Hydrocarbon hydroxylation by cytochrome P450 enzymes.
Hydrocarbon hydroxylation by cytochrome P450 enzymes.
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DOI：
10.1021/cr9002193
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发表时间：
2010-02-10
期刊：
影响因子：
62.1
通讯作者：
Ortiz de Montellano PR
中科院分区：
文献类型：
--
作者：
Ortiz de Montellano PR
在化学术语中，烃CH键的区域和立体选择性羟基化是非常困难的转化。然而，这些反应被各种金属酶巧妙地催化，其中最多样化的是细胞色素P450家族的许多成员。细胞色素P450酶存在于大多数种类的生物体中，包括细菌、真菌、植物、昆虫和哺乳动物。现在已知数千种这样的蛋白质（http：//drnelson.外展。edu/CytochromeP450。html），包括人类基因组中的57个，结核分枝杆菌中的1 20个，拟南芥中的2 272个，3以及水稻中惊人的457个。4这些酶的命名是基于它们在适当比对时的序列相似性，某种程度上任意的相似性截止值（大约> 40%同一性）用于定义家族成员和更高截止值（大约> 55%同一性）的亚家族成员。因此，CYP 3A 4对应于家族3，亚家族A中的第四种酶。这种命名法允许酶的命名，而不考虑它们的来源或具体性质。哺乳动物、植物和真菌蛋白通常是膜结合的，并且相对难以操作，但细菌蛋白通常是可溶性的单体蛋白。由于这个原因，许多关于细胞色素P450酶机制的早期研究是用细菌酶进行的，特别是用来自恶臭假单胞菌的原型酶CYP 101（P450 cam）。6，7从化学家的角度来看，嗜热酶特别令人感兴趣，目前包括CYP 119，8-10 P450 st，11 CYP 174 A1，12和CYP 231 A2。这些酶的热稳定性使它们成为开发工业上有用的催化剂的有吸引力的起点。在这种情况下，特别注意力还集中在CYP 102（P450 BM 3）上，CYP 102是来自巨大芽孢杆菌的自给自足的酶，其中从NADPH转移电子所需的黄素蛋白质与血红素蛋白融合。[14]由此产生的简单性和高催化速率导致了广泛的努力，以工程改造这种蛋白质用于实际的催化目的。15-19虽然这些蛋白质具有使它们对工程目的特别有吸引力的特性，大量的P450酶共同催化了惊人的多样性反应，这表明P450催化将发展成为一种非常有用的技术。细胞色素P450酶由蛋白质中存在的血红素定义（铁原卟啉IX）辅基通过硫醇根离子在近侧配位。20，21这一特征产生了定义这些酶的光谱特征，因为硫醇盐连接的亚铁-CO复合物的特征在于在λ 450 nm处的Soret吸收最大值。图21存在巯基配位的血红素基团
In chemical terms, the regio-and stereoselective hydroxylation of hydrocarbon CH bonds is a very difficult transformation. Nevertheless, these reactions are deftly catalyzed by a variety of metalloenzymes, among which the most diverse are the many members of the cytochrome P450 family. Cytochrome P450 enzymes are found in most classes of organisms, including bacteria, fungi, plants, insects, and mammals. Thousands of such proteins are now known (http://drnelson. utmem. edu/cytochromeP450. html), including 57 in the human genome, 1 20 in Mycobacterium tuberculosis, 2 272 in Arabidopsis, 3 and the amazing number of 457 in rice. 4 The nomenclature for these enzymes is based on their sequence similarity when appropriately aligned, a somewhat arbitrary similarity cutoff (approximately> 40% identity) being used to define members of a family and a higher cutoff (approximately> 55% identity) members of a subfamily. 5 Thus CYP3A4 corresponds to the fourth enzyme in family 3, subfamily A. This nomenclature allows the naming of enzymes without regard to their origin or specific properties. The mammalian, plant, and fungal proteins are commonly membrane bound and are relatively difficult to manipulate, but the bacterial proteins are usually soluble, monomeric proteins. For that reason, much of the early research on mechanisms of cytochrome P450 enzymes was carried out with bacterial enzymes, particularly with the prototypical enzyme CYP101 (P450cam) from Pseudomonas putida. 6, 7 From a chemist’s point of view, there is a particular interest in the thermophilic enzymes, which currently include CYP119, 8-10 P450st, 11 CYP174A1, 12 and CYP231A2. 13 The thermal stability of these enzymes makes them attractive starting points for the development of industrially useful catalysts. In this context, particular attention has also focused on CYP102 (P450BM3), a self-sufficient enzyme from Bacillus megaterium in which the flavoprotein protein required for transfer of electrons from NADPH is fused to the hemoprotein. 14 The resulting simplicity and high catalytic rate have led to extensive efforts to engineer this protein for practical catalytic purposes. 15-19 Although these proteins have properties that make them particularly attractive for engineering purposes, the large reservoir of P450 enzymes that collectively catalyze an astounding diversity of reactions suggests that P450 catalysis will develop into a highly useful technology.The cytochrome P450 enzymes are defined by the presence in the proteins of a heme (iron protoporphyrin IX) prosthetic group coordinated on the proximal side by a thiolate ion. 20, 21 This feature gives rise to the spectroscopic signature that defines these enzymes, as the thiolate-ligated ferrous-CO complex is characterized by a Soret absorption maximum at∼ 450 nm. 21 A thiolate-coordinated heme group is present
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