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首页> 外文期刊>Biological chemistry >Comparative studies of Aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase
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Comparative studies of Aspergillus fumigatus 2-methylcitrate synthase and human citrate synthase

机译：曲霉菌2-甲基硝酸酯合酶与人柠檬酸合酶的比较研究

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Aspergillus fumigatus is a ubiquitous fungus that is not only a problem in agriculture, but also in healthcare. Aspergillus fumigatus drug resistance is becoming more prominent which is mainly attributed to the widespread use of fungicides in agriculture. The fungi-specific 2-methylcitrate cycle is responsible for detoxifying propionyl-CoA, a toxic metabolite produced as the fungus breaks down proteins and amino acids. The enzyme responsible for this detoxification is 2-methylcitrate synthase (mcsA) and is a potential candidate for the design of new anti-fungals. However, mcsA is very similar in structure to human citrate synthase (hCS) and catalyzes the same reaction. Therefore, both enzymes were studied in parallel to provide foundations for design of mcsA-specific inhibitors. The first crystal structures of citrate synthase from humans and 2-methylcitrate synthase from A. fumigatus are reported. The determined structures capture various conformational states of the enzymes and several inhibitors were identified and characterized. Despite a significant homology, mcsA and hCS display pronounced differences in substrate specificity and cooperativity. Considering that the active sites of the enzymes are almost identical, the differences in reactions catalyzed by enzymes are caused by residues that are in the vicinity of the active site and influence conformational changes of the enzymes.
机译：曲霉属fumigatus是一种普遍的真菌，不仅是农业的问题，也是医疗保健。曲霉菌毒性抗药性变得越来越突出，主要归因于农业杀菌剂的广泛使用。真菌特异性的2-甲基柠檬酸循环负责解毒丙氨基-CoA，当真菌中产生的有毒代谢物破裂蛋白质和氨基酸。负责该解毒的酶是2-甲基柠檬酸合酶（MCSA），是设计新的抗真菌的潜在候选者。然而，MCSA在结构上与人柠檬酸合酶（HCS）非常相似并催化相同的反应。因此，并行研究了两种酶，以提供用于MCSA特异性抑制剂的设计。据报道了来自A.Fumigatus的人和2-甲基柠檬酸合成酶的柠檬酸盐合酶的第一晶体结构。确定的结构捕获酶的各种构象状态，并鉴定了几种抑制剂。尽管具有重要的同源性，但MCSA和HCS显示出衬底特异性和合作性的发音差异。考虑到酶的活性位点几乎相同，酶催化的反应的差异是由活性位点附近的残基引起的，并影响酶的构象变化。

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