Category: biosynthesis
Distinct from glycine_serine_threonine_metabolism (catabolic + interconversion overview). This pathway covers the de novo serine biosynthesis branch — its connection to the folate one-carbon pool, and its outsized importance in proliferating cells (cancer biology). Step 1: 3-phosphoglycerate (3-PG, glycolysis intermediate) → 3-phosphohydroxypyruvate via PHGDH (phosphoglycerate dehydrogenase — rate-limiting; oncology drug target with multiple PHGDH inhibitors in trials). Step 2: 3-PHP → 3-phosphoserine via PSAT1 (phosphoserine aminotransferase; transfers amino group from glutamate). Step 3: 3-phosphoserine → serine via PSPH (phosphoserine phosphatase). Step 4: serine → glycine via SHMT1/2 (serine hydroxymethyltransferase) — donates a methylene unit to tetrahydrofolate → N5,N10-methylene-THF (the major source of one-carbon units for thymidylate synthesis, purine synthesis, and methylation reactions). Step 5: glycine cleavage system (GCS, mitochondrial) further oxidizes glycine → CO₂ + NH₃ + another methylene-THF — parallel one-carbon source. Therapeutic significance: tumors with PHGDH amplification (estrogen-receptor-negative breast cancer, melanoma) are auxotrophic for serine via this de novo pathway — dietary serine + glycine restriction has clinical anti-tumor data; PHGDH inhibitors (NCT-503, WQ-2101) are in oncology development. Methotrexate (DHFR inhibitor) blocks regeneration of THF from DHF, depleting the entire one-carbon pool downstream of this pathway. Cross-links: [[glycine_serine_threonine_metabolism]], [[folate_one_carbon]], [[methionine_sam_cycle]] (SAM cycle methyl donor depends on this one-carbon pool), [[purine_de_novo_synthesis]], [[pyrimidine_metabolism]].