Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase
Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase
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DOI：
10.1182/blood.v92.9.3050.421k56_3050_3056
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发表时间：
1998-11-01
期刊：
影响因子：
20.3
通讯作者：
Youssoufian, H
中科院分区：
文献类型：
--
作者：
Kruyt, FAE;Hoshino, T;Youssoufian, H
由范可尼贫血 (FA) 互补组 C 基因编码的 FAC 蛋白被认为在 DNA 修复之前的步骤中在细胞质中发挥作用。由于 FA 细胞对丝裂霉素 C 敏感，我们考虑了 FAC 可能与参与该药物生物还原激活的酶相互作用的可能性。在此，我们报告在转染的 COS-1 和正常小鼠肝细胞中，FAC 与 NADPH 细胞色素 P450 还原酶 (RED) 结合，RED 是一种参与电子转移的微粒体膜蛋白。 FAC-RED 相互作用需要 FAC 的氨基末端区域和还原酶的胞质近膜结构域。后者含有已知的黄素单核苷酸 (FMN) 结合位点，将 FMN 添加到胞质裂解物中会破坏 FAC 还原酶复合物，而与不同羧基末端结构域结合的黄素二核苷酸在与 FMN 相似的浓度下无法改变 FAG-RED 复合物。 FAC 也与该酶功能性偶联，因为它在 COS-1 细胞中的表达抑制了 RED 在 NADPH 存在下还原细胞色素 c 的能力。我们认为 FAC 通过减弱 RED 的活性在体内发挥着重要作用，从而调节哺乳动物细胞中的主要解毒途径。 (C) 1998 年，美国血液学会。
The FAC protein encoded by the Fanconi anemia (FA) complementation group C gene is thought to function in the cytoplasm at a step before DNA repair. Because FA cells are susceptible to mitomycin C, we considered the possibility that FAC might interact with enzymes involved in the bioreductive activation of this drug, Here we report that FAC binds to NADPH cytochrome-P450 reductase (RED), a microsomal membrane protein involved in electron transfer, in both transfected COS-1 and normal murine liver cells. FAC-RED interaction requires the amino-terminal region of FAC and the cytosolic, membrane-proximal domain of the reductase. The latter contains a known binding site for flavin mononucleotide (FMN), Addition of FMN to cytosolic lysates disrupts FAC-reductase complexes, while flavin dinucleotide, which binds to a distinct carboxy-terminal domain, fails to alter FAG-RED complexes at concentrations similar to FMN. FAC is also functionally coupled to this enzyme as its expression in COS-1 cells suppresses the ability of RED to reduce cytochrome c in the presence of NADPH, We propose that FAC plays a fundamental role in vivo by attenuating the activity of RED, thereby regulating a major detoxification pathway in mammalian cells. (C) 1998 by The American Society of Hematology.