CDP-diacylglycerol pathway of phospholipid synthesis (PS, PE, PC by methylation, PI, PG and cardiolipin)

In the CDP-diacylglycerol (CDP-DAG) pathway, phosphatidic acid is activated with CTP to the liponucleotide CDP-DAG, which then donates its phosphatidyl group to a polar head-group acceptor, releasing CMP. Different CDP-alcohol phosphatidyltransferases use serine (phosphatidylserine synthase), myo-inositol (phosphatidylinositol synthase) and glycerol-3-phosphate (phosphatidylglycerophosphate synthase). In the aminophospholipid branch, phosphatidylserine (PS) is decarboxylated to phosphatidylethanolamine (PE) by pyruvoyl-dependent PS decarboxylases, and PE is converted to phosphatidylcholine (PC) by three successive S-adenosylmethionine-dependent N-methylations, performed by two enzymes in fungi or by a single PEMT enzyme in animals. In the mitochondrial branch, phosphatidylglycerophosphate is dephosphorylated to phosphatidylglycerol (PG), which is condensed with a second CDP-DAG by a eukaryotic CDP-alcohol phosphotransferase-type cardiolipin synthase to form cardiolipin. The pathway is distributed between compartments: CDP-DAG for PS and PI is made in the endoplasmic reticulum, whereas cardiolipin synthesis uses CDP-DAG made in the mitochondrial inner membrane by a distinct, Tam41-type CDP-DAG synthase; the major PS decarboxylase acts in the mitochondrial inner membrane and a second one in the endomembrane system, so PS and PE must move between the ER and mitochondria. In fungi this route makes PE and PC when ethanolamine and choline are not supplied, whereas the Kennedy pathway makes them from those precursors.

NEW (YeastPathways project, 2026-10). Scope: the eukaryotic CDP-DAG route, grounded in S. cerevisiae and S. pombe. The crosswalk scope also names bacteria; bacterial PS/PE and PG/CL synthesis are kept in their own modules (bacterial_phosphatidylethanolamine_biosynthesis, bacterial_phosphatidylglycerol_cardiolipin_biosynthesis) because the bacterial enzymes for the PS-synthase and cardiolipin-synthase steps belong to different families (the cardiolipin synthase of E. coli is a phospholipase D-type enzyme that condenses two PG molecules, whereas the eukaryotic enzyme uses CDP-DAG + PG) and because the eukaryotic route is compartmentalised. Mammals make PS by base exchange rather than with a CDP-DAG-dependent PS synthase, so the PS-synthase step is fungal (and plant/protist) here; the PI, PG and CL steps are shared with animals. Structure: CDP-DAG synthesis is a ONE_OR_MORE compartment variant set (ER CDS1-type for PS and PI; mitochondrial Tam41-type for PG/CL); PS decarboxylation is a ONE_OR_MORE compartment variant set (mitochondrial PSD1-type; endomembrane PSD2-type); PE methylation is an EXACTLY_ONE architecture variant set (fungal CHO2 then OPI3; animal PEMT). OPI3 and PEMT are in the same PANTHER family (PTHR15458), whereas CHO2 is unrelated (PTHR32138). PC made by the Kennedy pathway and PE methylation of Kennedy-derived PE are covered in kennedy_pathway_phospholipid_synthesis, which repeats the methylation step as its crosslink. YeastCyc corrections: GEP4 (P38812) added as the PGP phosphatase (PGPPHOSPHA-RXN has no gene in YeastCyc; PMID:20485265); TAM41 (P53230) added as the mitochondrial CDP-DAG synthase (PMID:23623749); CDS1 is ER-only. Compartments: the YeastPathways models place all activities in cytosol except PHOS-PWY, which puts PGS1, CRD1 and one PSD1 activity in mitochondrion; in yeast CHO1, PIS1, CHO2 and OPI3 are ER enzymes, PSD1 is in the mitochondrial inner membrane, PSD2 is Golgi/vacuole-associated, and PGS1, GEP4, CRD1 and Tam41 are mitochondrial (PMID:22345606, PMID:23623749, PMID:20485265). GO-CAM disagreements: (a) YeastPathways models give OPI3 the root MF GO:0003674 for RXN4FS-2 and its siblings in PWY3O-2 and PHOS-PWY; (b) no YeastPathways model has a PGP phosphatase gene; (c) the PomBase model 6796b94c00000009 places S. pombe psd2 in the ER membrane, whereas UniProt (Q9UTB5) annotates it as a mitochondrial proenzyme and PANTHER puts it in its own subfamily (PTHR10067:SF19); psd2 is therefore not used as an exemplar here until its compartment is resolved; the same model also contains CTP synthesis, ERMES PA transfer, scramblase, ale1, pld1 and the Kennedy enzymes, which are context or other modules; (d) PomBase model 67086be200000363 places tam41 and pgs1 in the mitochondrial matrix and includes pgc1 PG phospholipase C and unidentified lipid-transfer activities (turnover and transport, outside this module).