Identification of critical ligand binding determinants in Mycobacterium tuberculosis adenosine-5'-phosphosulfate reductase.
Mycobacterium tuberculosis adenosine-5'-phosphosulfate (APS) reductase is an iron-sulfur protein and a validated target to develop new antitubercular agents, particularly for the treatment of latent infection. To facilitate the development of potent and specific inhibitors of APS reductase, we have probed the molecular determinants that underlie binding and specificity through a series of substrate and product analogues. Our study highlights the importance of specific substitutent groups for substrate binding and provides functional evidence for ligand-specific conformational states. An active site model has been developed for M. tuberculosis APS reductase that is in accord with the results presented here as well as prior structural data reported for Pseudomonas aeruginosa APS reductase and related enzymes. This model illustrates the functional features required for the interaction of APS reductase with a ligand and provides a pharmacological roadmap for the rational design of small molecules as potential inhibitors of APS reductase present in human pathogens, including M. tuberculosis.
Hong
Jiyoung A
JA
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
Bhave
Devayani P
DP
Carroll
Kate S
KS
D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008274:Magnesium / Q000494:pharmacology; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000201:enzymology; D055672:Static Electricity; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D008024:Ligands; D050862:Oxidoreductases Acting on Sulfur Group Donors; C019618:adenylylsulfate reductase; D008274:Magnesium
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