Biology Department, Al Azhar University-Gaza, Palestine; Division of Hematology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America.
Division of Hematology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America; Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, United States of America; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, United States of America.
Blood Cells Mol Dis. 2021 Jul;89:102572. doi: 10.1016/j.bcmd.2021.102572. Epub 2021 Apr 27.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked inherited enzymopathic disorder that may lead to transfusion-requiring acute hemolytic anemia (AHA) triggered by fava beans ingestion, infection or some drugs. The gene encoding for G6PD carries a large number of genetic variants that have varying pathogenicity. We reported on three G6PD variants in the Gaza Strip Palestinian population with differing clinical impacts and frequencies: G6PD Mediterranean, African G6PD A-, and G6PD Cairo. We also identified a novel G6PD missense (Ser179Asn) mutation c.536G > A "G6PD Gaza". In this work we explore the effect of these four genetic variants on the structural and substrate (NADP and G6P) binding characteristics of the G6PD enzyme using the Monte Carlo (MC) flexible docking and molecular dynamics (MD) simulation approaches. We report that G6PD A-, G6PD Mediterranean, G6PD Cairo and G6PD Gaza mutations cause significant structural changes in G6PD enzyme to induce conformational instability leading to the loss of binding of one or both substrates and are causative of G6PD deficiency.
葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症是一种常见的 X 连锁遗传性酶病，可能导致食用蚕豆、感染或某些药物触发需要输血的急性溶血性贫血（AHA）。编码 G6PD 的基因携带大量具有不同致病性的遗传变异。我们报告了加沙地带巴勒斯坦人群中三种具有不同临床影响和频率的 G6PD 变异：地中海 G6PD、非洲 G6PD A- 和 G6PD 开罗。我们还鉴定了一种新的 G6PD 错义（Ser179Asn）突变 c.536G>A“G6PD Gaza”。在这项工作中，我们使用蒙特卡罗（MC）柔性对接和分子动力学（MD）模拟方法探索了这四种遗传变异对 G6PD 酶的结构和底物（NADP 和 G6P）结合特性的影响。我们报告称，G6PD A-、G6PD 地中海、G6PD 开罗和 G6PD Gaza 突变导致 G6PD 酶发生显著结构变化，诱导构象不稳定，导致一个或两个底物的结合丧失，是 G6PD 缺乏的原因。
