Issue 47, 2020

A click-flipped enzyme substrate boosts the performance of the diagnostic screening for Hunter syndrome

Abstract

We report on the unexpected finding that click modification of iduronyl azides results in a conformational flip of the pyranose ring, which led to the development of a new strategy for the design of superior enzyme substrates for the diagnostic assaying of iduronate-2-sulfatase (I2S), a lysosomal enzyme related to Hunter syndrome. Synthetic substrates are essential in testing newborns for metabolic disorders to enable early initiation of therapy. Our click-flipped iduronyl triazole showed a remarkably better performance with I2S than commonly used O-iduronates. We found that both O- and triazole-linked substrates are accepted by the enzyme, irrespective of their different conformations, but only the O-linked product inhibits the activity of I2S. Thus, in the long reaction times required for clinical assays, the triazole substrate substantially outperforms the O-iduronate. Applying our click-flipped substrate to assay I2S in dried blood spots sampled from affected patients and random newborns significantly increased the confidence in discriminating between these groups, clearly indicating the potential of the click-flip strategy to control the biomolecular function of carbohydrates.

Graphical abstract: A click-flipped enzyme substrate boosts the performance of the diagnostic screening for Hunter syndrome

Supplementary files

Article information

Article type
Edge Article
Submitted
25 Aug. 2020
Accepted
23 Okt. 2020
First published
23 Okt. 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2020,11, 12671-12676

A click-flipped enzyme substrate boosts the performance of the diagnostic screening for Hunter syndrome

M. Schwarz, P. Skrinjar, M. J. Fink, S. Kronister, T. Mechtler, P. I. Koukos, A. M. J. J. Bonvin, D. C. Kasper and H. Mikula, Chem. Sci., 2020, 11, 12671 DOI: 10.1039/D0SC04696E

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