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Cytochromes P450 in nanodiscs.纳米盘中的细胞色素P450
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Functional reconstitution of monomeric CYP3A4 with multiple cytochrome P450 reductase molecules in Nanodiscs.在纳米盘里用多个细胞色素 P450 还原酶分子对单体 CYP3A4 进行功能重建。
Biochem Biophys Res Commun. 2010 Jul 23;398(2):194-8. doi: 10.1016/j.bbrc.2010.06.058. Epub 2010 Jun 17.
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The least-squares analysis of data from binding and enzyme kinetics studies weights, bias, and confidence intervals in usual and unusual situations.结合和酶动力学研究数据的最小二乘法分析对常规和非常规情况下的权重、偏差及置信区间进行了考量。
Methods Enzymol. 2009;467:499-529. doi: 10.1016/S0076-6879(09)67019-1.
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Mixing apples and oranges: Analysis of heterotropic cooperativity in cytochrome P450 3A4.风马牛不相及：细胞色素P450 3A4的异源协同性分析
Arch Biochem Biophys. 2009 Aug 15;488(2):146-52. doi: 10.1016/j.abb.2009.06.013. Epub 2009 Jun 26.
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Cooperative properties of cytochromes P450.细胞色素 P450 的协同性质。
Pharmacol Ther. 2009 Nov;124(2):151-67. doi: 10.1016/j.pharmthera.2009.05.011. Epub 2009 Jun 23.
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Allosteric P450 mechanisms: multiple binding sites, multiple conformers or both?变构细胞色素P450机制：多个结合位点、多个构象体，还是两者皆有？
Expert Opin Drug Metab Toxicol. 2008 Dec;4(12):1523-35. doi: 10.1517/17425250802500028.
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Understanding cooperativity in human p450 mediated drug-drug interactions.理解人类细胞色素P450介导的药物-药物相互作用中的协同作用。
Drug Metab Rev. 2007;39(2-3):567-79. doi: 10.1080/03602530701498521.
8
Ligand binding to cytochrome P450 3A4 in phospholipid bilayer nanodiscs: the effect of model membranes.配体与磷脂双分子层纳米盘内细胞色素P450 3A4的结合：模型膜的影响
J Biol Chem. 2007 Sep 28;282(39):28309-28320. doi: 10.1074/jbc.M703568200. Epub 2007 Jun 15.
9
Cooperativity in cytochrome P450 3A4: linkages in substrate binding, spin state, uncoupling, and product formation.细胞色素P450 3A4中的协同性：底物结合、自旋状态、解偶联及产物形成之间的联系
J Biol Chem. 2007 Mar 9;282(10):7066-76. doi: 10.1074/jbc.M609589200. Epub 2007 Jan 9.
10
Mechanism of interactions of alpha-naphthoflavone with cytochrome P450 3A4 explored with an engineered enzyme bearing a fluorescent probe.利用带有荧光探针的工程酶探究α-萘黄酮与细胞色素P450 3A4的相互作用机制。
Biochemistry. 2007 Jan 9;46(1):106-19. doi: 10.1021/bi061944p.

利用 α-萘黄酮和睾酮分析细胞色素 P4503A4 的变构协同作用。

Analysis of heterotropic cooperativity in cytochrome P450 3A4 using alpha-naphthoflavone and testosterone.

机构信息

Department of Biochemistry, School of Molecular and Cellular Biology, University of Illinois, Urbana, Illinois 61801, USA.

出版信息

J Biol Chem. 2011 Feb 18;286(7):5540-5. doi: 10.1074/jbc.M110.182055. Epub 2010 Dec 22.

DOI:10.1074/jbc.M110.182055
PMID:21177853
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3037667/
Abstract

Cytochrome P450 3A4 (CYP3A4) displays non-Michaelis-Menten kinetics for many of the substrates it metabolizes, including testosterone (TST) and α-naphthoflavone (ANF). Heterotropic effects between these two substrates can further complicate the metabolic profile of the enzyme. In this work, monomeric CYP3A4 solubilized in Nanodiscs has been studied for its ability to interact with varying molar ratios of ANF and TST. Comparison of the observed heme spin state, NADPH consumption, and product formation rates with a non-cooperative model calculated from a linear combination of the global analysis of each substrate reveals a detailed landscape of the heterotropic interactions and indicates negligible binding cooperativity between ANF and TST. The observed effect of ANF on the kinetics of TST metabolism is due to the additive action of the second substrate with no specific allosteric effects.

摘要

细胞色素 P450 3A4（CYP3A4）对其代谢的许多底物表现出非米氏动力学，包括睾酮（TST）和α-萘黄酮（ANF）。这两种底物之间的变构效应会进一步使酶的代谢谱复杂化。在这项工作中，研究了在 Nanodiscs 中溶解的单体 CYP3A4 与不同摩尔比的 ANF 和 TST 相互作用的能力。通过对每个底物的全局分析的线性组合计算出的非协同模型与观察到的血红素自旋态、NADPH 消耗和产物形成速率进行比较，揭示了变构相互作用的详细情况，并表明 ANF 和 TST 之间几乎没有结合协同性。观察到的 ANF 对 TST 代谢动力学的影响是由于第二个底物的加和作用，没有特定的变构效应。