Covalent inhibitors of glycosidases and their applications in biochemistry and biology

Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Glycobiology (Impact Factor: 3.15). 09/2008; 18(8):570-86. DOI: 10.1093/glycob/cwn041
Source: PubMed


Glycoside hydrolases are important enzymes in a number of essential biological processes. Irreversible inhibitors of this
class of enzyme have attracted interest as probes of both structure and function. In this review we discuss some of the compounds
used to covalently modify glycosidases, their use in residue identification, structural and mechanistic investigations, and
finally their applications, both in vitro and in vivo, to complex biological systems.

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    • "Glycosyl hydrolases control many significant biological transformations, and are implicated in numerous pathophysiological events[1,2,3]. Therefore, chemical agents that can modulate the activity of these enzymes are of great value, both as biological tools for understanding disease mechanisms, and as potential therapeutic agents[4,5]. One of the most potent and selective classes of small molecule glycosyl hydrolase inhibitors are pseudodisaccharides, molecules comprising of a natural saccharide linked to a pseudomonosaccharide. Examples of pseudodisaccharides with activity against glycosyl hydrolase include natural products salbostatin, 1[6] and neamine, 2[7] as well as synthetic α-glucosidase inhibitors 3[8] and 4[9] (Figure 1). "
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    ABSTRACT: A novel methodology is described for the efficient and divergent synthesis of pseudodisaccharides, molecules comprising of amino carbasugar analogues linked to natural sugars. The methodology is general and enables the introduction of diversity both at the carbasugar and the natural sugar components of the pseudodisaccharides. Using this approach, a series of pseudodisaccharides are synthesised that mimic the repeating backbone unit of heparan sulfate, and are tested for inhibition of heparanase, a disease-relevant enzyme that hydrolyses heparan sulfate. A new homology model of human heparanase is described based on a family 79 β-glucuronidase. This model is used to postulate a computational rationale for the observed activity of the different pseudodisaccharides and provide valuable information that informs the design of potential inhibitors of this enzyme.
    PLoS ONE 11/2013; 8(11):e82111. DOI:10.1371/journal.pone.0082111 · 3.23 Impact Factor
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    • "Small molecule inhibitors of glycan biosynthesis can alter glycan structures.(30) Cell-surface glycans are constructed by the stochastic action of spatially constrained ER- and Golgi-associated glycosyltransferases as their target glycoconjugates traverse the secretory pathway. "
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    ABSTRACT: Chemical tools for perturbing, profiling, and perceiving glycans should reduce the barriers that have previously impeded progress in this field. Their implementation has already produced a body of knowledge that was formerly limited to the domain of proteins and nucleic acids. For example, a developing glycomic database has begun to facilitate bioinformatics studies on glycans. 78 As mentioned above, profiles of glycans from tissues and bodily fluids have produced new biomarker candidates. Many regents for perturbing glycans, including inhibitors and primers, are now commercially available. Similarly, azidosugars and both phosphine- and alkynebased labeling reagents can now be obtained from commercial suppliers. The future is bright for use of these tools in analyzing the dynamic glycomes of normal and diseased tissues.
    Accounts of Chemical Research 05/2009; 42(6):788-97. DOI:10.1021/ar800267j · 22.32 Impact Factor
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    ABSTRACT: As more information becomes available through the efforts of high-throughput screens, there is increasing pressure on the three main 'omic' fields, genomics, proteomics, and metabolomics, to organize this material into useful libraries that enable further understanding of biological systems. Proteomics especially is faced with two highly challenging tasks. The first is assigning the activity of thousands of putative proteins, the existence of which has been suggested by genomics studies. The second is to serve as a link between genomics and metabolomics by demonstrating which enzymes play roles in specific metabolic pathways. Underscoring these challenges in one area are the thousands of putative carbohydrate-processing enzymes that have been bioinformatically identified, mostly in prokaryotes, but that have unknown or unverified activities. Using two brief examples, we illustrate how biochemical pathways within bacteria that involve carbohydrate-processing enzymes present interesting potential antimicrobial targets, offering a clear motivation for gaining a functional understanding of biological proteomes. One method for studying proteomes that has been developed recently is to use synthetic compounds termed activity-based proteomics probes. Activity-based proteomic profiling using such probes facilitates rapid identification of enzyme activities within proteomes and assignment of function to putative enzymes. Here we discuss the general design principles for these probes with particular reference to carbohydrate-processing enzymes and give an example of using such a probe for the profiling of a bacterial proteome.
    Australian Journal of Chemistry 01/2009; 62(6). DOI:10.1071/CH09140 · 1.56 Impact Factor
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