De novo serine biosynthesis and serine/glycine one-carbon unit generation (PHGDH/PSAT1/PSPH + SHMT1/SHMT2)

De novo L-serine biosynthesis and its immediate use as a one-carbon donor form a central node of intermediary metabolism, supplying the building blocks and methyl groups for nucleotide synthesis, methylation and redox balance — a pathway on which proliferating and neural cells especially depend. Serine is made from the glycolytic intermediate 3-phospho-D-glycerate by the "phosphorylated pathway": PHGDH (D-3-phosphoglycerate dehydrogenase) oxidises 3-phosphoglycerate to 3-phosphonooxypyruvate using NAD+; PSAT1 (phosphoserine aminotransferase, PLP-dependent) transaminates it with glutamate to O-phospho-L-serine; and PSPH (phosphoserine phosphatase, Mg2+-dependent) hydrolyses the phosphate to release L-serine, the committed final step. The newly made serine then feeds one-carbon (folate) metabolism through serine hydroxymethyltransferase, which reversibly transfers a one-carbon unit from serine to tetrahydrofolate, producing glycine and 5,10-methylenetetrahydrofolate. Humans have two SHMT isozymes running this reaction in parallel compartments: cytosolic SHMT1 (supplying one-carbon units for cytosolic thymidylate/purine synthesis and the methylation cycle, with a nuclear role in the thymidylate-synthesis complex) and mitochondrial SHMT2 (the principal entry to mitochondrial one-carbon metabolism, exporting formate/one-carbon units to the cytosol and supplying glycine). Inherited defects cause serine deficiency: PHGDH — Neu-Laxova syndrome 1 / serine-deficiency with microcephaly and seizures; PSAT1 — Neu-Laxova syndrome 2; PSPH — phosphoserine phosphatase deficiency.