Science (American Association for the Advancement of Science), 2012-03, Vol.335 (6072), p.1110-1114
2012
Details
- Autor(en) / Beteiligte
- Titel
- Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase
- Ist Teil von
- Science (American Association for the Advancement of Science), 2012-03, Vol.335 (6072), p.1110-1114
- Ort / Verlag
- Washington, DC: American Association for the Advancement of Science
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- Science Online_科学在线
- Beschreibungen/Notizen
- The sulfonamide antibiotics inhibit dihydropteroate synthase (DHPS), a key enzyme in the folate pathway of bacteria and primitive eukaryotes. However, resistance mutations have severely compromised the usefulness of these drugs. We report structural, computational, and mutagenesis studies on the catalytic and resistance mechanisms of DHPS. By performing the enzyme-catalyzed reaction in crystalline DHPS, we have structurally characterized key intermediates along the reaction pathway. Results support an S N 1 reaction mechanism via formation of a novel cationic pterin intermediate. We also show that two conserved loops generate a substructure during catalysis that creates a specific binding pocket for p-aminobenzoic acid, one of the two DHPS substrates. This substructure, together with the pterin-binding pocket, explains the roles of the conserved active-site residues and reveals how sulfonamide resistance arises.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0036-8075eISSN: 1095-9203DOI: 10.1126/science.1214641Titel-ID: cdi_osti_scitechconnect_1039064
- Format
- –
- Schlagworte
- 4-Aminobenzoic Acid - chemistry, 4-Aminobenzoic Acid - metabolism, 60 APPLIED LIFE SCIENCES, Active sites, Amino Acid Sequence, Anti-Bacterial Agents - chemistry, Anti-Bacterial Agents - metabolism, Anti-Bacterial Agents - pharmacology, Antibacterials, ANTIBIOTICS, Antibiotics (antibacterial agents, antifungal agents), Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents, Applied microbiology, Bacillus anthracis - drug effects, Bacillus anthracis - enzymology, BACTERIA, Biocatalysis, Biological and medical sciences, CATALYSIS, Catalytic Domain, Crystal structure, Crystallization, Crystallography, X-Ray, Crystals, Dihydropteroate Synthase - chemistry, Dihydropteroate Synthase - genetics, Dihydropteroate Synthase - metabolism, Diphosphates, Diphosphates - chemistry, Diphosphates - metabolism, Drug resistance, Drug Resistance, Bacterial, ENZYMES, Fundamental and applied biological sciences. Psychology, Magnesium - chemistry, Microbiology, Models, Chemical, Models, Molecular, Molecular Sequence Data, Molecules, MUTAGENESIS, Mutation, MUTATIONS, Narcotics, Parabens - chemistry, Parabens - metabolism, Protein Conformation, PTERIDINES, Pterins, REACTION KINETICS, RESIDUES, SUBSTRATES, Sulfamethoxazole - chemistry, Sulfamethoxazole - metabolism, Sulfamethoxazole - pharmacology, Sulfathiazole, Sulfathiazoles - chemistry, Sulfathiazoles - metabolism, Sulfathiazoles - pharmacology, SULFONAMIDES, Yersinia pestis - drug effects, Yersinia pestis - enzymology