Abstract

Furanocoumarins are naturally occurring plant metabolites that are extremely toxic because they react with pyrimidine bases in DNA and with general cellular proteins when photoactivated and because they interact reversibly and irreversibly with P450 catalytic sites. These photobiologic properties of furanocoumarins have been exploited for the treatment of a variety of human skin diseases even though the mechanisms for their metabolism and their effects on endogenous drug metabolizing P450s have not been well established. Much can be learned about their metabolism and mechanism of P450 inhibition by studying the P450s that are in herbivorous insects specialized to feed on host plants containing high levels of liner and angular forms of these furanocoumarins.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050007-07
Application #
6519557
Study Section
Special Emphasis Panel (ZRG1-TMP (01))
Program Officer
Okita, Richard T
Project Start
1994-12-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2004-03-31
Support Year
7
Fiscal Year
2002
Total Cost
$277,693
Indirect Cost

  Institution

Name
University of Illinois Urbana-Champaign
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820

  Publications

Wen, Zhimou; Baudry, Jerome; Berenbaum, May R et al. (2005) Ile115Leu mutation in the SRS1 region of an insect cytochrome P450 (CYP6B1) compromises substrate turnover via changes in a predicted product release channel. Protein Eng Des Sel 18:191-9
Brown, Rebecca Petersen; McDonnell, Cynthia M; Berenbaum, May R et al. (2005) Regulation of an insect cytochrome P450 monooxygenase gene (CYP6B1) by aryl hydrocarbon and xanthotoxin response cascades. Gene 358:39-52
Petersen Brown, R; Berenbaum, M R; Schuler, M A (2004) Transcription of a lepidopteran cytochrome P450 promoter is modulated by multiple elements in its 5' UTR and repressed by 20-hydroxyecdysone. Insect Mol Biol 13:337-47
Li, W; Zangerl, A R; Schuler, M A et al. (2004) Characterization and evolution of furanocoumarin-inducible cytochrome P450s in the parsnip webworm, Depressaria pastinacella. Insect Mol Biol 13:603-13
Li, Xianchun; Baudry, Jerome; Berenbaum, May R et al. (2004) Structural and functional divergence of insect CYP6B proteins: From specialist to generalist cytochrome P450. Proc Natl Acad Sci U S A 101:2939-44
Pan, Liping; Wen, Zhimou; Baudry, Jerome et al. (2004) Identification of variable amino acids in the SRS1 region of CYP6B1 modulating furanocoumarin metabolism. Arch Biochem Biophys 422:31-41
Baudry, Jerome; Li, Weimin; Pan, Liping et al. (2003) Molecular docking of substrates and inhibitors in the catalytic site of CYP6B1, an insect cytochrome p450 monooxygenase. Protein Eng 16:577-87
Civjan, Natanya R; Bayburt, Timothy H; Schuler, Mary A et al. (2003) Direct solubilization of heterologously expressed membrane proteins by incorporation into nanoscale lipid bilayers. Biotechniques 35:556-60, 562-3
Li, Weimin; Schuler, Mary A; Berenbaum, May R (2003) Diversification of furanocoumarin-metabolizing cytochrome P450 monooxygenases in two papilionids: Specificity and substrate encounter rate. Proc Natl Acad Sci U S A 100 Suppl 2:14593-8
Wen, Zhimou; Pan, Liping; Berenbaum, May R et al. (2003) Metabolism of linear and angular furanocoumarins by Papilio polyxenes CYP6B1 co-expressed with NADPH cytochrome P450 reductase. Insect Biochem Mol Biol 33:937-47

Showing the most recent 10 out of 14 publications