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Functional Evolution and Structural Conservation in Chimeric Cytochromes P450: Calibrating a Structure-Guided Approach

Otey, Christopher R. and Silberg, Jonathan J. and Voigt, Christopher A. and Endelman, Jeffrey B. and Bandara, Geethani and Arnold, Frances H. (2004) Functional Evolution and Structural Conservation in Chimeric Cytochromes P450: Calibrating a Structure-Guided Approach. Chemistry and Biology, 11 (3). pp. 309-318. ISSN 1074-5521. doi:10.1016/j.chembiol.2004.02.018.

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Recombination generates chimeric proteins whose ability to fold depends on minimizing structural perturbations that result when portions of the sequence are inherited from different parents. These chimeric sequences can display functional properties characteristic of the parents or acquire entirely new functions. Seventeen chimeras were generated from two CYP102 members of the functionally diverse cytochrome P450 family. Chimeras predicted to have limited structural disruption, as defined by the SCHEMA algorithm, displayed CO binding spectra characteristic of folded P450s. Even this small population exhibited significant functional diversity: chimeras displayed altered substrate specificities, a wide range in thermostabilities, up to a 40-fold increase in peroxidase activity, and ability to hydroxylate a substrate toward which neither parent heme domain shows detectable activity. These results suggest that SCHEMA-guided recombination can be used to generate diverse P450s for exploring function evolution within the P450 structural framework.

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Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2004 Cell Press. Published by Elsevier Ltd. Under an Elsevier user license. Received 13 June 2003, Revised 12 November 2003, Accepted 2 December 2003, Available online 8 April 2004. The authors thank Claes von Wachenfeldt for kindly providing the CYP102A2 gene. This work was supported by the Army Research Office, the W.M. Keck Foundation, Maxygen Corporation, National Institutes of Health Grant R01 GM068664-01 and Fellowship F32 GM64949-01 (to J.J.S.), National Science Foundation (to C.A.V.), Burroughs-Welcome Fund (to C.A.V.), and National Defense Science and Engineering Fellowship (to J.B.E.).
Funding AgencyGrant Number
Army Research Office (ARO)UNSPECIFIED
W. M. Keck FoundationUNSPECIFIED
Maxygen CorporationUNSPECIFIED
NIHR01 GM068664-01
NIH Postdoctoral FellowshipF32 GM64949-01
Burroughs-Welcome FundUNSPECIFIED
National Defense Science and Engineering Graduate (NDSEG) FellowshipUNSPECIFIED
Issue or Number:3
Record Number:CaltechAUTHORS:20180821-150058089
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Official Citation:Christopher R Otey, Jonathan J Silberg, Christopher A Voigt, Jeffrey B Endelman, Geethani Bandara, Frances H Arnold, Functional Evolution and Structural Conservation in Chimeric Cytochromes P450: Calibrating a Structure-Guided Approach, Chemistry & Biology, Volume 11, Issue 3, 2004, Pages 309-318, ISSN 1074-5521, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:88994
Deposited By: Tony Diaz
Deposited On:21 Aug 2018 22:52
Last Modified:16 Nov 2021 00:31

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