Cocrystal structures of diaminopimelate decarboxylase: mechanism, evolution, and inhibition of an antibiotic resistance accessory factor.
Cocrystal structures of diaminopimelate decarboxylase: mechanism, evolution, and inhibition of an antibiotic resistance accessory factor.
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DOI：
10.1016/s0969-2126(02)00880-8
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发表时间：
2002-11
期刊：
影响因子：
5.7
通讯作者：
S. Ray;J. Bonanno;J. Bonanno;K. Rajashankar;M. G. Pinho;G. He;G. He;H. Lencastre;A. Tomasz;Stephen K. Burley;Stephen K. Burley
中科院分区：
文献类型：
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作者：
S. Ray;J. Bonanno;J. Bonanno;K. Rajashankar;M. G. Pinho;G. He;G. He;H. Lencastre;A. Tomasz;Stephen K. Burley;Stephen K. Burley
与底物类似物壬二酸及其 L-赖氨酸产物结合的詹氏甲烷球菌二氨基庚二酸脱羧酶 (DAPDC) 的共晶结构已分别确定为 2.6 Å 和 2.0 Å。这种 PLP 依赖性酶负责细菌中 L-赖氨酸生物合成的最后一步，并在金黄色葡萄球菌的 β-内酰胺抗生素耐药性中发挥作用。底物特异性源自对二氨基庚二酸的 L-手性中心和决定底物长度的离子“分子标尺”系统的识别。偶联酶测定系统可以测量重组 DAPDC 的动力学参数以及壬二酸 (89 μM) 和其他底物类似物的抑制常数 (Ki)。讨论了合理设计针对耐药细菌病原体（例如金黄色葡萄球菌）DAPDC 的广谱抗菌药物的意义。
Cocrystal structures ofMethanococcus jannaschiidiaminopimelate decarboxylase (DAPDC) bound to a substrate analog, azelaic acid, and its L-lysine product have been determined at 2.6 Å and 2.0 Å, respectively. This PLP-dependent enzyme is responsible for the final step of L-lysine biosynthesis in bacteria and plays a role in β-lactam antibiotic resistance inStaphylococcus aureus. Substrate specificity derives from recognition of the L-chiral center of diaminopimelate and a system of ionic "molecular rulers" that dictate substrate length. A coupled-enzyme assay system permitted measurement of kinetic parameters for recombinant DAPDCs and inhibition constants (Ki) for azelaic acid (89 μM) and other substrate analogs. Implications for rational design of broad-spectrum antimicrobial agents targeted against DAPDCs of drug-resistant strains of bacterial pathogens, such asStaphylococcus aureus,are discussed.