Torpey J, Ortiz de Montellano P R
Department of Pharmaceutical Chemistry, School of Pharmacy, and Liver Center, University of California, San Francisco, California 94143-0446, USA.
J Biol Chem. 1997 Aug 29;272(35):22008-14. doi: 10.1074/jbc.272.35.22008.
The oxidation of heme to biliverdin IXalpha by heme oxygenase involves regiospecific alpha-meso-hydroxylation followed by extrusion of the alpha-meso-carbon as CO. In an earlier study, enzymatic oxidation of the four meso-methylmesoheme isomers suggested that the reaction regiospecificity is sensitive to the electronic properties of the meso-methyl group (Torpey, J. W., and Ortiz de Montellano, P. R. (1996) J. Biol. Chem. 271, 26067-26073), although we could not exclude the possibility that the altered reaction regiochemistry was due to perturbation of the porphyrin structure by the meso-substituent. To examine this possibility, we have synthesized the four meso-formylmesoporphyrin isomers and have examined their oxidation by heme oxygenase. The meso-formyl and meso-methyl substituents differ in that the former is electron withdrawing and the latter is electron donating. In contrast to alpha-meso-methylmesoheme, which is exclusively oxidized at the methyl-substituted position, alpha-meso-formylmesoheme is exclusively oxidized at a non-formyl-substituted meso-carbon. The finding that the methyl and formyl groups channel the reaction regiospecificity in opposite directions establishes that the regiochemistry of the heme oxygenase reaction is primarily under electronic rather than steric control. It also confirms that the oxidation involves electrophilic addition of the oxygen to the porphyrin ring.
血红素加氧酶将血红素氧化为胆绿素IXα的过程包括区域特异性的α-中位羟基化，随后α-中位碳以CO的形式被挤出。在早期的一项研究中，四种中位甲基中位血红素异构体的酶促氧化表明，反应的区域特异性对中位甲基的电子性质敏感（Torpey, J. W., and Ortiz de Montellano, P. R. (1996) J. Biol. Chem. 271, 26067 - 26073），尽管我们不能排除反应区域化学变化是由于中位取代基对卟啉结构的扰动所致的可能性。为了研究这种可能性，我们合成了四种中位甲酰基中位卟啉异构体，并研究了它们被血红素加氧酶氧化的情况。中位甲酰基和中位甲基取代基的不同之处在于，前者是吸电子的，后者是供电子的。与仅在甲基取代位置被氧化的α-中位甲基中位血红素不同，α-中位甲酰基中位血红素仅在非甲酰基取代的中位碳上被氧化。甲基和甲酰基使反应区域特异性朝相反方向进行这一发现表明，血红素加氧酶反应的区域化学主要受电子而非空间控制。这也证实了氧化过程涉及氧对卟啉环的亲电加成。
