D-3-phosphoglycerate dehydrogenase

D-3-phosphoglycerate dehydrogenase (PHGDH, UniProt: O43175) is a 533-amino acid enzyme that catalyzes the first committed step of the phosphorylated L-serine biosynthesis pathway, converting 3-phospho-D-glycerate to 3-phosphonooxypyruvate. It also oxidizes 2-hydroxyglutarate and (S)-malate in related metabolic reactions. PHGDH is a cytosolic oxidoreductase critical for amino acid biosynthesis and cellular redox balance.

PHGDH mutations cause two rare neurological disorders: phosphoglycerate dehydrogenase deficiency (PHGDHD, MIM 601815), characterized by microcephaly, psychomotor retardation, and seizures, and Neu-Laxova syndrome 1 (NLS1, MIM 256520), a lethal autosomal recessive malformation syndrome affecting the central nervous system and multiple organ systems (UniProt: O43175). These genetic associations highlight the importance of PHGDH in neurodevelopment.

PHGDH is upregulated in Alzheimer's disease brain tissue compared to age-matched controls (Chaparral AD proteomics; mean log₂FC: 0.72 across two subcellular fractions). This elevation was detected in a human post-mortem AD proteomics study using TMT-labeled, data-dependent acquisition mass spectrometry across four subcellular fractions, suggesting involvement of serine metabolism or redox homeostasis in AD pathology.