A novel sugar in human muscle and brain

Lefeber Dirk

Mutations in ISPD have been identified as the second most common cause of a group of congenital muscular dystrophies, including Walker-Warburg Syndrome. The molecular function of ISPD (isoprenoid synthase domain containing) has not been studied in human. In plants and certain bacteria, ISPD is involved in the production of isoprenoids as part of the non-mevalonate pathway for cholesterol synthesis. In this week’s issue of Chemistry and Biology, Riemersma et al. report that human ISPD produces a novel nucleotide-sugar, not recognized before in man. A lack of this sugar causes muscular dystrophy. 

Patients  with Walker-Warburg syndrome present with muscular dystrophy and severe brain and eye abnormalities. Their life expectancy is usually only a few years or even less. The Walker-Warburg syndrome is caused by defective glycosylation of the protein dystroglycan in the cell membrane. Abnormal glycosylation results in deficient binding of dystroglycan to its extracellular ligands and thereby in muscle dystrophy and reduced neuronal migration. However, the exact glycan epitope and its composing sugars are currently unknown. 

In 2012, ISPD has been identified as novel causative gene for Walker-Warburg syndrome by a group of Radboudumc researchers led by Hans van Bokhoven. Follow-up research, led by Dirk Lefeber (photo), has now resulted in elucidation of the molecular function of human ISPD.

Guided by X-ray crystallization and biochemical studies in ISPD knockout and overexpressing cell models, human ISPD was shown to act as a CTP-dependent cytidyltransferase. Assaying a panel of potential substrates revealed highest activity towards pentose-phosphate sugars, especially ribose derivatives. Mass spectrometry and NMR spectroscopy validated the structural identify of the novel nucleotide sugar CDP-ribitol, which has thus far only been identified in several bacterial species. 

This research uncovers a novel sugar to be present in human muscle and brain and opens novel opportunities to intervene in cytosolic sugar metabolism with the potential development of future therapies. 

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