Xanthine oxidase (XO) and sulfite oxidase (SO) are mononuclear molybdenum enzymes found in humans that have been linked to Lesch-Nyhan syndrome and sulfite oxidase deficiency, respectively. Both of these diseases are genetic disorders that cause significant neurological defects and ultimately death. XO has also been implicated in oxidative injury as occurs following ischemic shock. Consensus structures derived from EXAFS and crystallographic studies have allowed for new and more detailed hypotheses to be put forth concerning the mechanism of these enzymes. The following testable hypotheses will be specifically addressed: (i) The O-Mo-Cys(S)-C dihedral angle in sulfite oxidase (SO) plays a critical role in modulating the reduction potential of the active site and in facilitating oxygen atom transfer (OAT). (ii) In addition to coupling the active site of SO info efficient sigma-mediated pathways for electron transfer the ene-1,2-dithiolate plays a pivotal role in selecting and activating the equatorial oxo group for atom transfer. Charge redistribution within the ene-1,2-dithiolate effectively facilitates sequential isopotential one-electron transfers. (iii) Conversion of the catalytically essential [MoVIOS(SH)]+ unit to [MoIVO(SH)]+ upon hydroxylation occurs via formal hydride transfer in the XO family of enzymes and is a necessary prerequisite for coupling the active site into efficient superexchange pathways for electron transfer involving the o-orbitals of the pyranopterin. The proposed experiments involve a combination of biochemical manipulation and synthetic chemistry to prepare samples for spectroscopic study.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK059724-03
Application #
6635385
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Hyde, James F
Project Start
2002-04-01
Project End
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$46,420
Indirect Cost
Name
University of New Mexico
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Kirk, Martin L; Peariso, Katrina (2003) Recent applications of MCD spectroscopy to metalloenzymes. Curr Opin Chem Biol 7:220-7
Peariso, Katrina; McNaughton, Rebecca L; Kirk, Martin L (2002) Active-site stereochemical control of oxygen atom transfer reactivity in sulfite oxidase. J Am Chem Soc 124:9006-7