NDLI: Engineering human cytochrome P450 enzymes into catalytically self-sufficient chimeras using molecular Lego

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Engineering human cytochrome P450 enzymes into catalytically self-sufficient chimeras using molecular Lego

Content Provider	Springer Nature Link
Author	Dodhia, Vikash Rajnikant Fantuzzi, Andrea Gilardi, Gianfranco
Copyright Year	2006
Abstract	The membrane-bound human cytochrome P450s have essential roles in the metabolism of endogenous compounds and drugs. Presented here are the results on the construction and characterization of three fusion proteins containing the N-terminally modified human cytochrome P450s CYP2C9, CY2C19 and CYP3A4 fused to the soluble NADPH-dependent oxidoreductase domain of CYP102A1 from Bacillus megaterium. The constructs, CYP2C9/BMR, CYP2C19/BMR and CYP3A4/BMR are well expressed in Escherichia coli as holo proteins. The chimeras can be purified in the absence of detergent and the purified enzymes are both active and correctly folded in the absence of detergent, as demonstrated by circular dichroism and functional studies. Additionally, in comparison with the parent P450 enzyme, these chimeras have greatly improved solubility properties. The chimeras are catalytically self-sufficient and present turnover rates similar to those reported for the native enzymes in reconstituted systems, unlike previously reported mammalian cytochrome P450 fusion proteins. Furthermore the specific activities of these chimeras are not dependent on the enzyme concentration present in the reaction buffer and they do not require the addition of accessory proteins, detergents or phospholipids to be fully active. The solubility, catalytic self-sufficiency and wild-type like activities of these chimeras would greatly simplify the studies of cytochrome P450 mediated drug metabolism in solution.
Starting Page	903
Ending Page	916
Page Count	14
File Format	PDF
ISSN	09498257
Journal	JBIC Journal of Biological Inorganic Chemistry
Volume Number	11
Issue Number	7
e-ISSN	14321327
Language	English
Publisher	Springer-Verlag
Publisher Date	2006-07-22
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Protein engineering Human cytochrome P450 fusion proteins Drug metabolism Electron transfer Molecular Lego
Content Type	Text
Resource Type	Article
Subject	Biochemistry Inorganic Chemistry

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