Structural perspective on enzymatic halogenation.
Structural perspective on enzymatic halogenation.
复制标题
酶卤化的结构观点。
DOI：
10.1021/ar800088r
复制
发表时间：
2009-01-20
影响因子：
18.3
通讯作者：
Drennan, Catherine L.
中科院分区：
文献类型：
--
作者：
Blasiak, Leah C.;Drennan, Catherine L.
简单的卤素取代物经常提供关键的结构特征，这些特征解释了包括抗生素和激素在内的天然产物的效力和选择性。例如，当抗生素万古霉素上的单个氯原子被氢气取代时，所产生的抗菌活性最高可降低70%(，−)。这篇文章分析了卤化酶中的结构是如何构成机制的，卤化酶是自然界设计的将卤素结合到不同底物中的分子机器。将卤素集成到复杂分子中的传统合成方法往往因缺乏特异性和区域选择性而变得复杂。然而，大自然已经开发出各种优雅的机制，用于卤化具有区域和立体选择性的特定底物。对卤化生物途径的更好理解可能会导致开发新的合成方法，以创造具有增强功能的新化合物。研究人员已经从微生物卡特莱亚链霉菌中增选了一种氟化酶，以生产用于正电子发射断层扫描(−)的18F标记分子。因此，发现和表征自然发生的酶卤化机理已成为一个活跃的研究领域。已知的卤化酶的目录已经从熟悉的卤代过氧化物酶扩大到包括氧依赖酶和氟化酶。最近，一种催化氯化反应的亲核卤化酶的发现扩大了生物卤化化学(，，−)的谱系。结构表征为从机理上理解这些酶的特异性和化学提供了基础。特别是，最新的活性部位结构和卤化物结合部位的结晶学快照为酶催化提供了关键的见解。本文综述了五类卤化酶，重点介绍了最近发现的三种卤化酶：依赖黄素的卤化酶、依赖非血红素铁的卤化酶和亲核的卤化酶。此外，还讨论了卤化物结合部位在决定卤化物选择性方面的潜在作用，以及结合部位的组成是否始终是选择性的重要因素。扩大我们对决定卤代酶活性的基本化学原理的理解将促进生物学和化学的发展。彻底的机理分析将阐明决定特异性的生物学原理，将这些原理应用于新的合成技术将扩大卤代化合物在小分子开发中的用途。
Simple halogen substituents frequently afford key structural features that account for the potency and selectivity of natural products, including antibiotics and hormones. For example, when a single chlorine atom on the antibiotic vancomycin is replaced by hydrogen, the resulting antibacterial activity decreases by up to 70% (, , −). This Account analyzes how structure underlies mechanism in halogenases, the molecular machines designed by nature to incorporate halogens into diverse substrates. Traditional synthetic methods of integrating halogens into complex molecules are often complicated by a lack of specificity and regioselectivity. Nature, however, has developed a variety of elegant mechanisms for halogenating specific substrates with both regio- and stereoselectivity. An improved understanding of the biological routes toward halogenation could lead to the development of novel synthetic methods for the creation of new compounds with enhanced functions. Already, researchers have co-opted a fluorinase from the microorganism Streptomyces cattleya to produce 18F-labeled molecules for use in positron emission tomography (PET) (, −). Therefore, the discovery and characterization of naturally occurring enzymatic halogenation mechanisms has become an active area of research. The catalogue of known halogenating enzymes has expanded from the familiar haloperoxidases to include oxygen-dependent enzymes and fluorinases. Recently, the discovery of a nucleophilic halogenase that catalyzes chlorinations has expanded the repertoire of biological halogenation chemistry (, , −). Structural characterization has provided a basis toward a mechanistic understanding of the specificity and chemistry of these enzymes. In particular, the latest crystallographic snapshots of active site architecture and halide binding sites have provided key insights into enzyme catalysis. Herein is a summary of the five classes of halogenases, focusing on the three most recently discovered: flavin-dependent halogenases, non-heme iron-dependent halogenases, and nucleophilic halogenases. Further, the potential roles of halide-binding sites in determining halide selectivity are discussed, as well as whether or not binding-site composition is always a seminal factor for selectivity. Expanding our understanding of the basic chemical principles that dictate the activity of the halogenases will advance both biology and chemistry. A thorough mechanistic analysis will elucidate the biological principles that dictate specificity, and the application of those principles to new synthetic techniques will expand the utility of halogenations in small-molecule development.
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DOI：
10.1046/j.1432-1327.2000.01491.x
发表时间：
2000-10-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Furtmüller, PC;Obinger, C;Dunford, HB
通讯作者：
Dunford, HB
影响因子：
2.9
作者：
Bitto, Eduard;Huang, Yu;Phillips, George N., Jr.
通讯作者：
Phillips, George N., Jr.
色氨酸7-卤代酶（PRNA）结构提出了一种区域选择性氯化的机制。
DOI：
10.1126/science.1116510
发表时间：
2005-09-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Dong C;Flecks S;Unversucht S;Haupt C;van Pée KH;Naismith JH
通讯作者：
Naismith JH
DOI：
10.1073/pnas.0506964102
发表时间：
2005-09-27
影响因子：
11.1
作者：
Dorrestein, PC;Yeh, E;Walsh, CT
通讯作者：
Walsh, CT
影响因子：
3.7
作者：
Messerschmidt, A;Prade, L;Wever, R
通讯作者：
Wever, R