Banerjee Kamalika, Gupta Utkarsh, Gupta Sanjay, Sharma Sanjeev Kumar, Jain Chakresh Kumar
Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, Uttar Pradesh, India.
Bioinformation. 2011;7(1):5-8. doi: 10.6026/97320630007005. Epub 2011 Aug 20.
Invasive fungal opportunistic infections or mycoses have been on the rise with increase in the number of immuno-compromised patients accounting for associated high morbidity and mortality rates. The antifungal drugs are not completely effective due to increased resistance and varied susceptibility of fungi. Hence, the functional diversification study of novel targets has to be carried out. The enzyme glucosamine-6-phosphate synthase [EC 2.6.1.16], a novel drug target, catalyzes the rate-limiting step of the fungal cell-wall biosynthetic pathway, comprising four conserved domains, two glutaminase and sugar-isomerising (SIS) domains with active site. The amino acids within these domains tend to mutate simultaneously and exert mutual selective forces which might result in untoward fungal adaptations that are fixed through random genetic drift over time. The current study is an attempt to investigate such 'non-independent' coevolving residues which play critical functional and structural role in the protein. Residues with Shannon entropy ≦1 (calculated by the Protein Variability Server) were considered and subsequently, positional correlations were estimated by InterMap3D 1.3 server. It was observed that majority of coevolving pairs of first SIS domain involved interactions with hydrophobic leucine and found to be spatially coupled in 3-dimensional structure of the enzyme. The coevolving groups of Aspergillus niger and Rhizopus oryzae species might play a role in drug resistance. Such coevolutionary analysis is important for understanding the receptor-ligand interactions and effective drug designing.
侵袭性真菌机会性感染或真菌病的发病率随着免疫功能低下患者数量的增加而上升，这导致了相关的高发病率和死亡率。由于真菌耐药性增加和易感性各异，抗真菌药物并不完全有效。因此，必须开展针对新靶点的功能多样化研究。氨基葡萄糖-6-磷酸合酶[EC 2.6.1.16]是一种新型药物靶点，它催化真菌细胞壁生物合成途径的限速步骤，该酶包含四个保守结构域，两个谷氨酰胺酶和糖异构化（SIS）结构域以及活性位点。这些结构域内的氨基酸倾向于同时发生突变并施加相互选择力，这可能导致不良的真菌适应性变化，随着时间的推移通过随机遗传漂变固定下来。本研究旨在调查此类在蛋白质中发挥关键功能和结构作用的“非独立”协同进化残基。考虑了香农熵≤1的残基（由蛋白质变异性服务器计算得出），随后通过InterMap3D 1.3服务器估计位置相关性。观察到第一个SIS结构域的大多数协同进化对涉及与疏水性亮氨酸的相互作用，并且发现在该酶的三维结构中在空间上耦合。黑曲霉和米根霉物种的协同进化组可能在耐药性中起作用。这种协同进化分析对于理解受体-配体相互作用和有效的药物设计很重要。
