The long range goal of this project is to study structure-function relationships in cytochromes P450 and related proteins using x-ray crystallography, molecular biology, and biochemistry. The focus will be on redox complexes formed between protein electron donors and acceptors in various P450 systems with an emphasis on three bacterial systems: P450cam, P450cin, and P450BM3. In addition to the traditional tools of crystallography, spectroscopy, protein engineering, and enzymology high field NMR will be employed to study protein-protein interactions.

Public Health Relevance

This proposal centers on structure function relationships in cytochromes P450. P450s are one of the largest known enzyme families and participate in a vast array of biological processes. Especially important is the role played by P450s in drug metabolism, cancer, and the biosynthesis of critical steroid intermediates and antibiotics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033688-28
Application #
8383476
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Smith, Ward
Project Start
1987-03-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
28
Fiscal Year
2013
Total Cost
$269,574
Indirect Cost
$93,382
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Poulos, Thomas L (2014) Heme enzyme structure and function. Chem Rev 114:3919-62
Madrona, Yarrow; Hollingsworth, Scott A; Tripathi, Sarvind et al. (2014) Crystal structure of cindoxin, the P450cin redox partner. Biochemistry 53:1435-46
Sevrioukova, Irina F; Poulos, Thomas L (2014) Ritonavir analogues as a probe for deciphering the cytochrome P450 3A4 inhibitory mechanism. Curr Top Med Chem 14:1348-55
Madrona, Yarrow; Hollingsworth, Scott A; Khan, Bushra et al. (2013) P450cin active site water: implications for substrate binding and solvent accessibility. Biochemistry 52:5039-50
Sevrioukova, Irina F; Poulos, Thomas L (2013) Dissecting cytochrome P450 3A4-ligand interactions using ritonavir analogues. Biochemistry 52:4474-81
Sevrioukova, Irina F; Poulos, Thomas L (2013) Pyridine-substituted desoxyritonavir is a more potent inhibitor of cytochrome P450 3A4 than ritonavir. J Med Chem 56:3733-41
Sevrioukova, Irina F; Poulos, Thomas L (2013) Understanding the mechanism of cytochrome P450 3A4: recent advances and remaining problems. Dalton Trans 42:3116-26
Batabyal, Dipanwita; Li, Huiying; Poulos, Thomas L (2013) Synergistic effects of mutations in cytochrome P450cam designed to mimic CYP101D1. Biochemistry 52:5396-402
Poulos, Thomas L; Madrona, Yarrow (2013) Oxygen activation and redox partner binding in cytochromes P450. Biotechnol Appl Biochem 60:128-33
Tripathi, Sarvind; Li, Huiying; Poulos, Thomas L (2013) Structural basis for effector control and redox partner recognition in cytochrome P450. Science 340:1227-30

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