PHGDH

PHGDH, short for phosphoglycerate dehydrogenase, is a cytosolic enzyme that catalyzes the first and rate-limiting step of the phosphorylated serine biosynthesis pathway. It oxidizes 3-phosphoglycerate to 3-phosphohydroxypyruvate with the concomitant reduction of NAD+ to NADH. This reaction links glycolysis to the production of serine, a non-essential amino acid used for protein synthesis and as a precursor for one-carbon metabolism.

In many organisms, including humans, PHGDH supplies the carbon backbone for de novo serine synthesis, which feeds into the folate cycle to support nucleotide biosynthesis and methylation reactions. Serine can be converted to glycine or channeled into broader metabolic pathways, making PHGDH activity important for cell growth and proliferation, especially under conditions where serine availability limits metabolism.

PHGDH is expressed across a variety of tissues, with relatively high levels in developing brain and other metabolic tissues. Its activity is regulated by cellular serine levels and metabolic state, and disruptions in PHGDH function can alter serine availability and downstream pathways such as one-carbon metabolism and nucleotide synthesis.

Mutations in the PHGDH gene cause congenital serine deficiency disorders, which can present with neurological abnormalities, microcephaly, and developmental delay; some patients show improvement with serine supplementation. In cancer biology, PHGDH amplification or overexpression has been observed in several tumor types, promoting de novo serine synthesis to support rapid cell growth. As a result, PHGDH is investigated as a potential therapeutic target, with various inhibitors studied in preclinical models.