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2-Hydroxyglutarate production is necessary for the reaction catalyzed by 3-phosphoglycerate dehydrogenase in Escherichia coli

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Abstract

Phosphoglycerate dehydrogenase (PGDH, EC 1.1.1.95) catalyzes the NAD+-dependent oxidation of D-3-phosphoglycerate (PG), an intermediate of glycolysis, into 3-phosphohydroxypyruvate (PHP), an intermediate of the serine biosynthetic pathway. The equilibrium of the reaction catalyzed by PGDH is strongly directed towards its substrate, PG. PGDH from Escherichia coli possesses the ability to reduce 2-ketoglutarate (KG) into two isomeric forms of 2-hydroxyglutaric acid (HG). The reductase activity of PGDH is considered “unphysiological”. E. coli PGDH has a very high affinity to NADH (Km = 10 nM) and, after binding NADH, undergoes a conformational change that results in the tight binding of NADH. The order of substrate binding in the reverse reaction is: NADH is the first to bind to the enzyme. Given these findings as well as the known concentrations of substrates in the E. coli pool and the Km’s, we propose that the E-NADH enzyme complex preferably binds KG. It prevents binding of PHP and inhibits the reverse reaction. E. coli PGDH catalyzes two consecutive reactions: E-NADH + KG = E-NAD+ + HG and E-NAD+ + PG = E-NADH + PHP. Oxidation of PG occurs at the expense of KG reduction, resulting in the production of HG, which is a necessary product of the PGDH reaction in E. coli. Over-production of HG has been found in human tumor cells and was thought to be caused by mutant forms of isocitrate dehydrogenase (IDH1/2) gained a new ability to reduce KG to HG (D-2-HG). There is contradictory evidence supporting HG production without the mutations in IDH in several tumors and vice versa. A potential role of human PGDH in HG production is discussed. The role of mutant IDH’s may not be in the production of HG but in the consumption of HG produced by other enzymes.

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  1. Closed Joint-Stock Company Ajinomoto-Genetika Research Institute, 1st Dorozhny proezd, 1-1, Moscow, 117545, Russia

    M. M. Gusyatiner & M. Kh. Ziyatdinov

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  1. M. M. Gusyatiner
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Correspondence to M. M. Gusyatiner.

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Original Russian Text © M.M. Gusyatiner, M.Kh. Ziyatdinov, 2015, published in Obzornyi Zhurnal po Khimii, 2015, Vol. 5, No. 1, pp. 25–35.

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Gusyatiner, M.M., Ziyatdinov, M.K. 2-Hydroxyglutarate production is necessary for the reaction catalyzed by 3-phosphoglycerate dehydrogenase in Escherichia coli . Ref. J. Chem. 5, 21–29 (2015). https://doi.org/10.1134/S2079978015010021

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  • DOI: https://doi.org/10.1134/S2079978015010021

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