Regulation of acetyl-CoA carboxylase by guanine nucleotides.
Acetyl-CoA carboxylase, a major rate-limiting enzyme for fatty acid synthesis, is subject to acute regulation by both allosteric modulation and covalent enzyme phosphorylation. Because citrate activation of the enzyme in vitro requires citrate concentrations far in excess of intracellular levels, we have attempted to identify other ligands which might mediate carboxylase activity. Heated liver extracts contain a potent endogenous activator of carboxylase assayed in dialyzed high speed liver supernatant; the activator elutes behind the salt volume of a Bio-Gel P-6 gel filtration column, is destroyed by alkaline phosphatase, and is adsorbed by charcoal. This activator activity is shared by several guanine nucleotides (5'-GTP, 5'-GDP, 5'-GMP, and 3':5'-cyclic GMP). Further separation of the endogenous activator by high pressure liquid chromatography reveals a carboxylase-activating compound which co-elutes with 5'-GMP. The guanine nucleotides are potent activators of carboxylase activity at intracellular nucleotide concentrations and permit expression of maximal enzyme velocity at cytosolic citrate concentrations. However, we have been unable to document any effects of guanine nucleotides on isolated rat liver acetyl-CoA carboxylase. While the mechanisms of these effects remain to be elucidated, they suggest that the guanine nucleotides may be important intracellular regulators of carboxylase activity and of fatty acid synthesis.
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000818:Animals; D010450:Endopeptidases / Q000494:pharmacology; D004789:Enzyme Activation; D006150:Guanine Nucleotides / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D007700:Kinetics; D008025:Ligases / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D013329:Structure-Activity Relationship
D006150:Guanine Nucleotides; D006160:Guanosine Triphosphate; D010450:Endopeptidases; D008025:Ligases; D000103:Acetyl-CoA Carboxylase