page_title: Phosphoglycerate dehydrogenase
section_title: Structure
hierarchical_section_title: Phosphoglycerate dehydrogenase / Structure
caption_attribution_description: English: Crystal structure of inhibited PHGDH from "M. tuberculosis" due to allosterically bound serine. From on 3DC2 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 is a tetramer, composed of four identical, asymmetric subunits. At any time, only a maximum of two adjacent subunits present a catalytically active site; the other two are forced into an inactive conformation. This results in half-of-the-sites activity with regard to both active and allosteric sites, meaning that only the two sites of the active subunits must be bound for essentially maximal effect with regard to catalysis and inhibition respectively. There is some evidence that further inhibition occurs with the binding of the third and fourth serine molecules, but it is relatively minimal.
  The subunits from the E. coli PHGDH have three distinct domains, whereas those from M. tuberculosis have four. It is noted that the human enzyme more closely resembles that of M. tuberculosis, including the site for allosteric substrate inhibition. Concretely, three general types of PHGDH have been proposed: Type I, II, and III. Type III has two distinct domains, lacks both allosteric sites, and is found in various unicellular organisms. Type II has serine binding sites and encompasses the well-studied E. coli PHGDH. Type I possesses both the serine and substrate allosteric binding sites and encompasses M. tuberculosis and mammalian PHGDHs.
  The regulation of catalytic activity is thought to be a result of the movement of rigid domains about flexible “hinges.” When the substrate binds to the open active site, the hinge rotates and closes the cleft. Allosteric inhibition thus likely works by locking the hinge in a state that produces the open active site cleft.
  The variant from M. tuberculosis also exhibits an uncommon dual pH optimum for catalytic activity.
caption: Crystal structure of inhibited PHGDH from M. tuberculosis due to allosterically bound serine. From 3DC2 rendering.
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