Tetrahydrobiopterin rapidly reduces the SOD mimic Mn(III) ortho-tetrakis(N-ethylpyridinium-2-yl)porphyrin
Tetrahydrobiopterin rapidly reduces the SOD mimic Mn(III) ortho-tetrakis(N-ethylpyridinium-2-yl)porphyrin
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DOI：
10.1016/j.freeradbiomed.2004.04.041
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发表时间：
2004-08-01
影响因子：
7.4
通讯作者：
Fridovich, I
中科院分区：
文献类型：
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作者：
Batinic-Haberle, I;Spasojevic, I;Fridovich, I
在不同的啮齿动物氧化应激损伤模型中，Mn(III)ortho-tetrakis(N-ethylpyridinium-2-yl)porphyrin((MnTe)-T-III-2-PYP5+)在体外有效地清除活性氧和氮物种，并在体内起到保护作用。此外，(MnTe)-T-III-2-PyP5+很容易被抗坏血酸和谷胱甘肽等细胞还原剂还原。我们现在证明四氢生物蝶呤(BH4)也能够还原金属中心。在厌氧条件下，(MnTe)-T-III-2-PYP5+在25+/-0.1℃磷酸盐缓冲溶液中的还原反应分两步进行，反应速率常数k(1)=1.0×10(4)M-1 S(-1)和k(2)=1.5×10(3)M-1 S(-1)。我们将这些步骤归因于四氢生物蝶呤自由基(BH4.+)(k(1))的形成，然后氧化成6，7-二氢-8H-生物蝶呤(k(2))，再重排生成7，8-二氢生物蝶呤(7，8-BH2)。在好氧条件下，(MnTe)-T-III-2-PyP5+催化氧化BH4。它的长链烷基类似物Mn(III)ortho-tetrakis(N-n-octylpyridinium-2yl)porphyrin.也是如此还原的锰(II)卟啉不能被7，8-BH_2或L-海风蝶呤氧化。讨论了(MnTE)-T-III-2-PyP5+与BH4相互作用对内皮细胞增殖的可能影响，从而通过抑制一氧化氮合酶抑制肿瘤血管生成。(C)2004 Elsevier Inc.保留所有权利。
Mn(III) ortho-tetrakis(N-ethylpyridinium-2-yl)porphyrin ((MnTE)-T-III-2-PyP5+) effectively scavenges reactive oxygen and nitrogen species in vitro, and protects in vivo, in different rodent models of oxidative stress injuries. Further, (MnTE)-T-III-2-PyP5+ was shown to be readily reduced by cellular reductants such as ascorbic acid and glutathione. We now show that tetrahydrobiopterin (BH4) is also able to reduce the metal center. Under anaerobic conditions, in phosphate-buffered saline (pH 7.4) at 25 +/- 0.1degreesC, reduction of (MnTE)-T-III-2-PyP5+ occurs through two reaction steps with rate constants k(1) = 1.0 x 10(4) M-1 s(-1) and k(2) = 1.5 x 10(3) M-1 s(-1). We ascribe these steps to the formation of tetrahydrobiopterin radical (BH4.+) (k(1)) that then undergoes oxidation to 6,7-dihydro-8H-biopterin (k(2)), which upon rearrangement gives rise to 7,8-dihydrobiopterin (7,8-BH2). Under aerobic conditions, (MnTE)-T-III-2-PyP5+ catalytically oxidizes BH4. This is also true for its longer chain alkyl analog, Mn(III) ortho-tetrakis(N-n-octylpyridinium-2yl)porphyrin. The reduced Mn(II) porphyrin cannot be oxidized by 7,8-BH2 or by L-sepiapterin. The data are discussed with regard to the possible impact of the interaction of (MnTE)-T-III-2-PyP5+ with BH4 on endothelial cell proliferation and hence on tumor antiangiogenesis via inhibition of nitric oxide synthase. (C) 2004 Elsevier Inc. All rights reserved.