PHGDH

PHGDH is human D-3-phosphoglycerate dehydrogenase (3-PGDH; EC 1.1.1.95), an NAD+-dependent oxidoreductase of the D-isomer-specific 2-hydroxyacid dehydrogenase family that assembles as a homotetramer and acts in the cytosol. It catalyzes the first and rate-limiting step of the phosphorylated pathway of de novo L-serine biosynthesis, oxidizing the glycolytic intermediate 3-phospho-D-glycerate to 3-phosphonooxypyruvate (3-phosphohydroxypyruvate) with reduction of NAD+ to NADH. Serine produced by this pathway supplies one-carbon units, nucleotides, glycine, phospholipids and redox cofactors. Human PHGDH additionally displays secondary NAD+-dependent 2-hydroxyacid dehydrogenase side-activities, most notably reduction of 2-oxoglutarate to the oncometabolite D-2-hydroxyglutarate, and in vitro malate dehydrogenase activity. Biallelic loss-of-function variants cause the serine-deficiency disorders phosphoglycerate dehydrogenase deficiency (congenital microcephaly, psychomotor retardation, seizures) and the more severe Neu-Laxova syndrome 1, while PHGDH amplification/overexpression drives serine biosynthesis in a subset of cancers. Two enzyme-independent moonlighting activities have additionally been reported in Alzheimer's-disease models: a nuclear, chromatin-associated transcriptional-regulator role acting through a predicted DNA-binding helix-helix-turn-helix subdomain, and, separately, an RNA-binding activity that binds the EIF2AK1 3'UTR and promotes BACE1 translation. Both are stated to be independent of catalysis, the second also independent of the first; both come from a single laboratory and neither has been independently replicated.

Disorders

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