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Fatty acid synthesis
Uni of Notts, Signalling & Metabolic Regulation, Year 2, Topic 12
| Term | Definition |
|---|---|
| Fatty acid synthesis step 1: Transport | Acetyl-CoA too big and polar to leave the cell so citrate leaves through transporters when in excess mito-cyto. It's cleaved by citrate lyase to release Acetyl-CoA and oxaloacetate |
| Fatty acid synthesis step 2: Formation (+control of formation) | Acetyl-CoA carboxylated by ACC & biotin to malonyl-CoA. ACC can be regulated by phosphorylation from AMPk in low energy |
| Fatty acid synthesis step 3: Extension | 2C units are added to the growing chain by condensation (C-C bond formed & CO2 released), reduction (NADPH), dehydration (2* alcohol to alkene), & reduction again (alkene to alkane) |
| Fatty acid synthase (FAS) | 500kDa homodimer containing 7 catalytic domains which must align within the dimer interface to form a reaction chamber to synthesise fatty acids from acetyl-CoA |
| Acyl Carrier Protein (ACP) & 4'-phosphopantetheine (4'-PP) | 4'-PP derives from vitamin B5 & attaches to serine residue of ACP (holoenzyme). Terminal thiol group binds growing acyl-groups to shuttle them between catalytic sites within FAS |
| Fatty acid extension Step 1: Priming | Malonyl-CoA is transferred to β-ketoacyl synthase (KS) cysteine residue & new acetyl-CoA is transferred to ACP |
| Fatty acid extension Step 2: Conensation | Acetyl-CoA condenses with malonyl-CoA to remove CO2 & form a C-C bond with a ketone. Chain length increases from 2C-4C |
| Fatty acid extension Step 3: First reduction | β-ketoacyl reductase (KR) uses NADPH to reduce it to a 2* alcohol |
| Fatty acid extension Step 4: Dehydration | Dehydratase (DH) converts β-hydroxyacyl-ACP → trans-enoyl-ACP releasing H2O & making a C=C bond (unsaturated acyl) |
| Fatty acid extension Step 5: Second reduction | Enoyl reductase (ER) uses NADPH to convert the alkene to an alkane (saturated acyl-ACP) |
| Fatty acid extension Step 6: Translocation | Growing 4C acyl chain moves to KS & malonyl-CoA binds to ACP. Cycle can begin again |
| Fatty acid extension Step 7: Repetition | Cycle repeated a further 6 times until 16C palmitoyl-ACP forms |
| Fatty acid extension Step 8: Termination | Thioesterase (TE) hydrolyses the acyl-ACP to palmitate & free ACP |
| How decarboxylation drives the reaction | Decarboxylated chain forms a carbocation/enol reactive intermediate that can nucleophilically attack the other carbon chain, diffusion of resonance-stable CO2 makes the reaction irreversible |
| Overall reaction equation | 8 acetyl CoA + 7 ATP + 14 NADPH + 6H+ → palmitate + 14 NADP+ + 8 CoA + 6H2O + 7 ADP + 7 Pi |
| Key catalytic subunits in FAS: KS, MAT, KR, DH, ER, TE | KS = β-ketoacyl synthase MAT = malonyl/acetyl transferase KR = β-ketoacyl reductase DH = dehydratase ER = Enoyl reductase TE = Thioesterase |
| Fatty acid-glycerol condensation | Glycerol-3-phosphate (from phosphorylated glycerol or reduced DHAP), 1st condensation (C1) to lysophosphatidic acid, 2nd (C2) to phosphatidic acid, C3 dephosphorylated commits process from DAG to TAG |
| Role of hormone sensitive lipases | Adrenaline causes it to release free fatty acids to be circulated by albumin to skeletal muscle, glucagon represses it |
| α-Oxidation & ω-Oxidation | α occurs in peroxisomes, removes carboxyl carbon to process branched fatty acids. ω occurs in ER & mitochondria, converts terminal methyl group into carboxyl if fatty acid concentration is too high |
| Long Chain Fatty Acid (LFCA) activation | Fatty acids are too stable to be oxidised directly & require a thioester bond. The carboxyl end attacks the α-phosphate of ATP forming acyl-AMP (PPi hydrolysed) which can transfer the acyl to CoASH |
| LFCA import | Carnitine binds to LFCA to transport it using carnitine-palmitoyl transferase I to get to the intermembrane space of the mitochondrion & CP transferase II to reach the matrix where it reassociates with CoASH |
| Why short & medium chain fatty acids don't need the carnitine-palmitoyl shuttle | They can enter the matrix through simple diffusion |
| β-oxidation | Oxidation (acyl → acyl trans-enol, +FADH2), hydration (trans-enoyl → β-hydroxyacyl), oxidation (β-hydroxyacyl → β-ketoacyl, + NADH), thiolysis (β-ketoacyl + CoA → acetyl-CoA + shortened acyl) |
| β-oxidation enzymes: Acyl-CoA oxidation, Enoyl-CoA hydration, β-hydroxyacyl-CoA oxidation, β-ketoacyl-CoA thiolysis | Oxidation - Acyl-CoA dehydrogenase Hydration - Enoyl-CoA hydratase Oxidation - β-hydroxyacyl-CoA dehydrogenase Thiolysis - Thyolase |
| β-oxidation of odd number chained fatty acids | Same process as before, except the final cycle when there is propionyl-CoA instead of acetyl-CoA which can be converted to succinyl-CoA & entered into the TCA cycle for gluconeogenesis |
Created by:
Denny12
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