Lipid Metabolism

Lipid Metabolism - Chapter 25 Lipid Metabolism Processing...

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Unformatted text preview: Chapter 25 Lipid Metabolism Processing of dietary lipids in vertebrates Mobilization of triacylglycerol stored in adipose tissue Acyl-CoA synthase: Fatty acid activation Fatty acid + CoA + ATP ↔ acyl-CoA + AMP + PPi Entry of glycerol into the glycolytic pathway Carnitine is an acyl carrier The transport of fatty acids into the mitochondrion Stages of fatty acid oxidation The β-oxidation of fatty acyl-CoA • Acyl-CoA dehydrogenase – Formation of trans-α,β double bond • Enoyl-CoA hydratase – Hydration of the double bond to form a β-hydroxyacyl-CoA • 3-L-Hydroxyacyl-CoA dehydrogenase – Formation of β-ketoacyl-CoA • Thiolase – Cα-Cβ bond cleavage to form acetylCoA and a new acyl-CoA containing two less C atoms The β-oxidation pathway of fatty acyl-CoA Acyl-CoA dehydrogenase Enoyl-CoA hydratase 3-L-Hydroxyacyl-CoA dehydrogenase Thiolase The mechanism of thiolase Oxidation of unsaturated fatty acids Oxidation of unsaturated fatty acids Oxidation of odd-chain fatty acids The reaction of methylmalonyl-CoA mutase Coenzyme B12 Mechanism of methylmalonyl-CoA mutase Ketone bodies • In liver mitochondria, a significant fraction of acetyl-CoA is converted to ketone bodies (acetoacetate, acetone or D-β-hydroxybutyrate) • Metabolic fuels for many peripheral tissues including heart and skeletal muscle • Brain’s main fuel source during starvation Ketogenesis Conversion of ketone bodies to acetyl-CoA Differences between the fatty acid degradation and biosynthesis ACP vs CoA Transport of mitochondrial acetyl-CoA into the cytosol Acetyl-CoA carboxylase: Generation of malonyl-CoA The mechanism of C-C bond formation in fatty acid biosynthesis Biosynthesis of fatty acids Palmitate is the final product of fatty acid synthase Organization of fatty acid synthase An example of polyketide biosynthesis Longer chain saturated and unsaturated fatty acids • Palmitate, a saturated C16 fatty acid, is converted to longer chain saturated and unsaturated fatty acids by elongases and desaturases • Elongases are present in both mitochondria and the endoplasmic reticulum (but the mechanism of elongation differs) – Mitochondria: Condensation of acetyl-CoA with acyl-CoA (Reversal of β-oxidation; but NADPH is the final reductant instead of FADH2) – ER: Successive condensation of malonyl-CoA with acyl-CoA • Unsaturated fatty acids are produced by terminal desaturases Mitochondrial fatty acid elongation The reaction of terminal desaturases Essential fatty acids • Animal cannot make certain polyunsaturated fatty acids including linoleic acid (Δ9,12octadecadienoic acid), a required precursor of prostaglandin and other eicosanoids • These essential fatty acids must be obtained in the diet Synthesis of triacylglycerol Synthesis of phospholipids The cyclic and linear pathways of arachidonic acid metabolism The cyclic pathway of arachidonic acid metabolism Synthesis of prostaglandin precursors The reaction catalyzed by PGH synthase Leukotriene synthesis Summary of lipid metabolism Regulation of fatty acid oxidation • Epinephrine, norepinephrine and glucagon activate hormone-sensitive triacylglycerol lipase in adipose tissue by cAMP-dependent phosphorylation → Increase in the hydrolysis of triacylglycerols → High the blood fatty acid levels → Activation of β-oxidation in other tissues such as liver and muscle • Insulin has the opposite effects, stimulating formation of triacylglycerols Regulation of fatty acid biosynthesis • Short-term regulation – Acetyl-CoA carboxylase is inhibited by palmityl-CoA and by the glucagon-stimulated cAMP dependent phosphorylation – Acetyl-CoA carboxylase is activated by citrate and by insulin-stimulated dephosphorylation • Long-term regulation – Insulin stimulates the synthesis of acetyl-CoA carboxylase and fatty acid synthase – Starvation and polyunsaturated fatty acids decreases the concentration of these enzymes Regulation of fatty acid metabolism Cholesterol biosynthesis Acetate → isoprenoid intermediate → squalene → cyclized product → cholesterol Squalene Isoprene units Isoprenoid metabolism in mammalian cells Formation of isopentenyl pyrophosphate from HMG-CoA The reaction mechanism of pyrophosphomevalonate decarboxylase Formation of dimethylallyl pyrophosphate Formation of squalene Reaction mechanism of prenyl transferase Epoxidation and cyclization of squalene Oxidosqualene cyclase Conversion of lanosterol to cholesterol 19 steps Control of cholesterol biosynthesis and transport • Regulation of HMG-CoA reductase – Short term regulation: competitive inhibition, allosteric effectors and covalent modification – Long term regulation: modulation of the rates of synthesis and degradation • Regulation of LDL receptor synthesis (rate of cholesterol uptake) • Regulation of cholesterol esterification LDL receptor-mediated endocytosis Control of plasma LDL production and uptake Statins inhibit HMG-CoA reductase Biosynthesis of steroid hormones Bile acids ...
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