fatty acid and cholesterol biosynthesis Flashcards
fatty acid synthesis
- majority of fatty acids supplied by diet
- de novo pathway [mainly in liver]
- formed upon excess intake of carbohydrate
- stored as triglycerides (TG; utilized in starved state]
- components of cell membranes
fatty acid synthesis: acetyl CoA
- acetyl CoA [2 carbons] is transported from mitochondrial matrix to the cytosol via citrate intermediate
- citrate is transported across the membrane, and then converted back to acetyl CoA
- requires energy- ATP
fatty acid synthesis: malonyl CoA
- 3 carbons- required for fatty acid synthesis
- formed from acetyl CoA by reaction with a bicarbonate anion [HCO3]
- the original carbon is lost as CO2 during fatty acid synthesis- tightly regulated]
- high [citrate] denotes high substrate concentration
fatty acid synthase
- produces the 16:0 fatty acid palmitate from acetyl CoA
- the enzyme is a dimer
- each monomer is multi-catalytic [7 diff enzyme activities]
- the acyl primer domain [ACP] binds to the growing fatty acid chain and moves it between the different catalytic sites
biosynthesis of fatty acids:
1) acetyl group transferred from acetyl CoA to ACP [acyl carrier protein]
2) temporarily transferred to Cys-SH group
3) ACP accepts 3-carbon group from malonyl CoA
4) condensation reaction: 2-C and 3-C groups form 4-C chain and carbon dioxide.
5) the keto group is reduced to an alcohol by NADPH
6) a dehydration reaction forms a trans double bond between carbons 2 and 3
7) the double bond is reduced again by NADPH
steps 2-7 repeated to extend chain by two carbons each time
overall reaction of biosynthesis of fatty acids
8 acetyl CoA + 7 ATP + 14 NADPH + 6 H+ —-» palmitate + 14 NAPD+ + 8 CoA + 6H20 + 7 ADP + 7 Pi
7 of the acetyl CoA molecules are converted into malonyl CoA- the step that requires ATP
regulation of biosynthesis of fatty acids
- fatty acid synthesis occurs when carbohydrate and energy are plentiful
- acetyl CoA carboxylase is the key regulatory enzyme
- malonyl CoA also inhibits beta-oxidation [i.e. breakdown] of fatty acids
elongation of fatty acids
- palmitate (16:0) can be lengthened in two carbon steps, provided by malonyl CoA
- longer chains can be synthesised in the brain
cholesterol
- component of cell membrane- modulates fluidity
- precursor of bile acids, steroid hormones, vitamin D
- endogenous- de novo
- exogeneous- diet
biosynthesis of cholesterol overview
- mainly in liver
- in cytosol
- synthesis of 1 molecule of cholesterol requires:
- 18 molecules of acetyl CoA
- 36 molecules of ATP
- 16 molecules of NAPDH
acetyl CoA to mavalonate
HMG CoA is formed from 3 molecules of acetyl CoA, then reduced to form mavalonate
HMG CoA reductase (cytosolic)
- rate-limiting enzyme of cholesterol biosynthesis
- regulated by:
- phosphorylation [inhibits]
- transcriptionally [synthesis is inhibited by free cholesterol]
- inhibited by statins:
- upregulate the LDL receptor
- reduce plasma cholesterol by 20-40%
- mitochondrial isozyme involved in ketone body synthesis
cholesterol biosynthesis
1&2) mavalonate to Isopentyl pyrophosphate [IPP]
3) IPP to Dimethylallyl pyrophosphate
4&5) Dimethylallyl pyrophosphate to Farnesyl pyrophosphate [FPP]
- these 2 reactions [ and the subsequent ones] are made irreversible by the release of pyrophosphate, which immediately hydrolyses, preventing the reverse reaction.
6) FPP condensation [i.e. combination of two molecules] and reduction to squalene
- release of pyrophosphate again makes these 2 steps irreversible
- squalene, and all subsequent intermediates, must bind to a sterol carrier-protein within the cytosol
7&8) squalene to cholesterol
atherosclerotic plaques
- excess cholesterol can be deposited in the lumen of blood vessels to form plaque
- restricts blood flow and can rupture to form clots
