?
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7a- hydoxylase (MFO using cytochrom p450)
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How does conjugation of bile acids with taurine or glycine lead to better detergents?
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It lowers the pkA of the products making them easier to ionize in the intestine
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Where does bile acid synthesis occur in the liver?
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Liver microsomes
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What regulates 7a-Hydoxylase?
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Negative feedback from bile acids
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What do bacteria do to bile salts?
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They deconjugate and dehydroxylate them, making them worse detergents; lower solubility.
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What are more hyrophobic triacylglycerols or cholesterol?
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triacylglycerols (this is why they are located in the core of lipoproteins as well as cholesterol esters)
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What is the difference between the exogenous and endogenous pathway?
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Exo is from dietary lipids to peripheral tissue and liver; endo is from liver to peripheral
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Where are chylomicrons synthesized?
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intestinal mucosa (ApoB-48 from RER and TG from sER)
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What transfers TGs and cholesterol esters from the sER onto apo-B48?
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Microsomal TG transfer protein (MTP)
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What does ApoCII do?
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Activates lipoprotein lipase
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What does ApoE do?
|
recognizes receptor on liver, receptor mediated uptake
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How is lipoprotein lipase anchored to the plasma membrane?
|
heparin sulfate (this is why heparin injections release LPL into the circulation and have fat-clearing effects)
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What does hepatic triacylglycerol lipase do?
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breaks down lipoprotein remnants and HDL (located on the liver)
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Where does glycerol go after it is removed from the lipoprotein via LPL?
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to the liver
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How can u explain why FA are delivered to specific tissues during fasting states?
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LPL Km values are differnent between tissues (heart is low and thus will always take it up, adipose is high Km and takes up FA in well fed states only)
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What happens to excess chylomicron remnants?
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taken up by the liver and stored in phospholipid coated droplets within the sER (1-4 hrs)
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How do the intestinal cells change the apoprotein B gene?
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RNA edit a stop codon halfway (this is why ApoB-48 is half the size of ApoB-100); LDL receptors do not recognize ApoB-48
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What converts IDL to LDL?
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HTGL
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Where does half of our LDL deliver cholesterol to?
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adrenal tissue and gonads
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How can failure of LDL to bind to the LDL receptor lead to increased risk of atherosclerosis and CAD?
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Increased LDL circulation will saturate LDL receptors and cause nonspecific cavenger receptors to bind to and recognize the LDL, such as macrophages which then become foam cells.
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What is the function of HDL?
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to remove cholesteral from peripheral tissues and bring it back to the liver
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What enzyme esterfies cholesterol?
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LCAT (the purpose is to trap cholesterol and bring it into the core of HDL)
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Where does HDL acquire LCAT?
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from the circulation (secreted by the liver)
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What transporter moves cholesterol from the inner to the outer leaflet of peripheral cells?
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ABC (this allows cholesterol to freely diffuse through the phospholipid monolayer of HDL
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What is an alternative for HDL returning cholesteol to the liver?
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It can trade its cholesterol esters with VLDL (remnants) for TG; The enzyme is cholesterol ester transfer protein (CETP)
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CETP
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cholesterol ester transfer protein; HDL trades cholesterol esters for TG with VLDL
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What is Tangier Disease?
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Mutation of the ABC1 gene, prevents peripheral cells from moving cholesterol to HDL; Cholesterol builds up in tonsils and other organs, enlarged yellow-orange tonsils; macrophages become foam cells; Low Apo-A1, low HDL
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Familial hypercholesterolemia
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defective LDL receptors or mutations in ApoB-100; high LDL levels in blood
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Dysbetalipoproteinemia
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apoE mutation, accumulation of remnants; high plasma TG and cholesterol
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Hypertriglyceridemia
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LPL or ApoC-II defect; unable to process chylomicrons and VLDL
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