Biochemistry

What's It All Good For?

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Science  15 Feb 2008:
Vol. 319, Issue 5865, pp. 879
DOI: 10.1126/science.319.5865.879b

Enzyme kinetics is a subject dreaded by all but hard-core biochemists. Purifying proteins and measuring product generated or substrate consumed at varying concentrations of enzyme and substrate—not to mention the characterization of competitive and noncompetitive inhibitors—and then integrating these data within a mechanistic scheme that spits out rate constants… well, this is not the stuff that dreams are made of, and neither is reading someone else's enzyme kinetics papers.

Umejiego et al. have applied this kind of information (a random order of substrate binding and a rate-limiting hydrolysis of the covalent enzyme intermediate) in designing a small-molecule screen for inhibitors of the enzyme inosine-5′-monophosphate dehydrogenase (IMPDH). Why should we care? Because IMPDH salvages purines in order to supply guanine in the human pathogen Cryptosporidium parvum, and because the C. parvum enzyme differs enough from human IMPDH to serve as a drug target. By screening under kinetically defined conditions where the conserved IMP site was occupied, whereas the less conserved NAD site was empty, they managed to fish out 10 candidates from a starting pool of 44,000 compounds. Four of these were more potent inhibitors of C. parvum growth than the standard drug paromomycin in a cell culture assay. — GJC

Chem. Biol. 15, 70 (2008).

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