title: Phosphomannose isomerase inhibitors improve N-glycosylation in selected phosphomannomutase-deficient fibroblasts.
abstract: Congenital disorders of glycosylation (CDG) are rare genetic disorders due to impaired glycosylation. The patients with subtypes CDG-Ia and CDG-Ib have mutations in the genes encoding phosphomannomutase 2 (PMM2) and phosphomannose isomerase (MPI or PMI), respectively. PMM2 (mannose 6-phosphate → mannose 1-phosphate) and MPI (mannose 6-phosphate ⇔ fructose 6-phosphate) deficiencies reduce the metabolic flux of mannose 6-phosphate (Man-6-P) into glycosylation, resulting in unoccupied N-glycosylation sites. Both PMM2 and MPI compete for the same substrate, Man-6-P. Daily mannose doses reverse most of the symptoms of MPI-deficient CDG-Ib patients. However, CDG-Ia patients do not benefit from mannose supplementation because >95% Man-6-P is catabolized by MPI. We hypothesized that inhibiting MPI enzymatic activity would provide more Man-6-P for glycosylation and possibly benefit CDG-Ia patients with residual PMM2 activity. Here we show that MLS0315771, a potent MPI inhibitor from the benzoisothiazolone series, diverts Man-6-P toward glycosylation in various cell lines including fibroblasts from CDG-Ia patients and improves N-glycosylation. Finally, we show that MLS0315771 increases mannose metabolic flux toward glycosylation in zebrafish embryos.
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Vandana
authors.initials: V
authors.lastname: Sharma
authors.forename: Mie
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.forename: Yalda
authors.initials: Y
authors.lastname: Bravo
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
mesh_terms: D000818:Animals; D018981:Congenital Disorders of Glycosylation / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005347:Fibroblasts / Q000201:enzymology*; D006031:Glycosylation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008358:Mannose / Q000235:genetics / Q000378:metabolism; D008359:Mannose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008360:Mannosephosphates / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017875:Phosphotransferases (Phosphomutases) / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008360:Mannosephosphates; C027693:mannose-6-phosphate; D008359:Mannose-6-Phosphate Isomerase; D017875:Phosphotransferases (Phosphomutases); C519582:phosphomannomutase 2, human; D008358:Mannose