page_title: Phosphoglycerate dehydrogenase
section_title: Mechanism and regulation
hierarchical_section_title: Phosphoglycerate dehydrogenase / Mechanism and regulation
caption_attribution_description: English: active site and key catalytic residues of E. coli 3-phosphoglycerate dehydrogenase based on 2g76 rendering
context_page_description: In enzymology, D-3-phosphoglycerate dehydrogenase is an enzyme that primarily catalyzes the chemical reactions
  3-phospho-D-glycerate + NAD⁺ 3-phosphonooxypyruvate + NADH + H⁺
  2-hydroxyglutarate + NAD⁺ 2-oxoglutarate + NADH + H⁺
  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.
context_section_description: 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.
  Although L-serine's allosteric effects are usually the focus of regulatory investigation, it has been noted that in some variants of the enzyme, 3-phosphoglycerate dehydrogenase is inhibited at separate positively charged allosteric site by high concentrations of its own substrate.
caption: Active site of human PHGDH. Key residues (two Arg and one His) and substrates shown. The 4.2 Å distance is between the carbons undergoing hydride transfer. From 2G76 rendering of PHGDH crystallized with NAD+ and D-malate.
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