近日，国际著名杂志Science在线刊登了国外研究人员的最新研究成果“Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase”，文章中，研究者揭示了磺胺药物的抗药性是如何产生的。
俗称磺胺类药物的磺酰胺抗生素已经被人们用来治疗感染达70多年的时间了，但不断出现的对该类药物的抗药性严重限制了它们的临床应用。 如今，Mi-Kyung Yun及其同事报道了磺胺类药物所抑制的细菌关键酶——二氢蝶酸合酶，或DHPS——的结构性、计算性及突变形成等的研究。
通过在结晶的DHPS中进行一个酶催化的反应，研究人员可以观察到在反应中的关键性的中间体。 他们接着将其新的结构数据与先前的研究结果相结合以期能够为DHPS的催化提出一个详尽的机制。 Yun和其他的研究人员还显示了一个与某一磺胺药物结合的DHPS的晶体结构，它帮助解释了磺胺药物的抗药性是如何产生的。（生物谷Bioon.com）
doi:10.1126/science.1214641
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Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase
Mi-Kyung Yun1,*, Yinan Wu1,2,*, Zhenmei Li1, Ying Zhao3, M. Brett Waddell4, Antonio M. Ferreira1,5, Richard E. Lee3, Donald Bashford1,2, Stephen W. White1,2,†
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 SN1 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.
