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118 Cards in this Set
- Front
- Back
How are fatty acids activated for oxidation?
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acyl-coA synthetases attach them to Coenzyme A (CoA-SH)
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What defect causes Leigh syndrome?
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no PDH --> pyruvate cannot be converted to acetyl-coA --> can't start TCA cycle
feed fatty acids as alternate source of acetyl-coA |
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What is the first step in fatty acid activation?
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R-COO- + ATP --> R-COO-AMP + PPi
FA displaces PPi on ATP PPi + H2O --> 2 Pi PP hydrolysis drives rxn forward. |
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What is the second step in fatty acid activation?
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R-COO-AMP + CoA-SH --> acyl-coA + AMP
CoA-SH displaces AMP. |
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How are fatty acids liberated from triacylglycerides?
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LIPASE ENZYME cleaves fatty acids from glycerol backbone.
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How is Lipase regulated?
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Epinephrine/glucagon --> G protein cascade --> make cAMP
Lipase activated by cAMP dependent kinase (protein kinase A) |
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What happens to glycerol from breakdown of fats?
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goes to gluconeogenesis
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What happens to fatty acids from breakdown of fats?
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transport thru blood with ALBUMIN
goes to liver |
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What are the major characteristics of most fatty acids found in the human body?
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-even # of carbons (16, 18, 20)
-cis double bonds separated by -CH2- -usually has unbranched carbon chain |
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What is the first step in β oxidation of fatty acids?
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acyl-coA dehydrogenase (AD)
oxidize FA with FAD; make FADH2 trans double bond forms between α and β carbons product: trans-Δ2-Enoyl-CoA |
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What is the second step in β oxidation of fatty acids? (What do we do with the enoyl-coA?)
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enoyl-CoA hydratase (EH)
hydration of double bond --> β hydroxyl product: 3-L-Hydroxyacyl-CoA |
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What is the third step in β oxidation of fatty acids?
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3-L-hydroxyacyl-CoA dehydrogenase (HAD)
oxidizes 3-hydroxyl --> keto group product: β-ketoacyl-CoA |
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What is the fourth step in β oxidation of fatty acids? What do we do with the β-keto acyl-coA?
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β-ketoacyl-CoA thiolase (KT) + CoA-SH
CoA-SH attacks β carbonyl, displaces acyl coA. products: Acetyl-CoA + fatty acyl-coA (2 C's shorter) |
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18 C fatty acid name?
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stearate
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16 C fatty acid name?
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plamitate
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20 C fatty acid name?
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arachidonate
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What is the difference between the Δ and ω fatty acid numbering systems?
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Δ counts α-carbon as C1
ω counts end carbon as C1 |
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Numbering scheme for fatty acids?
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(name) A:B ΔC
(name) A:B ωD A = # of C's in chain B = # of double bonds C = location of first C in double bond, counting from α carbon D = location of first C in double bond, counting from ω carbon |
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What is the first step in fatty acid elongation?
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Attachment to Acyl Carrier Protein
Malonyl-CoA --> Malonyl-ACP |
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Why cannot one simply hydrate the double bond in a cis-unsaturated fatty acid and skip the cis --> trans isomerization step?
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need L-isomer of the beta-OH FA!
Hydration of the cis form yields D-isomer |
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What happens in MCAD deficiency?
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no Medium Chain Acyl-CoA Dehydrogenase --> cannot generate trans β-γ alkene
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Where are the FA oxidation enzymes located?
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mitochondrial matrix
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Where are the FA synthesis enzymes located?
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cytosol/in mitochondria outside matrix
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How many ATP produced per acyl coA cleaved from a FA?
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1 FADH2 --> 1.5 ATP
1 NADH --> 2.5 ATP 1 Acetyl-CoA --> 10 ATP in TCA total 14 - 2 for activation of whole FA = 12 |
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Where does ketogenesis take place?
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LIVER ONLY.
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Why can't the liver utilize the ketone bodies it produces?
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lacks CoA transferase enzyme:
acetoacetate + succinyl-coA --X--> AA-coA + succinate |
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What is the energy "cost" for utilizing acetoacetate in tissues except liver?
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acetoacetate + succ.-coA --> AA-coA + succinate
bypasses GTP producing step of TCA cycle! "costs" a GTP. |
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Why can the liver carry out ketogenesis efficiently under starvation conditions? Why doesn't TCA cycle just eat up all the acetyl-coA from fatty acid degradation like it does in other tissues?
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gluconeogenesis is also occurring --> oxaloacetate is being siponed off for use in GNG!
no OAA --> acetyl-coA cannot enter TCA cycle accumulate acetyl-coA --> combine to make KB's |
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What is the efficiency of FA oxidation?
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~33%
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What controls the rate of acetoacetate to hydroxybutyrate in the last step of ketogenesis?
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availability of NADH from FA oxidation!
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What is the first step in ketogenesis?
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THIOLASE
2 Acetyl-CoA --> acetoacetyl-CoA + CoA-SH |
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What is the second step in ketogenesis?
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HMG CoA SYNTHETASE
Acetoacetyl-CoA + Acetyl-coA --> HMG-CoA + CoA-SH incoming Acetyl-CoA attacks γ-keto group |
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What is the third step in ketogenesis? (what do we do with HMG coA?)
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HMG CoA LYASE
HMG-CoA --> Acetoacetate + Acetyl-CoA γ-OH on HMG-CoA collapses into keto group, ejects Acetyl-CoA |
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What are the two fates of acetoacetate ofter it is formed?
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1. reduction by D-β-OH butyrate DeHase:
acetoacetate + NADH --> D-3-β-OH butyrate + NAD+ 2. decarboxylation to acetone by Acetoacetate Decarboxylase: Acetoacetate --> acetone + CO2 |
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How do tissues other than the liver utilize ketone bodies?
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convert back to Acetyl-CoA and run TCA cycle.
Acetoac + Succinyl-coA --> succinate + acetoacetyl coA aa-CoA + CoA-SH --> 2 acetyl-coA |
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What is the first step in FA biosynthesis?
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Acetyl-CoA Carboxylase (ACC)
2 step formation of malonyl-coA: Biotin-ACC + HCO3- + ATP --> ACC-Biotin-COO- + ADP + Pi ACC-Biotin-COO- + Acetyl-coA --> malonyl-coA + ACC-Biotin |
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What is the second step in FA biosynthesis?
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Transacylase
attachment of malonate to ACP malonyl-CoA + ACP-SH --> malonyl-ACP + CoA-SH rxn ΔG ~ 0 |
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What is the third step in FA biosynthesis? (after malonyl grp is attached to ACP)
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KS
decarboxylation/condensation with Acetyl-CoA malonyl-ACP + Acetyl-CoA --> Acetoacetyl-ACP + CO2 + CoA-SH |
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What is the fourth step in FA biosynthesis? (after acetoacetate gets attached to ACP)
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β-ketoacetyl-ACP reductase (KR)
Reduction with NADPH Acetoacetyl-ACP + NADPH --> D-3-OH butyryl-ACP + NADP+ |
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What is the fifth step in FA biosynthesis? (after reduction of keto group)
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β-OHacyl-ACP dehydrase (DH)
Dehydration to trans alkene D-3-OH butyryl-ACP --> a/b-alkenyl-ACP + H2O |
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What is the sixth step in FA biosynthesis? (after alkene formation)
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enoyl-ACP reducase (ER)
Hydrogenation of double bond a/β-alkenyl-ACP + NADPH --> alkyl-ACP + NADP+ |
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Describe the cycle of FA elongation.
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ACP's acyl tail transferred back to enzyme
gets stolen by a NEW malonyl-ACP. new C2 units added to point of attachment to ACP, not at end of tail. |
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What promotes activation of ACC (acetyl-coA carboxylase)?
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-citrate (plentiful after a meal; carries acetyl-coA from matrix to cytosol)
-polymerization of ACC into active filamentous form -dephosphorylation of enzyme by phosphatase 2 |
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What promotes deactivation of ACC (acetyl-coA carboxylase)?
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-AMP-dependent kinase (phosphorylates ser 79)
-AMP levels -high palmitate levels (end product feedback) |
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oleate
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18:1 Δ9
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linoleate
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18:2 Δ9, Δ12
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linolenate
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18:3 Δ9, Δ12, Δ15
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palmitoleate
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16:1 Δ9
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arachidonate
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20:4 Δ5, Δ8, Δ11, Δ14
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What is the difference between synthesis of neutral and negative phospholipids?
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neutral: activate polar head group with CTP for attachment to diacylglycerol
negative: activate phosphatidate with CTP (1,2-diacyl glycerol-3-phosphate) |
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What provides the glycerol for triacylglycerol backbones?
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DHAP from glycolysis + NADH --> glycerol-3-P ---> glycerol + Pi
to make phosphatidate: glycerol + ATP --> glycerol-3-P + ADP |
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What reaction in gluconeogenesis is the major drain on the cell's supply of oxaloacetate?
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PEP Carboxykinase
Oxaloacetate + GTP --> PEP + CO2 + GDP |
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What enables ACC2 to make malonyl coA that suppressess CAT I (when ACC1 makes the same thing that doesn't repress)?
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ACC2 has homing peptide that targets it to CAT I complex
--> makes malonyl coA very close to CAT I ACC1 floating free in cytosol so its malonyl coA doesn't repress CAT I |
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What is the function of ACC?
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carries out carboxylation of acetyl coA to malonyl coA with CO2-biotin-ACC.
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What is the significance of phosphopantetheine?
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It is the prosthetic group on ACP to which malonate is attached.
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Which enzymes involved in fatty acid synthesis use biotin as a cofactor?
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Acetyl-coA Carboxylase (makes malonyl-coA)
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What is the tricarboxylate transport system?
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method for getting Acetyl-coA from FA oxidation out of mito. matrix into cytosol.
pyruvate --> OAA (pyruvate carboxylase) OAA + acetyl-coA --> citrate citrate --> acetyl-coA + OAA OAA --> pyruvate |
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What two processes in the cell utilize pyruvate carboxylase?
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PC-biotin-CO2 + pyruvate --> oxaloacetate
1. gluconeogenesis 2. tricarboxylate transport of acetyl-coA |
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What is the first committed step of fatty acid synthesis?
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Formation of malonyl coA by Acetyl-CoA Carboxylase.
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Why can't humans synthesize ω-3 fatty acids?
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We can't make <ω-7 FA's because desaturase can only reach C9 of palmitate.
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How is arachidonate converted into prostaglandins?
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cyclooxygenase (COX) adds heterocyclic bridge to molecule.
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Why are nonspecific COX inhibitors likely to cause gastrointestinal upset?
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They inhibit COX-1 which is necessary for maintaining organ homeostasis.
COX-2 is the one that makes prostaglandins that cause inflammation. |
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What is the mechanism of aspirin (acetylsalicylic acid) on COX enxymes?
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acylates ser on cyclooxygenase --> deactivate
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What is the mechanism of ibuprofen on COX enzymes?
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substrate analog --> competitive inhibition
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What is the difference between an oxidase and an oxygenase?
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oxidase: does not incorporate O into product; O is just e- acceptor
oxygenase: O incorporated into product. |
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What is the major source of arachidonate for prostaglandin synthesis?
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often hydrolyzed from C2 of phospholipids.
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How do phospholipids function as precursors to second messengers in cell signaling pathways?
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cleavage of head group from phospholipid by phospholipase C
produces diacylglycerol (Protein Kinase C) + head group (can mediate other processes--ex. inositol/ion channels) |
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What is the importance of phospholipids as detergents/surfactants?
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keep surfaces slippery
prevent alveolar lung collapse or adhesion of other cavity walls to one another |
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What is the difference between synthesis of a neutral vs. negatively charged phospholipid?
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neutral: activate head group w/CDP
negative: activate backbone (phosphatidate) w/CDP |
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What is the cofactor of ACC?
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biotin
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What is the cofactor of 3-ketosphinganine synthase?
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PLP
pyridoxal phosphate |
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How are triacylglycerols synthesized (summary)?
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-attach FA's 1 and 2 to glycerol-3-P
-dephosphorylate -attach FA #3. |
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What does inositol 1,4,5 triphosphate regulate?
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Ca2+ channels
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What is the net charge on phosphatidylcholine?
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neutral
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What are the steps in activating head groups or phosphatidates during the last steps of phospholipid biosynthesis?
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1. X + ATP --> X-P + ADP
2. X-AMP + CTP --> X-CDP + PPi phosphorylate then attach CMP |
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Where do phospholipase A1 and A2 cut?
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cleave FA esters from C1 and C2 on phospholipid
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Where does phospholipase C cut?
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cleaves phosphoryl head group --> generate DIACYLGLYCEROL
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Where does phospholipase D cut?
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cleaves just the head group --> generates PHOSPHATIDATE.
differs from PLC b/c it leaves phosphate on |
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Step 1 in synthesis of sphingosine?
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ser + palmitoyl-coA --> dehydrosphingernine + CO2
enzyme has PLP cofactor ser's α-C displaces coA-SH |
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Step 2 in synthesis of sphingosine?
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deydrophingernine + NADPH --> dihydrosphingosine
reduce keto grp --> -OH |
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Step 3 in synthesis of sphingosine?
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dihydrosphingosine + FAD+ --> SPHINGOSINE + FADH2
oxidize to alkene between what were the α&β carbons of palmitoyl-coA |
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How do you make ceramide?
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attach acetylcoA to amino group of sphingosine.
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How do you make sphingomyelin?
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attach choline-CMP to terminal -OH of ceramide
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How do you make a cerebroside?
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attach sugar-UDP to terminal -OH of ceramide.
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How do you make a glycosphingolipid?
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attach an oligosaccharide to terminal -OH of ceramide.
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What is the major function of gangliosides?
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have n-acetyl-neuraminic (sialic) acid in their oligosaccharide chains
function as cell antigens: ceramide embedded in membrane, oligo waving in the breeze like a name tag/cell ID marker |
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Where are sphingolipids degraded?
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lysozomes
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What is special about lysozomal enzymes?
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only function at low pH.
lysozome pumps H+ into itself to maintain optimal pH prevents enzymes from eating cell if lysozome accidentally bursts. |
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What is the function of hexosaminidase A?
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degrades ganglioside GM2 --> ganglioside GM3
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What is the defect in Tay Sachs disease?
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sphingolipidosis
no hexosaminidase A --> GM2 and GM3 accumulate in neurons, which swell death by 4 y/o :( |
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What is the building block of cholesterol?
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acetyl coA
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What is the function of cholesterol in cell membranes?
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regulate membrane fluidity with temperature fluctuations
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How do we get cholesterol?
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liver makes it in cytoplasm under well-fed conditions.
intestines absorb dietary cholesterol. |
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What is the difference between cytoplasmic and mitochondrial HMG-CoA?
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cytoplasmic is made as choesterol precursor out of extra acetyl coA.
mitochondrial one made under starvation conditions with xs acetylcoA from FA oxidation. |
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What enzyme catalyzes the first committed step in cholesterol synthesis?
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HMG-coA Reductase
uses NADPH to reduce HMG-coA to mevalonate. |
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What happens to mevalonate during cholesterol synthesis?
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ATP used to add PP: yields 5-pyrophospho-mevalonate.
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What happens to 5-pyrophosphomevalonate?
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ATP-mediated decarboxylation to isopentenyl pyrophosphate.
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What happens to isopentenyl pyrophosphate?
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polymerize to geranyl-PP
geranyl-PP + isopentenyl-PP --> farnesyl-PP 2x farnesyl-PP --> SQUALENE |
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What general changes are made to convert squalene to cholesterol?
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-cyclization
-double bond migration -formation of epoxide that is later reduced to hydroxide -some double bonds get reduced -3 methyl groups removed |
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How are cholesterol + other lipids transported in the blood?
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lipoproteins
"oil droplet" of TAG's and cholesterol esters enclosed by phospholipid monolayer membrane with apoproteins and unesterified cholesterol in it. |
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What is the function of apoproteins?
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interact with lipoprotein lipases on adipocyte surfaces.
Lipoprotein lipase tethered to surface by oligosaccharide chain, lyses lipoprotein, liberates FA's from TAG's and takes them into the cell. |
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What happens to empty chylomicrons?
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endocytosed by liver cells for degradation.
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How is cholesterol transported from the lipoprotein membrane into the interior of the droplet?
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Lecithin Cholesterol Acyl Transferase (LCAT):
esterifies FA on C2 of lecithin (phos. choline) to -OH on cholesterol to increase hydrophobicity |
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How is cholesterol converted in an inert form for storage in the cell?
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Acyl-coA Cholesterol Acyl Transferase (ACAT):
esterifies palmitoleoyl-coA or oleyl-coA to cholesterol. |
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How does the liver export cholesterol it makes to other parts of the body?
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VLDL particles
Very Low Density Lipoproteins 28-70 nm diameter |
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How do intestinal cells transport dietary cholesterol to other parts of the body?
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chylomicrons
80-500 nm diameter |
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How is blood [cholesterol] regulated?
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-cells take up cholesterol for their own use (membrane, steroids)
-endothelial surface of cell has clathrin coated pit with LDL receptors that trigger endocytosis of LDLs. |
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How is cholesterol synthesis regulated by SREBP?
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HMG-coA reductase = major control pt
low cholesterol --> transcriptional activation by Sterol Regulating Element Binding Protein (SREBP) high cholesterol --> SREBP prevented from reaching nucleus (no transcriptional activation) |
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How is cholesterol synthesis regulated aside from SREBP?
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HMG-coA reductase = major control pt
high [cholesterol]/derivatives: destabilize HR AMP-dependent kinase: phosphorylate HR to turn off during low energy state -regulate # of membrane LDL receptors to modulate cholesterol levels in cell |
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How are atherosclerotic plaques formed?
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monocytes enter lesions in arteries and become macrophages that scavenge LDL's
macrophages accumulate cholesterol and become foam cells --> plaque. |
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What is another name for ceramide?
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N-Acyl sphingosine.
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VLDL's
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-Liver packages TAG's it makes in VLDL's
-Carries TAG's to other parts of body -covered in apo C-II (trigger Lipoprotein Lipase on adipocyte) -becomes LDL after TAG's removed |
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What happens to excess cholesterol in the body?
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-forms atherosclerotic plaques
-ideally, packaged into HDL's, sent to liver, & converted to bile salts for excretion |
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LDL's
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-more cholesterol rich (40% by weight) than VLDL
-covered in apoprotein B-100 -cholesterol transporter |
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HDL's
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-scavenge cholesterol from LDL, chylomicron remnants, dying cells
-esterify cholesterol and transfer to core of particle using LCAT -transport xs cholesterol back to liver for excretion via bile salts. |
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Where do HDL's come from?
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made by liver
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How is cholesterol taken up by cells?
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-Apo B-100 on LDL encounters clathrin coated pit --> binds LDL TM receptor
-cell does LDL endocytosis -LDL degraded in lysosome to liberate cholesterol. |
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Chylomicrons
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-intestinal cells package dietary fats, cholesterol in chylomicrons
-covered in apoprotein C-II -encounters LPL on adipocyte surface, TAG's get hydrolyzed and taken up by cell |