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.

中文翻译：

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3-磷酸​​甘油酸脱氢酶在大肠杆菌中催化反应所必需的2-羟基戊二酸的产生

磷酸甘油酸脱氢酶（PGDH，EC 1.1.1.95）催化NAD ⁺D-3-磷酸甘油酸酯（PG）的依赖依赖性氧化，转化为3-磷酸羟基丙酮酸（PHP），丝氨酸生物合成途径的中间体。PGD​​H催化的反应平衡强烈地指向其底物PG。大肠杆菌的PGDH具有将2-酮戊二酸（KG）还原为两种异构形式的2-羟基戊二酸（HG）的能力。PGD​​H的还原酶活性被认为是“不生理的”。大肠杆菌PGDH对NADH的亲和力非常高（Km = 10 nM），并且在结合NADH后会发生构象变化，从而导致NADH紧密结合。逆向反应中底物结合的顺序为：NADH是第一个与酶结合的物质。鉴于这些发现以及已知的E. coli池和Km's中底物的浓度，我们提出E-NADH酶复合物优选结合KG。它防止PHP绑定并抑制逆反应。大肠杆菌PGDH催化两个连续的反应：E-NADH + KG = E-NAD⁺ + HG和E-NAD ⁺ + PG = E-NADH + PHP。PG的氧化以KG的减少为代价，导致HG的产生，HG是大肠杆菌中PGDH反应的必要产物。在人类肿瘤细胞中发现了过量产生的HG，并且认为它是由异柠檬酸脱氢酶（IDH1 / 2）的突变形式引起的，获得了将KG还原为HG（D-2-HG）的新能力。有相反的证据支持在某些肿瘤中HG的产生没有IDH突变，反之亦然。讨论了人类PGDH在HG生产中的潜在作用。突变IDH的作用可能不是在HG的产生中，而是在其他酶产生的HG的消耗中。