Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.4.2.8 (phosphomannomutase)
 238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with Type I congenital disorders of glycosylation (CDG-I) make incomplete lipid-linked oligosaccharides (LLO). These glycans are poorly transferred to proteins resulting in unoccupied glycosylation sequons. Mutations in phosphomannomutase (PMM2) cause CDG-Ia by reducing the activity of PMM, which converts mannose (Man)-6-P to Man-1-P before formation of GDP-Man. These patients have reduced Man-1-P and GDP-Man. To replenish intracellular Man-1-P pools in CDG-Ia cells, we synthesized two hydrophobic, membrane permeable acylated versions of Man-1-P and determined their ability to normalize LLO size and N-glycosylation in CDG-Ia fibroblasts. Both compounds, compound I (diacetoxymethyl 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl phosphate) (C-I) and compound II (diacetoxymethyl 2,3,4,6-tetra-O-ethyloxycarbonyl-alpha-D-mannopyranosyl phosphate) (C-II), contain two acetoxymethyl (CH2OAc) groups O-linked to phosphorous. C-I contains acetyl esters and C-II contains ethylcarbonate (CO2Et) esters on the Man residue. Both C-I and C-II normalized truncated LLO, but C-II was about 2-fold more efficient than C-I. C-II replenished the GDP-Man pool in CDG-Ia cells and was more efficiently incorporated into glycoproteins than exogenous Man at low concentrations (25-75 mM). In a glycosylation assay of DNaseI in CDG-Ia cells, C-II restored glycosylation to control cell levels. C-II also corrected impaired LLO biosynthesis in cells from a Dolichol (Dol)-P-Man deficient patient (CDG-Ie) and partially corrected LLO in cells from an ALG12 mannosyltransferase-deficient patient (CDG-Ig), whereas cells from an ALG3-deficient patient (CDG-Id) and from an MPDU1-deficient patient (CDG-If) were not corrected. These results validate the general concept of using pro-Man-1-P substrates as potential therapeutics for CDG-I patients.
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PMID:Hydrophobic Man-1-P derivatives correct abnormal glycosylation in Type I congenital disorder of glycosylation fibroblasts. 1607 17

Increasing intracellular mannose-6-phosphate (Man-6-P) was previously reported to reduce the amount of the major lipid linked oligosaccharide (LLO) precursor of N-glycans; a loss that might decrease cellular N-glycosylation. If so, providing dietary mannose supplements to glycosylation-deficient patients might further impair their glycosylation. To address this question, we studied the effects of exogenous mannose on intracellular levels of Man-6-P, LLO, and N-glycosylation in human and mouse fibroblasts. Mannose (500microM) did not increase Man-6-P pools in human fibroblasts from controls or from patients with Congenital Disorders of Glycosylation (CDG), who have 90-95% deficiencies in either phosphomannomutase (CDG-Ia) or phosphomannose isomerase (MPI) (CDG-Ib), enzymes that both use Man-6-P as a substrate. In the extreme case of fibroblasts derived from Mpi null mice (<0.001% MPI activity), intracellular Man-6-P levels greatly increased in response to exogenous mannose, and this produced a dose-dependent decrease in the steady state level of the major LLO precursor. However, LLO loss did not decrease total protein N-glycosylation or that of a hypoglycosylation indicator protein, DNaseI. These results make it very unlikely that exogenous mannose could impair N-glycosylation in glycosylation-deficient CDG patients.
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PMID:Exogenous mannose does not raise steady state mannose-6-phosphate pools of normal or N-glycosylation-deficient human fibroblasts. 1915 45