Structural Basis of the Change in the Interaction Between Mycophenolic Acid and Subdomain IIA of Human Serum Albumin During Renal Failure
Structural Basis of the Change in the Interaction Between Mycophenolic Acid and Subdomain IIA of Human Serum Albumin During Renal Failure
复制标题
肾衰竭期间霉酚酸与人血清白蛋白亚结构域 IIA 相互作用变化的结构基础
DOI：
10.1021/acs.jmedchem.2c01790
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发表时间：
2022
影响因子：
7.3
通讯作者：
Kawai Akito
中科院分区：
文献类型：
--
作者：
Yamasaki Keishi;Teshima Honoka;Yukizawa Reina;Kuyama Koki;Tsukigawa Kenji;Nishi Koji;Otagiri Masaki;Kawai Akito
霉酚酸（MP）是广泛应用的免疫抑制剂霉酚酸酯的活性代谢产物。MP通常表现出较高的血浆蛋白结合率（97-99%），但在肾功能不全患者中其结合率降低。这种降低的蛋白结合被认为与白细胞减少症有关，这是MP的副作用。在这项研究中，我们的特点是蛋白结合的变化，MP在肾功能衰竭患者。我们的研究结果表明，MP强烈结合到人血清白蛋白的亚结构域IIA。X射线晶体学数据表明，MP的异苯并呋喃基团与Trp 214形成堆叠相互作用，MP的羧基位于允许与Tyr 150、His 242或Arg 257形成氢键的位置。由于MP与亚结构域IIA特异性结合，MP被认为被尿毒症毒素（3-羧基-4-甲基-5-丙基-2-呋喃-丙酸）和可与亚结构域IIA结合的脂肪酸（油酸或肉豆蔻酸）取代，导致MP在肾衰竭中的血浆蛋白结合降低。
Mycophenolic acid (MP) is an active metabolite of mycophenolate mofetil, a widely used immunosuppressive drug. MP normally exhibits high plasma protein binding (97–99%), but its binding rate is decreased in patients with renal insufficiency. This decreased protein binding is thought to be associated with leukopenia, a side effect of MP. In this study, we characterized the change in protein binding of MP in renal failure patients. Our findings indicate that MP binds strongly to subdomain IIA of human serum albumin. X-ray crystallographic data indicated that the isobenzofuran group of MP forms a stacking interaction with Trp214, and the carboxyl group of MP is located at a position that allows the formation of hydrogen bonds with Tyr150, His242, or Arg257. Due to the specific binding of MP to subdomain IIA, MP is thought to be displaced by uremic toxin (3-carboxy-4-methyl-5-propyl-2-furan-propionic acid) and fatty acids (oleate or myristate) that can bind to subdomain IIA, resulting in the decreased plasma protein binding of MP in renal failure.