Dolicholphosphatemannose

Dolicholphosphatemannose, commonly known as dolichol phosphate mannose (Dol-P-Man), is a lipid-linked sugar donor that plays a critical role in the early stages of eukaryotic protein and lipid glycosylation. It consists of a long-chain polyisoprenoid dolichol molecule linked by a phosphate group to a single mannose residue. Dol-P-Man serves as the mannose donor for the assembly of the dolichol-linked oligosaccharide used in N-linked glycosylation and for the initiation of glycosylphosphatidylinositol (GPI) anchor synthesis in the endoplasmic reticulum.

Biosynthesis and metabolism: Dol-P-Man is synthesized in the endoplasmic reticulum by the dolichol phosphate mannose synthase (DPMS) complex, which in humans comprises DPM1, DPM2, and DPM3 subunits. The enzyme transfers a mannose moiety from GDP-mannose to dolichol phosphate, yielding Dol-P-Man and GDP. The Dol-P-Man produced is then utilized by ER-resident mannosyltransferases to build the core dolichol-linked oligosaccharide destined for transfer to nascent polypeptides, and to contribute mannose residues to GPI anchor precursors. The cellular pool of Dol-P-Man is maintained by the coordinated regulation of synthesis and turnover; impaired DPMS activity reduces N-linked glycosylation efficiency and can affect glycoprotein maturation.

Clinical and biological significance: Because Dol-P-Man is essential for proper N-glycosylation, defects in the DPMS pathway or in Dol-P-Man synthesis can contribute to congenital disorders of glycosylation (CDG). Patients with CDG may exhibit developmental delay, hypotonia, growth failure, and multi-systemic abnormalities. Dol-P-Man biosynthesis is conserved across eukaryotes and remains a focus of glycosylation biology and ER quality-control studies.