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.
Organ Systems
immune-hematologic
nervous
Pathway Steps
3-phosphoglycerate (3-PG, glycolysis) → 3-phosphohydroxypyruvate — via PHGDH (phosphoglycerate dehydrogenase) — RATE-LIMITING; oncology drug target. PHGDH diverts the glycolytic intermediate 3-phosphoglycerate into serine synthesis and is rate-limiting; it is amplified in several cancers (breast, melanoma), an oncology target because tumors lean on serine/one-carbon flux for nucleotides and methylation.
3-phosphohydroxypyruvate + glutamate → 3-phosphoserine + α-KG — via PSAT1 (phosphoserine aminotransferase). PSAT1 transaminates using glutamate, coupling serine synthesis to nitrogen and α-ketoglutarate balance — a route by which proliferating cells also generate one-carbon units and NADPH.
3-phosphoserine → serine — via PSPH (phosphoserine phosphatase). Phosphoserine phosphatase completes de-novo serine synthesis. Serine is both proteinogenic and the principal donor of one-carbon units (via SHMT) for thymidylate, purines, and methylation, so its supply gates nucleotide synthesis.
serine + THF → glycine + N5,N10-methylene-THF — via SHMT1/2 — donates 1-carbon unit; cytosolic + mitochondrial isoforms. Serine hydroxymethyltransferase is the major one-carbon source, making 5,10-methylene-THF and glycine. Cytosolic SHMT1 and mitochondrial SHMT2 compartmentalize one-carbon flux, with SHMT2 frequently upregulated in tumors.
glycine + THF → CO₂ + NH₃ + N5,N10-methylene-THF — via glycine cleavage system (GCS, mitochondrial) — parallel 1-carbon source. The mitochondrial glycine cleavage system is a second one-carbon source, degrading glycine into the folate pool. Its defect causes nonketotic hyperglycinemia; with SHMT it balances serine/glycine and one-carbon supply.
methylene-THF + dUMP → dTMP + DHF — via thymidylate synthase — pyrimidine synthesis. Thymidylate synthase uses 5,10-methylene-THF to make dTMP for DNA, oxidizing folate to DHF (which DHFR must re-reduce) — the node hit by 5-fluorouracil, and indirectly by antifolates that starve it of reduced folate.
methylene-THF → methyl-THF (for SAM regeneration) — via MTHFR — methionine cycle remethylation arm. MTHFR irreversibly commits one-carbon units to the remethylation arm (homocysteine → methionine → SAM), trading nucleotide-synthesis folate for methylation capacity — the branch point shifted by the common C677T variant.
Known Modulators
serine (substrate) — direct serine supplementation — bypasses PHGDH/PSAT1/PSPH
glycine (substrate) — glycine pool — major sink for one-carbon units; also GSH precursor
methylfolate (cofactor) — active folate downstream of methylene-THF
folic acid (cofactor) — folate substrate — reduced to DHF → THF by DHFR