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 β-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. 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 β-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. acetyl-CoA carboxylase AMP-activated protein kinase cAMP-dependent protein kinase 3-(N-morpholino)propanesulfonic acid high-performance liquid chromatography Acetyl-CoA carboxylase (ACC1; EC 6.4.1.2) catalyzes the ATP- and biotin-dependent formation of malonyl-CoA, an essential substrate for fatty-acid synthase and for fatty acyl chain elongation systems (1.Wakil S.J. Stoops J.K. Joshi V.C. Annu. Rev. Biochem. 1983; 52: 537-579Crossref PubMed Google Scholar, 2.Kim K.H. Annu. Rev. Nutr. 1997; 17: 77-99Crossref PubMed Scopus (314) Google Scholar, 3.Hardie D.G. Biochim. Biophys. Acta. 1992; 1094: 292-299Google Scholar, 4.Brownsey R.W. Zhande R. Boone A.N. Biochem. Soc. Trans. 1997; 25: 1232-1238Crossref PubMed Scopus (60) Google Scholar). 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ACC is activated following treatmentin vitro of fat or liver cells with insulin or by hyperinsulinemia in vivo and is rapidly deactivated when cells or tissues are exposed to catecholamines or glucagon (2.Kim K.H. Annu. Rev. Nutr. 1997; 17: 77-99Crossref PubMed Scopus (314) Google Scholar, 3.Hardie D.G. Biochim. Biophys. Acta. 1992; 1094: 292-299Google Scholar, 4.Brownsey R.W. Zhande R. Boone A.N. Biochem. Soc. Trans. 1997; 25: 1232-1238Crossref PubMed Scopus (60) Google Scholar, 20.Brownsey, R. W., and Denton, R. M. (1987) in The Enzymes (Boyer, P. D., and Krebs, E. G., eds) Volume XVIII, Part B, pp. 123–146, Academic Press, Inc., Orlando, FLGoogle Scholar,21.Brownsey R.W. Boone A.N. Jelveh K.A. Kulpa J.E. Zhande R. Can. J. Diabetes Care. 1999; 23: S7-S13Google Scholar). Similarly, malonyl-CoA levels rise in insulin-treated muscle and heart and are decreased by counter-regulatory hormones, exercise, or ischemic stress (6.Saha A.K. Kurowski T.G. Ruderman N.B. Am. J. 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We the glutamate sensitivity of rat liver ACC and that following of the enzyme from rat liver by and In the of citrate, glutamate induced activation of ACC, activity that was of the with The activity of ACC as well as the also by glutamate treatment by whereas the a for was not In agreement with the previous the effects of glutamate a within and the glutamate not of glutamate on properties of acetyl-CoA carboxylase from rat liver and white adipose to properties of a of glutamate of glutamate of glutamate of glutamate of glutamate of glutamate of glutamate of glutamate of microcystin LR of microcystin LR of glutamate of microcystin LR of glutamate of microcystin LR of microcystin LR of microcystin LR of glutamate of microcystin LR of microcystin LR of glutamate of microcystin LR of glutamate of microcystin LR of microcystin LR was purified by from liver or adipose tissue or from adipose tissue in the of to with the of glutamate citrate, and to and a as K.A. Denton R.M. Brownsey R.W. 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Two this is by of protein and with that was significant of ACC or of not was possible to purified preparations with PKA or AMPK to phosphorylation of serine or by not These serine residues are the amino and a of the of the of the ACC of purified ACC with PKA or AMPK in vitro evidence that the sensitivity to glutamate is by phosphorylation of hepatic ACC in the of AMPK the activation of the enzyme by glutamate, whereas the effects of PKA also although of ACC that been from adipose tissue or heart also diminished activation by glutamate following treatment with purified protein The effects of glutamate on adipose tissue ACC by AMPK and by PKA in ACC In a of rat heart ACC, AMPK the effects of glutamate by of adipose tissue in the of formation of phosphorylated of ACC R.W. Denton R.M. J. Biochem. J. 1977; PubMed Scopus Google Scholar, R.W. Denton R.M. Biochem. J. PubMed Scopus Google Scholar). This treatment ACC activation by glutamate or concentrations of citrate, when microcystin LR was and In the phosphorylation of ACC by adipose tissue with a β-adrenergic to a of glutamate sensitivity of the of protein is possible that of the effects of glutamate on highly purified ACC might be by phosphatase activity. This is glutamate is in purified ACC that is purified ACC preparations or phosphatase activity. purified ACC was phosphorylated with AMPK and of the was for to with The effects of allosteric and of in phosphorylation of ACC are by in activity and between inactive dimers and active We the effects of glutamate on the state of polymerization of ACC. from rat liver, ACC was with microcystin LR in the or of glutamate and to size-exclusion chromatography. that ACC that been dephosphorylated was as dimers and that with glutamate to and to a ACC preparations that not been to in the of polymerization induced by glutamate with dephosphorylated ACC. ACC from liver or adipose and in the and of highly ACC to with concentrations of of glutamate on acetyl-CoA carboxylase ACC ACC was to size-exclusion chromatography and the to in the or of glutamate preparations of ACC by or following The enzyme was purified to the phosphorylation state or to as The of ACC between and was on ACC in and as activity. in a ACC was to size-exclusion chromatography and the to in the or of glutamate preparations of ACC by or following The enzyme was purified to the phosphorylation state or to as The of ACC between and was on ACC in and as activity. The and activation of hepatic ACC by a type 2A protein phosphatase A. M. L. Eur. J. Biochem. 1993; PubMed Scopus Google Scholar, L. M. Biochem. J. 1996; 316: PubMed Scopus Google Scholar). We also that and activation following and that this is by both major ACC isoforms in from rat heart and white adipose tissue. of adipose tissue preparations in the of microcystin from liver, induced ACC activation glutamate was also and is a significant ACC phosphatase in from liver, not from adipose tissue. The that glutamate also activation of ACC isoforms by that glutamate directly as an allosteric activator of ACC, as activation of highly purified ACC is that The of and glutamate be of This that and glutamate might with residues on ACC. The that glutamate and have effects on ACC activity also sites mechanisms of The phosphorylation state of ACC a role in the sensitivity of the enzyme to glutamate as well as to and other allosteric The effects of phosphorylation on glutamate sensitivity are when purified ACC is with protein kinases or when the phosphorylation state is or decreased by intact tissue. AMPK the in glutamate sensitivity in the important role of this protein kinase as an allosteric activator (3.Hardie D.G. Biochim. Biophys. Acta. 1992; 1094: 292-299Google Scholar). The sensitivity to glutamate of ACC from liver and heart probably also reflects the actions of activated by and tissue direct effects of glutamate not in in with glucagon to of A. M. L. Eur. J. Biochem. 1993; PubMed Scopus Google Scholar, L. M. Biochem. J. 1996; 316: PubMed Scopus Google Scholar). is that the of direct glutamate in was the of ACC phosphorylation induced in by the previous and a of of glutamate on ACC may a of ACC that is also to direct activation by This is of the of of on AMPK and on the AMPK kinase and of on kinase and its kinase kinase (3.Hardie D.G. Biochim. Biophys. Acta. 1992; 1094: 292-299Google Scholar, M.A. D. Hardie D.G. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). systems that display such and control also that provide to in ligand D.G. Davies S.P. 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