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DOI10.1016/j.taap.2013.12.005
Functional characterization of cytochromes P450 2B from the desert woodrat Neotoma lepida
Wilderman, P. Ross1; Jang, Hyun-Hee1; Malenke, Jael R.2; Salib, Mariam1; Angermeier, Elisabeth1; Lamime, Sonia1; Dearing, M. Denise2; Halpert, James R.1
通讯作者Wilderman, P. Ross
来源期刊TOXICOLOGY AND APPLIED PHARMACOLOGY
ISSN0041-008X
EISSN1096-0333
出版年2014
卷号274期号:3页码:393-401
英文摘要

Mammalian detoxification processes have been the focus of intense research, but little is known about how wild herbivores process plant secondary compounds, many of which have medicinal value or are drugs. cDNA sequences that code for three enzymes of the cytochrome P450 (CYP) 2B subfamily, here termed 2B35, 2B36, and 2B37 have been recently identified from a wild rodent, the desert woodrat (Malenke et al., 2012). Two variant clones of each enzyme were engineered to increase protein solubility and to facilitate purification, as reported for CYP2B enzymes from multiple species. When expressed in Escherichia coli each of the woodrat proteins gave the characteristic maximum at 450 nm in a reduced carbon monoxide difference spectrum but generally expressed at lower levels than rat CYP2B1. Two enzymes, 2B36 and 2B37, showed dealkylation activity with the model substrates 7-ethoxy-4-(trifluoromethyl)coumarin and 7-benzyloxyresorufin, whereas 2B35 was inactive. Binding of the monoterpene (+)-alpha-pinene produced a Type I shift in the absorbance spectrum of each enzyme. Mutation of 2B37 at residues 114, 262, or 480, key residues governing ligand interactions with other CYP2B enzymes, did not significantly change expression levels or produce the expected functional changes. In summary, two catalytic and one ligand-binding assay are sufficient to distinguish among CYP2B35, 2B36, and 2B37. Differences in functional profiles between 2B36 and 2B37 are partially explained by changes in substrate recognition site residue 114, but not 480. The results advance our understanding of the mechanisms of detoxification in wild mammalian herbivores and highlight the complexity of this system. (C) 2013 Elsevier Inc. All rights reserved.


英文关键词Biotransformation Woodrats Cytochrome P450 Juniper Detoxification
类型Article
语种英语
国家USA
收录类别SCI-E
WOS记录号WOS:000331155200004
WOS关键词PLANT SECONDARY COMPOUNDS ; KOALA PHASCOLARCTOS-CINEREUS ; JUNIPER JUNIPERUS-MONOSPERMA ; SUBSTRATE RECOGNITION SITES ; CYP3A SUBFAMILY MEMBER ; HUMAN LIVER-MICROSOMES ; IN-VITRO INHIBITION ; XENOBIOTIC METABOLISM ; MOLECULAR RECOGNITION ; DIRECTED MUTAGENESIS
WOS类目Pharmacology & Pharmacy ; Toxicology
WOS研究方向Pharmacology & Pharmacy ; Toxicology
资源类型期刊论文
条目标识符http://119.78.100.177/qdio/handle/2XILL650/185148
作者单位1.Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA;
2.Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA
推荐引用方式
GB/T 7714
Wilderman, P. Ross,Jang, Hyun-Hee,Malenke, Jael R.,et al. Functional characterization of cytochromes P450 2B from the desert woodrat Neotoma lepida[J],2014,274(3):393-401.
APA Wilderman, P. Ross.,Jang, Hyun-Hee.,Malenke, Jael R..,Salib, Mariam.,Angermeier, Elisabeth.,...&Halpert, James R..(2014).Functional characterization of cytochromes P450 2B from the desert woodrat Neotoma lepida.TOXICOLOGY AND APPLIED PHARMACOLOGY,274(3),393-401.
MLA Wilderman, P. Ross,et al."Functional characterization of cytochromes P450 2B from the desert woodrat Neotoma lepida".TOXICOLOGY AND APPLIED PHARMACOLOGY 274.3(2014):393-401.
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