Phosphoglycerate dehydrogenase

2G7626227236539ENSG00000092621ENSMUSG00000053398O43175Q61753NM_006623NM_016966NP_006614NP_058662In enzymology, D-3-phosphoglycerate dehydrogenase (PHGDH) (EC 1.1.1.95) is an enzyme that primarily catalyzes the chemical reactions2g76: Crystal structure of human 3-phosphoglycerate dehydrogenase In enzymology, D-3-phosphoglycerate dehydrogenase (PHGDH) (EC 1.1.1.95) is an enzyme that primarily catalyzes the chemical reactions Thus, in the first case, the two substrates of this enzyme are 3-phospho-D-glycerate and NAD+, whereas its 3 products are 3-phosphohydroxypyruvate, NADH, and H+; in the second case, the two substrates of this enzyme are 2-hydroxyglutarate and NAD+, whereas its 3 products are 2-oxoglutarate, NADH, and H+. This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The most widely studied variants of PHGDH are from the E. coli and M. tuberculosis genomes. In humans, this enzyme is encoded by the PHGDH gene. 3-Phosphoglycerate dehydrogenase catalyzes the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the committed step in the phosphorylated pathway of L-serine biosynthesis. It is also essential in cysteine and glycine synthesis, which lie further downstream. This pathway represents the only way to synthesize serine in most organisms except plants, which uniquely possess multiple synthetic pathways. Nonetheless, the phosphorylated pathway that PHGDH participates in is still suspected to have an essential role in serine synthesis used in the developmental signaling of plants. Because of serine and glycine’s role as neurotrophic factors in the developing brain, PHGDH has been shown to have high expression in glial and astrocyte cells during neural development. 3-phosphoglycerate dehydrogenase works via an induced fit mechanism to catalyze the transfer of a hydride from the substrate to NAD+, a required cofactor. In its active conformation, the enzyme’s active site has multiple cationic residues that likely stabilize the transition state of the reaction between the negatively charged substrate and NAD+. The positioning is such that the substrate’s alpha carbon and the C4 of the nicotinamide ring are brought into a proximity that facilitates the hydride transfer producing NADH and the oxidized substrate. PHGDH is allosterically regulated by its downstream product, L-serine. This feedback inhibition is understandable considering that 3-phosphoglycerate is an intermediate in the glycolytic pathway. Given that PHGDH represents the committed step in the production of serine in the cell, flux through the pathway must be carefully controlled. L-serine binding has been shown to exhibit cooperative behavior. Mutants that decreased this cooperativity also increased in sensitivity to serine’s allosteric inhibition, suggesting a separation of the chemical mechanisms that result in allosteric binding cooperativity and active site inhibition. The mechanism of inhibition is Vmax type, indicating that serine affects the reaction rate rather than the binding affinity of the active site.