Extending the capabilities of nature's most versatile catalysts: Directed evolution of mammalian xenobiotic-metabolizing P450s

Gillam, EMJ (2007) Extending the capabilities of nature's most versatile catalysts: Directed evolution of mammalian xenobiotic-metabolizing P450s. Archives of Biochemistry And Biophysics, 464 2: 176-186. doi:10.1016/j.abb.2007.04.033


Author Gillam, EMJ
Title Extending the capabilities of nature's most versatile catalysts: Directed evolution of mammalian xenobiotic-metabolizing P450s
Journal name Archives of Biochemistry And Biophysics   Check publisher's open access policy
ISSN 0003-9861
Publication date 2007
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1016/j.abb.2007.04.033
Volume 464
Issue 2
Start page 176
End page 186
Total pages 11
Editor Scarpa, A
Place of publication New York
Publisher Elsevier Science Inc
Collection year 2008
Language eng
Subject C1
270108 Enzymes
780105 Biological sciences
Abstract Cytochrome P450 enzymes are amongst the most versatile enzymatic catalysts known. The ability to introduce a single atom of oxygen into an organic substrate has led to the diversification and exploitation of these enzymes throughout nature. Nowhere is this versatility more apparent than in the mammalian liver, where P450 monooxygenases catalyze the metabolic clearance of innumerate drugs and other environmental chemicals. In addition to the aromatic and aliphatic hydroxylations, N- and O-dealkylations, and heteroatorn oxidations that are common in drug metabolism, many more unusual reactions catalyzed by P450s have been discovered, including reductions, group transfers and other biotransformations not typically associated with monooxygenases. A research area that shows great potential for development over the next few decades is the directed evolution of P450s as biocatalysts. Mammalian xenobiotic-metabolizing P450s are especially well suited to such protein engineering due to their ability to interact with relatively wide ranges of substrates with marked differences in structure and physicochernical properties. Typical characteristics, such as the low turnover rates and poor coupling seen during the metabolism of xenobiotics, as well as the enzyme specificity towards particular substrates and reactions, can be improved by directed evolution. This mini-review will cover the fundamental enabling technologies required to successfully engineer P450s, examine the work done to date on the directed evolution of mammalian forms, and provide a perspective on what will be required for the successful implementation of engineered enzymes. (c) 2007 Elsevier Inc. All rights reserved.
Keyword Biochemistry & Molecular Biology
Biophysics
cytochrome p450
directed evolution
biocatalysis
DNA shuffling
indole
Human Cytochrome-p450 1a2
Oxidative Drug-metabolism
Escherichia-coli
Saturation Mutagenesis
In-vitro
Combinatorial Approach
Genetic-polymorphism
Nadph-p450 Reductase
Crystal-structure
Purification
Q-Index Code C1
Q-Index Status Confirmed Code
Additional Notes This document is a journal review.

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Journal Article Import (ISI/CVs)
Excellence in Research Australia (ERA) - Collection
2008 Higher Education Research Data Collection
School of Biomedical Sciences Publications
 
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Created: Mon, 18 Feb 2008, 14:45:31 EST