Structure of CYP2A6: the principal nicotine oxidase

Institution:	Scripps Research Institute
Investigator(s):	Jason Yano, Ph.D.
Award Cycle:	2003 (Cycle 12)	Grant #: 12FT-0185	Award: $75,060
Subject Area:	General Biomedical Science
Award Type:	Postdoctoral Fellowship Awards

Abstracts

Initial Award Abstract

The significant social cost and health risks associated with tobacco have prompted a continued effort to reduce and ultimately eliminate it’s use. The identification of nicotine as the primary addictive component has spawned a therapeutic approach termed “nicotine replacement” to help diminish the grasp of addiction. The logic is simple and compelling. Nicotine provided in the form of chewing gum, skin patches or oral medications is used to replace tobacco as the source of nicotine. However, the body’s ability to rapidly degrade and remove nicotine has been a major obstacle to realizing the full benefits of this approach because of the difficulty in maintaining blood levels that are sufficient to curb craving while remaining below levels that cause nausea and toxicity.

One enzyme, designated CYP2A6, is primarily responsible for the breakdown and removal of nicotine. Recent research indicates that chemical compounds that block the activity of this enzyme can stabilize nicotine levels and enhance the effectiveness and reliability of nicotine replacement therapy. The objective of the research proposed in this application is to determine the structure of the CYP2A6 enzyme using a technique of x-ray crystallography. X-ray crystallography will allow us to build a comprehensive model of the enzyme down to the atomic positions of all the atoms. This will aid us in the characterization of the features that determine inhibitor binding which will provide critical information for the eventual design of drugs that can efficiently and specifically disrupt nicotine inactivation by CYP2A6. A three dimensional model of the enzyme will enable inexpensive and rapid computer searches and simulations to identify and evaluate likely inhibitors.

Publications

THe crystal structure of human microsomal cytochrome P450 2A6 (CYP2A6): the principle nicotine oxidase.
Periodical: SWP			Index Medicus:
Authors: Yano JK, Griffin K, Stout CD, Johnson EF				ABS
Yr: 2004	Vol: 450	Nbr:	Abs:	Pg: 47

The crystal structure of human microsomal cytochrome.
Periodical: MDO			Index Medicus:
Authors: Yano JK, Griffin K, Stout CD, Johnson EF				ABS
Yr: 2004	Vol:	Nbr:	Abs:	Pg:

Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen.
Periodical: Nature Reviews, Molecular Cell Biology			Index Medicus:
Authors: Yano JK, Hsu MH, Griffin JK, Stout CD, Johnson EF				ART
Yr: 0	Vol:	Nbr:	Abs:	Pg:

THe crystal structure of human microsomal cytochrome P450 2A6 (CYP2A6): the principle nicotine oxidase.
Periodical: SWP			Index Medicus:
Authors: Yano JK, Griffin K, Stout CD, Johnson EF				ABS
Yr: 2004	Vol: 450	Nbr:	Abs:	Pg: 47

The crystal structure of human microsomal cytochrome.
Periodical: MDO			Index Medicus:
Authors: Yano JK, Griffin K, Stout CD, Johnson EF				ABS
Yr: 2004	Vol:	Nbr:	Abs:	Pg:

Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen.
Periodical: Nature Reviews, Molecular Cell Biology			Index Medicus:
Authors: Yano JK, Hsu MH, Griffin JK, Stout CD, Johnson EF				ART
Yr: 0	Vol:	Nbr:	Abs:	Pg: