Dolichol / dolichyl-phosphate biosynthesis (cis-PT -> DOLPP1 -> SRD5A3 -> DOLK)

Dolichyl phosphate (Dol-P) is the essential polyprenol lipid carrier on which the eukaryotic glycosylation machinery assembles and delivers glycans: it anchors the lipid-linked oligosaccharide for N-linked glycosylation, the mannose/glucose donors (Dol-P-Man, Dol-P-Glc) for N-glycan, O-mannose, GPI-anchor and C/O-mannosylation, and it is regenerated after each transfer cycle. Its biosynthesis begins where the isoprenoid-diphosphate trunk ends: the ER-membrane cis-prenyltransferase (cis-PT) complex — catalytic subunit DHDDS plus the non-catalytic partner NUS1 (NgBR) — elongates (2E,6E)-farnesyl diphosphate (FPP) by many cis (Z)-condensations of isopentenyl diphosphate (IPP) to the long-chain dehydrodolichyl diphosphate (dehydro-Dol-PP). This polyprenyl diphosphate is dephosphorylated by the dolichyl-diphosphate phosphatase DOLPP1 (which also recycles the Dol-PP released after oligosaccharyltransferase moves the glycan onto protein), and the alpha-terminal isoprene unit is saturated by the polyprenol reductase SRD5A3 to give dolichol. Dolichol kinase DOLK then phosphorylates dolichol (CTP-dependent) to Dol-P, completing the carrier pool. All five enzymes reside in the endoplasmic reticulum membrane. Defects across this module cause congenital disorders of glycosylation (DHDDS-CDG/RP59, NUS1-CDG/epileptic encephalopathy, SRD5A3-CDG, DOLK-CDG) and inherited retinal dystrophy.