Integrated Data Science Section, Research Technologies Branch, National Institute of Allergies and Infectious Diseases, Bethesda, MD, USA.
Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Chem Biol Interact. 2023 Mar 1;373:110378. doi: 10.1016/j.cbi.2023.110378. Epub 2023 Feb 1.
Uric acid is the end product of purine metabolism. Uric acid transporters in the renal proximal tubule plays a key role in uric acid transport. Functional abnormalities in these transporters could lead to high or low levels of uric acid in the blood plasma, known as hyperuricemia and hypouricemia, respectively. GLUT9 has been reported as a key transporter for uric acid reuptake in renal proximal tubule. GLUT9 mutation is known as causal gene for renal hypouricemia due to defective uric acid uptake, with more severe cases resulting in urolithiasis and exercise induced acute kidney injury (EIAKI). However, the effect of mutation is not fully investigated and hard to predict the change of binding affinity. We comprehensively described the effect of GLUT9 mutation for uric acid transport using molecular dynamics and investigated the specific site for uric acid binding differences. R171C and R380W showed the significant disruption of the structure not affecting transport dynamics whereas L75R, G216R, N333S, and P412R showed the reduced affinity of the extracellular vestibular area towards urate. Interestingly, T125 M showed a significant increase in intracellular binding energy, associated with distorted geometries. We can use this classification to consider the effect mutations by comparing the transport profiles of mutants against those of chemical candidates for transport and providing new perspectives to urate lowering drug discovery using GLUT9.
尿酸是嘌呤代谢的终产物。肾脏近端小管中的尿酸转运体在尿酸转运中起着关键作用。这些转运体的功能异常可导致血液中尿酸水平升高或降低，分别称为高尿酸血症和低尿酸血症。GLUT9 已被报道为肾脏近端小管中尿酸重吸收的关键转运体。GLUT9 突变是导致肾脏低尿酸血症的致病基因，因为尿酸摄取缺陷，更严重的病例会导致尿石症和运动诱导的急性肾损伤（EIAKI）。然而，突变的影响尚未完全研究，难以预测结合亲和力的变化。我们使用分子动力学全面描述了 GLUT9 突变对尿酸转运的影响，并研究了尿酸结合差异的特定部位。R171C 和 R380W 显示出结构的明显破坏，不影响转运动力学，而 L75R、G216R、N333S 和 P412R 显示出尿酸结合的亲和力降低了细胞外前庭区对尿酸的亲和力。有趣的是，T125M 显示出细胞内结合能的显著增加，与扭曲的几何形状有关。我们可以使用这种分类方法来考虑突变的影响，方法是将突变体的转运谱与转运的化学候选物的转运谱进行比较，并为使用 GLUT9 降低尿酸药物的发现提供新的视角。
