Bimodal activation of acetyl-CoA carboxylase by glutamate.
Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, an essential substrate for fatty acid biosynthesis and a potent inhibitor of fatty acid oxidation. Here, we provide evidence that glutamate may be a physiologically relevant activator of ACC. Glutamate induced the activation of both major isoforms of ACC, prepared from rat liver, heart, or white adipose tissue. In agreement with previous studies, a type 2A protein phosphatase contributed to the effects of glutamate on ACC. However, the protein phosphatase inhibitor microcystin LR did not abolish the effects of glutamate on ACC activity. Moreover, glutamate directly activated purified preparations of ACC when protein phosphatase activity was excluded. Phosphatase-independent ACC activation by glutamate was also reflected by polymerization of the enzyme as judged by size-exclusion chromatography. The sensitivity of ACC to direct activation by glutamate was diminished by treatment in vitro with AMP-activated protein kinase or cAMP-dependent protein kinase or by beta-adrenergic stimulation of intact adipose tissue. We conclude that glutamate, an abundant intracellular amino acid, induces ACC activation through complementary actions as a phosphatase activator and as a direct allosteric ligand for dephosphorylated ACC. This study supports the general hypothesis that amino acids fulfill important roles as signal molecules as well as intermediates in carbon and nitrogen metabolism.
Boone
A N
AN
Department of Biochemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Chan
A
A
Kulpa
J E
JE
Brownsey
R W
RW
D000103:Acetyl-CoA Carboxylase / Q000187:drug effects* / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D004789:Enzyme Activation; D018698:Glutamic Acid / Q000494:pharmacology*; D007527:Isoenzymes / Q000187:drug effects; D008099:Liver / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000201:enzymology; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010766:Phosphorylation; D011108:Polymers / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D007527:Isoenzymes; D011108:Polymers; D018698:Glutamic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D000103:Acetyl-CoA Carboxylase