THE 3-DIMENSIONAL STRUCTURE OF NAD(P)H-QUINONE REDUCTASE, A FLAVOPROTEIN INVOLVED IN CANCER CHEMOPROTECTION AND CHEMOTHERAPY - MECHANISM OF THE 2-ELECTRON REDUCTION
THE 3-DIMENSIONAL STRUCTURE OF NAD(P)H-QUINONE REDUCTASE, A FLAVOPROTEIN INVOLVED IN CANCER CHEMOPROTECTION AND CHEMOTHERAPY - MECHANISM OF THE 2-ELECTRON REDUCTION
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DOI：
10.1073/pnas.92.19.8846
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发表时间：
1995-09-12
影响因子：
11.1
通讯作者：
AMZEL, LM
中科院分区：
文献类型：
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作者：
LI, RB;BIANCHET, MA;AMZEL, LM
醌还原酶[NAD（P）H：（醌受体）氧化还原酶，EC 1.6.99.2]，也称为DT黄递酶，是一种含FAD的同型二聚体酶，其催化醌的强制性NAD（P）H依赖性双电子还原，并保护细胞免受由单电子还原产生的自由基和活性氧的毒性和肿瘤作用。这两个电子还原参与肿瘤细胞中癌症化疗剂如丝裂霉素C的还原性生物活化。因此，令人惊讶的是，保护正常细胞的相同酶促反应激活癌症化疗中使用的细胞毒性药物。大鼠肝醌还原酶的2.1埃晶体结构揭示每个单体的一部分的折叠类似于黄素氧还蛋白，一种细菌含FMN的蛋白，多肽链的另外两个部分参与二聚化和两个单体都参与的两个相同催化位点的形成，两种含FAD的酶复合物（一种含NADP（+），另一种含杜醌）的晶体结构表明，从NAD（P）H到FAD和从FADH（2）到醌（占据NAD（P）H空出的位点）的直接氢化物转移为涉及乒乓机制的强制性双电子还原提供了简单的理论基础。
Quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2], also called DT diaphorase, is a homodimeric FAD-containing enzyme that catalyzes obligatory NAD(P)H-dependent two-electron reductions of quinones and protects cells against the toxic and neoplastic effects of free radicals and reactive oxygen species arising from one-electron reductions, These two electron reductions participate in the reductive bioactivation of cancer chemotherapeutic agents such as mitomycin C in tumor cells, Thus, surprisingly, the same enzymatic reaction that protects normal cells activates cytotoxic drugs used in cancer chemotherapy, The 2.1-Angstrom crystal structure of rat liver quinone reductase reveals that the folding of a portion of each monomer is similar to that of flavodoxin, a bacterial FMN-containing protein, Two additional portions of the polypeptide chains are involved in dimerization and in formation of the two identical catalytic sites to which both monomers contribute, The crystallographic structures of two FAD-containing enzyme complexes (one containing NADP(+), the other containing duroquinone) suggest that direct hydride transfers from NAD(P)H to FAD and from FADH(2) to the quinone [which occupies the site vacated by NAD(P)H] provide a simple rationale for the obligatory two-electron reductions involving a ping-pong mechanism.