BIOC 3560 FA metabolisn.docx

For brain which cannot use fas ketone bodies

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Ketone bodies act as an alternative fuel eg. for brain (which cannot use FAs) Ketone bodies anabolism Acetoacetate is formed by condensing three acetyl-CoA molecules, then cleaving one D-β-hydroxybutyrate is formed by reducing acetoacetate Acetone is a minor product, formed by decarboxylation, and is exhaled In liver cell, instead of going to TCA it goes to ketone body pathway Ketone bodies catabolism Conversion back to acetyl-CoA In the end, two molecules of acetyl-CoA are regenerated for the citric acid cycle The point is to make something that can be transported in the blood and tissues Fatty acid biosynthesis Occurs in the cytoplasm (β-oxidation in the mitochondria)
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Is reductive, using NADPH Acetyl-CoA is the starting substrate, and is converted to malonyl-CoA as the committed step Acetyl group shuttle Acetyl-CoA is not directly transported from the mitochondria to the cytosol Instead, mitochondria acetyl-CoA is combined with oxaloacetate to produce citrate Citrate is transported to the cytosol Citrate lyase in the cytosol produces acetyl-CoA Oxaloacetate is reduced to malate, which can then return to the mitochondria either directly, or after decarboxylation to pyruvate Mitochondrial enzymes use malate/pyruvate to regenerate oxaloacetate Most of these enzymes are part of other metabolic pathways (eg. TCA, gluconeogenesis) FA biosynthesis uses malonyl-CoA FAs are made from the activated intermediate malonyl-CoA (not found in FA degradation) Malonyl-CoA is made from acetyl-CoA and HCO3 in an ATP dependent reaction This reaction is catalyzed by acetyl-CoA carboxylase Acetyl-CoA carboxylase Biotin carrier protein o Carries the biotin cofactor Biotin carboxylase o Enzyme that uses ATP to activate biotin with CO2 Transcarboxylase o Transfers CO2 from biotin to acetyl CoA to form malonyl-CoA FA biosynthesis cycle Carbon atoms are added two at a time by a repeating, four step sequence o Condensation of malonyl-CoA with growing FA o Keto reduction o Dehydration o Enoyl reduction Saturated acyl groups are the substrates for condensation with activated malonyl groups Each cycle extends the chain by 2 carbon atoms Reduction is accomplished using NADPH The growing FA chain is covalently attached to a small protein – acyl carrier protein (ACP) Step 0: FA synthase gets charged with acetyl-CoA and malonyl-CoA; by malonyl/acetyl- CoA-ACP transferase Step 1: condensation of activated acyl group with malonyl-CoA by β-ketoacyl-ACP synthase; the CO2 that acetyl-CoA carboxylase added is lost during condensation Step 2: reduction of β-keto to β-alcohol by β-ketoacyl-ACP reductase Step 3: elimination of H2O to form C=C by β-hydroxyacyl-ACP dehydratase Step 4: C=C reduced to saturated acyl group by enoyl-ACP reductase FA synthase organization
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Plants and bacteria: separate polypeptides Vertebrates: single polypeptide, bilobed dimer Fungi: two separate chains (double ring) Mammalian FA synthase
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  • Spring '10
  • dawson
  • FAS, Ketone bodies

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