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. Structure 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. Evolution 3-Phosphoglycerate dehydrogenase possesses less than 20% homology to other NAD-dependent oxidoreductases and exhibits significant variance between species. There does appear to be conservation in specific binding domain residues, but there is still some variation in the positively charged active site residues between variants. For example, Type III PHGDH enzymes can be broken down into two subclasses where the key histidine residue is replaced with a lysine residue. Disease relevance Homozygous or compound heterozygous mutations in 3-phosphoglycerate dehydrogenase cause Neu–Laxova syndrome and phosphoglycerate dehydrogenase deficiency. In addition significantly shortening lifespan, PHGDH