Functions

DPM1 forms a complex with DPM2 and DPM3 [1] [2] (DPM synthase) which produces the Dol-P-Man which is the mannose donor in the N-glycan pathway.

In the N-glycan biosynthesis pathway, a sugar composed of 9 mannoses and other 5 sugars is assembled in 14 consecutive reactions, each one catalyzed by a different enzyme, and divided in two parts.

In the first part, the N-glycan precursor is synthetized on the ER membrane but in the cytosol; while in the second part, the sugar is flipped in the ER lumen and assembled there.

The function of the DPM1 complex is to provide the Dol-P-Man necessary for the Man addition reactions in the second part of the biosynthesis ; without Dol-P-Man, glycosilation can't occur, because it is impossible to add the mannoses necessary to complete the N-glycan precursor.

Functions (from Uniprot)

Transfers mannose from GDP-mannose to dolichol monophosphate to form dolichol phosphate mannose (Dol-P-Man) which is the mannosyl donor in pathways leading to N-glycosylation, glycosyl phosphatidylinositol membrane anchoring, and O-mannosylation of proteins.

Disease relevance of DPM1

• Here we show that a gene encoding the homologue to dolichol-phosphate-mannose synthase is also essential for phage sensitivity [3].

High impact information on DPM1

• Furthermore, mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblast cells, thus precluding a possible therapeutic application of mannose in the patients [4].
• DPM1, the gene coding for the catalytic subunit of Dol-P-Man synthase, was altered in both patients [5].
• Here, we report that GPI-GnT requires another component, termed PIG-P, and that DPM2, which regulates dolichol-phosphate-mannose synthase, also regulates GPI-GnT [6].
• We provide evidence that L.mexicana dolichol-phosphate-mannose synthase (DPMS), a key enzyme in GPI biosynthesis, is localized to a distinct tubular subdomain of the endoplasmic reticulum (ER), based on the localization of a green fluorescent protein (GFP)-DPMS chimera and subcellular fractionation experiments [7].
• DPMS catalyzes the formation of dolichol-phosphate mannose, the sugar donor for all mannose additions in the biosynthesis of both the anchor and free GPIs, except for a alpha1-3-linked mannose residue that is added exclusively to the free GPIs and lipophosphoglycan anchor precursors [8].

Biological context of DPM1

• A coiled-coil domain near the C terminus of DPM3 was important for tethering DPM1, the catalytic subunit of the enzyme, to the endoplasmic reticulum membrane and, therefore, was critical for enzyme activity [9].
• Moreover, DPM1 expression was reduced by more than 90% in MS cells, in a nonsense-mediated mRNA decay (NMD)-independent manner [10].
• Defects in DPM1 define a new glycosylation disorder, CDG-Ie [5].
• Neither did a chimeric cDNA containing the complete hamster DPM1 open reading frame fused to the Saccharomyces cerevisiae DPM1 C-terminal transmembrane domain [11].
• To investigate whether the anchor or free GPIs are required for parasite growth we cloned the L.mexicana gene for dolichol-phosphate-mannose synthase (DPMS) and attempted to create DPMS knockout mutants by targeted gene deletion [8].

Anatomical context of DPM1

• CHO2.38 cells were negative for GPI-anchored proteins, and microsomes from these cells showed no detectable DPM synthase activity, indicating that DPM3 is an essential component of this enzyme [9].
• Perturbation of microtubules and DPMS tubule structure in vivo results in the selective accumulation of GPI anchor precursors, but not free GPIs [7].
• This tubular membrane (termed the DPMS tubule) is also enriched in other enzymes involved in GPI biosynthesis, can be specifically stained with the fluorescent lipid, BODIPY-C5-ceramide, and appears to be connected to specific subpellicular microtubules that underlie the plasma membrane [7].
• Finally, the increased degradation of the DPMS chimeras in stationary phase promastigotes coincides with an increase in the lytic capacity of the MVT lysosome and changes in the morphology of this organelle [12].
• These factors, then, appear to be more useful than clinical and physical data as indicators of the potential response of facial pain patients with either MPDS or organic TMJ deficits to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)[13]

Associations of DPM1 with chemical compounds

• Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an accumulation of the dolichyl pyrophosphate Man(5)GlcNAc(2) structure, compatible with the reduced dolichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in these patients [4].
• The DPMS tubule is closely associated morphologically with the single Golgi apparatus in non-dividing and dividing cells, appears to exclude luminal ER resident proteins and is labeled, together with the Golgi apparatus, with another GFP chimera containing the heterologous human Golgi marker beta1,2-N-acetylglucosaminyltransferase-I [7].
• In conclusion, it appears that therapeutic ultrasound can be used effectively to alleviate discomfort of MPDS that does not respond to occlusal splint therapy [14].

Other interactions of DPM1

• With microsomes from cells treated with translation blockers, there was no interference with LLO initiation by GlcNAc-1-P transferase (GPT), mannose-P-dolichol synthase, glucose-P-dolichol synthase, or LLO synthesis in vitro, as reported previously [15].

Analytical, diagnostic and therapeutic context of DPM1

• Free DPM1 was strongly associated with the C terminus of Hsc70-interacting protein (CHIP), a chaperone-dependent E3 ubiquitin ligase, suggesting that DPM1 is ubiquitinated, at least in part, by CHIP [9].
• Electron microscopy and subcellular fractionation studies suggest that the DPMS chimeras are transported from the ER to the lumen of the MVT via the Golgi apparatus and a population of 200-nm multivesicular bodies [12].
• METHODS: All 9-1-1 calls were processed using MPDS protocols to determine whether the patient required ALS or basic life support (BLS) services [16].
• Thirty-one patients with spinal tumors underwent reconstructive surgery with our spinal instrumentation system (MPDS and MADS), with or without our new vertebral tumor prosthesis [17].
• Objective: This retrospective study evaluated the appropriateness of requests assigned the alpha determinant at the time of dispatch by Emergency Medical Dispatchers using the Medical Priority Dispatch System (MPDS) [18].

References