Phosphomannose isomerase inhibitors improve N-glycosylation in selected phosphomannomutase-deficient fibroblasts

J Biol Chem. 2011 Nov 11;286(45):39431-8. doi: 10.1074/jbc.M111.285502. Epub 2011 Sep 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Congenital Disorders of Glycosylation / drug therapy*
  • Congenital Disorders of Glycosylation / enzymology*
  • Congenital Disorders of Glycosylation / genetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Fibroblasts / enzymology*
  • Glycosylation / drug effects
  • HeLa Cells
  • Humans
  • Mannose / genetics
  • Mannose / metabolism
  • Mannose-6-Phosphate Isomerase / antagonists & inhibitors*
  • Mannose-6-Phosphate Isomerase / genetics
  • Mannose-6-Phosphate Isomerase / metabolism
  • Mannosephosphates / genetics
  • Mannosephosphates / metabolism
  • Mutation
  • Phosphotransferases (Phosphomutases) / genetics*
  • Zebrafish / genetics
  • Zebrafish / metabolism

Substances

  • Enzyme Inhibitors
  • Mannosephosphates
  • mannose-6-phosphate
  • Mannose-6-Phosphate Isomerase
  • Phosphotransferases (Phosphomutases)
  • phosphomannomutase 2, human
  • Mannose