THE BIOINORGANIC CHEMISTRY OF HEME PROTEINS

本研究的目标涉及合成和表征 各种血红素蛋白的合成类似物。 兴趣的反应 包括1）O 2、CO和通过血红蛋白、肌红蛋白 非哺乳动物血红素蛋白，2）O2活化和烃羟基化 通过单加氧酶细胞色素P-450，和3）与和 氧化剂被过氧化氢酶和过氧化物酶还原。 这些酶 与心血管功能有关;药物、激素和外来生物质 代谢;以及氧化剂解毒和底物氧化。 我们 研究的方向是了解分子机制 在密切相关的模型金属卟啉的这些反应。 我们已经合成、表征和定量研究了02和 其他配体结合到一系列的卟啉合铁（II）络合物。 的 特别感兴趣的是我们的"双口袋"生物蛋白，它提供保护 在大环的两面上都有口袋， 健壮。 这种卟啉口袋的非极性性质使我们能够 量化极性、氢键等因素的贡献 O2和CO的亲和力。 这种卟啉也被证明可用于 显著稳定高氧化态络合物， 类似于过氧化物酶和过氧化氢酶的化合物I和II以及类似于 细胞色素P-450的活性羟化酶种类。 此外，立体 口袋的保护有利于末端羟基化和环氧化， 证明了形状选择性底物识别。 额外的工作有 对高度氧化的单原子桥连铁卟啉进行了 二聚体，这表明电子结构的敏感性， 这类系统与连接的性质有关。 继续努力， 这些领域应该导致对影响的定量理解， 其将O2和CO结合调节至完全表征， 高氧化态血红素蛋白合成类似物的分离 中间，并更深入地了解基板形状的选择性 和单加氧酶的区域特异性。

The objectives of this research involve the synthesis and characterization of synthetic analogues of various heme proteins. The reactions of interest include 1) O2, CO and ligand binding by hemoglobin, myoglobin and nonmammalian hemoproteins, 2) O2 activation and hydrocarbon hydroxylation by the monooxygenase cytochrome P-450, and 3) the reaction with and reduction of oxidants by catalase and peroxidase. These enzymes are relevant to cardiovascular functioning; drug, hormone and exobiotic metabolism; and to oxidant detoxification and substrate oxidation. Our studies are directed towards an understanding of the molecular mechanisms of these reactions in closely related model metalloporphyrine. We have synthesized, characterized, and quantitatively studied the 02 and other ligand binding to a series of porphyrinatoiron(II) complexes. Of special interest in our "bis-pocket" prophyrin, which provides protected pockets on both faces of the macrocyle and which is extremely oxidatively robust. The non-polar nature of this porphyrin's pockets allows us to quantitate the contribution of polarity, hydrogen bonding and other factors of 02 and CO affinities. This porphyrin has also proved useful in dramatically stabilizing high oxidation state complexes which may be analogous to Compounds I and II of peroxidase and catalase and to the active hydroxylase species of cytochrome P-450. In addition, the steric protection of the pocket favors terminal hydroxylation and epoxidation, demonstrating shape-selective substrate recognition. Additional work has been carried out on highly oxidized single atom bridged iron porphyrin dimers which has demonstrated the sensitivity of electronic structure in such systems to the nature of ligation. Continuation of our efforts in these areas should lead to a quantitative understanding of the influences which modulate 02, and CO binding, to the full characterization and isolation of synthetic analogs of high oxidation state heme protein intermediate, and to a closer understanding of substrate shape selectivity and regiospecificity by monooxygenases.