P642
“Fatty acids are derived from triglyceride metabolism by lipases and transported across membranes into cells. Fatty acyl-CoA, synthesized from a fatty acid and Coenzyme A molecule by fatty acyl-CoA synthetases at the expense of one ATP molecule, can be further metabolized through beta oxidation (occurring at second carbon of the chain) or converted to other lipid metabolites. Fatty acyl-CoA are transesterified with carnitine and transported across inner mitochondrial membrane by carnitine acyl transferase I and II proteins, where carnitine is removed to regenerate acyl-CoA. In the mitochondrial matrix they are converted, as shown below, to acetyl-CoA through a cycle consisting of oxidation, hydration, oxidation and thiolytic cleavage.
Acetyl-CoA that is synthesized in mitochondria feeds into the Krebs cycle and are utilized for energy. Since two carbon moieties are removed during this process, odd-numbered fatty acids form propionyl-CoA, which is later converted to the Krebs cycle intermediate succinyl-CoA through the intermediate stage of methylmalonyl-CoA. Unsaturated fatty acids require function of additional two enzymes, Enoyl CoA isomerase or 2,4 Dienoyl CoA reductase, for complete beta-oxidation to occur. Fatty acids longer than 22 carbon atoms are initially processed by beta oxidation in peroxysomes and then transferred to mitochondria.
Beta oxidation is a highly regulated process. All the enzymes in the pathway are regulated by their products as we all as by NADH/NAD+ and acetyl-CoA/CoA ratio. Different proteins functioning in the beta oxidation pathway are regulated transcriptionally by peroxisome proliferator-activated receptors (PPARs) and the coactivator PGC-1α. AMPK, the energy-sensing kinase in cells indirectly regulates PGC-1α function as well as expression, and is a major regulator of beta oxidation in cells.”
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