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首页> 外文期刊>Biochemistry >Catalytic versus Inhibitory Promiscuity in Cytochrome P450s: Implications for Evolution of New Function
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Catalytic versus Inhibitory Promiscuity in Cytochrome P450s: Implications for Evolution of New Function

机译：细胞色素P450的催化性与抑制性混杂：对新功能进化的启示

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Catalytically promiscuous enzymes are inter-nmediates in the evolution of new function from an existing poolnof protein scaffolds. However, promiscuity will only confer annevolutionary advantage if other useful properties are notncompromised or if there is no “negative trade-off” induced bynthe mutations that yield promiscuity. Therefore, identificationnand characterization of negative trade-offs incurred during thenemergence of promiscuity are required to further develop thenevolutionary models and to optimize in vitro evolution. Onenpotential negative trade-off of catalytic promiscuity is increasednsusceptibility to inhibition, or inhibitory promiscuity. Here wenexploit cytochrome P450s (CYPs) as a model protein scaffoldnthat spans a vast range of catalytic promiscuity and apply anquantitative index to determine the relationship between pro-nmiscuity of catalysis and promiscuity of inhibition for a series ofnhomologues. The aim of these studies is to begin to identifynproperties that, in general, correlate with catalytic promiscuity, hypothetically such as inhibitory promiscuity. Interestingly, the datanindicate that the potential negative trade-off of inhibitory promiscuity is nearly insignificant because even highly substrate specificnCYPs have high inhibitory promiscuity, with little incremental increase in susceptibility to inhibitory interactions as the substratenpromiscuity increases across the series of enzymes. In the context of evolution, inhibitory promiscuity is not an obligate negativentrade-off for catalytic promiscuity
机译：催化混杂酶是从现有蛋白质骨架中进化出新功能的中间媒介。但是，如果不损害其他有用特性，或者不存在由产生滥交的突变引起的“负交易”，那么滥交只会赋予后代优势。因此，为了进一步发展进化模型和优化体外进化，需要在滥交出现期间识别和表征负面交易。催化混杂的潜在负交易是增加了对抑制或抑制混杂的敏感性。在这里，wenexploit细胞色素P450（CYP）作为模型蛋白被广泛使用，并广泛应用于各种催化混杂物中，并应用定量指标来确定催化混杂和抑制混杂之间的关系。这些研究的目的是开始鉴定通常与催化混杂有关的性质，如假设为抑制混杂。有趣的是，该数据表明抑制性混杂的潜在负平衡几乎是微不足道的，因为即使底物特异性CYPs含量高，抑制性也很高，随着底物在整个系列酶中的增加，抑制相互作用的敏感性几乎没有增加。在进化的背景下，抑制性混杂不是催化性混杂的专性负贸易。

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  • 来源
    《Biochemistry》 |2011年第13期|p.2387-2393|共7页
  • 作者

    Robert S. Foti Mathew Honaker Abhinav Nath Josh T. Pearson Brian Buttrick Nina Isoherranen and William M. Atkins;

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    †Department of Drug Metabolism and Pharmacokinetics, Amgen Inc., Seattle, Washington 98119, United States‡Department of Medicinal Chemistry, Box 357610, University of Washington, Seattle, Washington 98195-7610, United States§Department of Molecular Biophysics and Biochemistry, Yale University, Box 208114, New Haven, Connecticut 06520-8114, UnitedStates) Department of Pharmaceutics, Box 357, University of Washington, Seattle, Washington 98195-76, United States;

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