Gupta Utkarsh, Banerjee Kamalika, Gabrani Reema, 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;6(5):196-9. doi: 10.6026/97320630006196. Epub 2011 May 26.
The immunosuppressive individuals are highly prone to get afflicted with invasive opportunistic fungal infections such as Candidiasis, Aspergillosis, Histoplasmosis, Coccidioidomycosis, Blastomycosis, Penicilliosis, Cryptococcosis and Zygomycosis which are becoming a cause of concern to the mankind due to their high morbidity and mortality rates. The existing antifungal agents are not completely effective due to their severe side-effects and recurrent drug resistance in fungi. Hence, there is an urgent need to develop newer and better antifungal drugs. The enzyme Glucosamine-6-phosphate (G-6-P) synthase catalyzes the ratelimiting step of the fungal cell-wall biosynthetic pathway and targeting it can inhibit the growth of the fungus. The present study attempts to investigate the inherent variations in functional domain viz. Glutaminase (GATase II) and Sugar Isomerising (SIS) of Glucosamine-6-phosphate (G-6-P) synthase enzyme of mycoses-causing fungi. These domains may be identified as probable active site(s). Multiple sequence alignment performed using ClustalX2 and construction of phylogenetic tree of individual domains by MEGA v5.0 helped in the analyses of several variable amino acid sites within the domains suggesting their vital role in the pathogenesis of the fungi. Further, the online server ConSurf implied that mostly, the highly conserved residues of the domains were functional and exposed on the surface of the active site, making it an easy target for the drugs. Consequently, variable analysis of functional domains of target implicated the importance of target specific drug discovery for the treatment of invasive fungal infections or mycoses.
免疫抑制个体极易感染侵袭性机会性真菌感染，如念珠菌病、曲霉病、组织胞浆菌病、球孢子菌病、芽生菌病、青霉病、隐球菌病和接合菌病，由于其高发病率和死亡率，这些感染正成为人类关注的问题。现有的抗真菌药物由于其严重的副作用和真菌中反复出现的耐药性而并非完全有效。因此，迫切需要开发更新、更好的抗真菌药物。葡糖胺-6-磷酸（G-6-P）合酶催化真菌细胞壁生物合成途径的限速步骤，靶向该酶可抑制真菌生长。本研究试图调查致病真菌的葡糖胺-6-磷酸（G-6-P）合酶的功能域即谷氨酰胺酶（GATase II）和糖异构化（SIS）的内在变异。这些结构域可能被确定为可能的活性位点。使用ClustalX2进行多序列比对，并通过MEGA v5.0构建各个结构域的系统发育树，有助于分析结构域内的几个可变氨基酸位点，表明它们在真菌发病机制中的重要作用。此外，在线服务器ConSurf表明，这些结构域的高度保守残基大多具有功能并暴露在活性位点表面，使其成为药物的容易靶点。因此，对靶点功能域的可变分析表明了针对侵袭性真菌感染或真菌病治疗进行靶点特异性药物发现的重要性。
