Abstract

Copper-containing amine oxidases are widely distributed in nature and are involved in the metabolism of biogenic primary amines. Amine oxidases may have a variety of functions in the cardiovascular, gastrointestinal, and nervous systems of mammals. Amine oxidases are also responsible for the cross-linking of connective tissue structural proteins (elastin and collagen). It appears that numerous compounds with antifungal; antiprotozoal, or anticancer activities may target amine oxidases; for example pentamidine,a leading drug for the treatment of Pneumocystis carinii pneumonia (PCP) in AIDS patients belongs to class of compounds that inhibit amine oxidases. The principal goals are to determine the 3-D structures of multiple amine oxidases, including at least one human enzyme, and to elucidate the mechanisms of amine oxidation and cofactor (TPQ) biogenesis. In addition, the structure and biosynthesis of a related enzyme, galactose oxidase, will be examined. Site-directed mutagenesis, spectroscopy, kinetics measurements, and crystallography are employed. The crystal structures of two amine oxidases have been solved, revealing several novel features, including a second metal-binding site. Combining structural and mechanistic data WI permit a detailed understanding of the structure and function of these important enzymes to be developed.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM027659-20
Application #
6018514
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1980-07-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
20
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Montana State University Bozeman
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Bozeman
State
MT
Country
United States
Zip Code
59717

  Publications

Cowley, Ryan E; Cirera, Jordi; Qayyum, Munzarin F et al. (2016) Structure of the Reduced Copper Active Site in Preprocessed Galactose Oxidase: Ligand Tuning for One-Electron O2 Activation in Cofactor Biogenesis. J Am Chem Soc 138:13219-13229
Liu, Yi; Mukherjee, Arnab; Nahumi, Nadav et al. (2013) Experimental and computational evidence of metal-O2 activation and rate-limiting proton-coupled electron transfer in a copper amine oxidase. J Phys Chem B 117:218-29
Mills, Stephen A; Brown, Doreen E; Dang, Kaitlyn et al. (2012) Cobalt substitution supports an inner-sphere electron transfer mechanism for oxygen reduction in pea seedling amine oxidase. J Biol Inorg Chem 17:507-15
Rokhsana, Dalia; Howells, Alta E; Dooley, David M et al. (2012) Role of the Tyr-Cys cross-link to the active site properties of galactose oxidase. Inorg Chem 51:3513-24
McGrath, Aaron P; Hilmer, Kimberly M; Collyer, Charles A et al. (2010) A new crystal form of human diamine oxidase. Acta Crystallogr Sect F Struct Biol Cryst Commun 66:137-42
Ran, Yanchao; Liu, Mengyao; Zhu, Hui et al. (2010) Spectroscopic identification of heme axial ligands in HtsA that are involved in heme acquisition by Streptococcus pyogenes. Biochemistry 49:2834-42
McGrath, Aaron P; Hilmer, Kimberly M; Collyer, Charles A et al. (2009) Structure and inhibition of human diamine oxidase. Biochemistry 48:9810-22
Zhu, Hui; Xie, Gang; Liu, Mengyao et al. (2008) Pathway for heme uptake from human methemoglobin by the iron-regulated surface determinants system of Staphylococcus aureus. J Biol Chem 283:18450-60
Rogers, Melanie S; Hurtado-Guerrero, Ramon; Firbank, Susan J et al. (2008) Cross-link formation of the cysteine 228-tyrosine 272 catalytic cofactor of galactose oxidase does not require dioxygen. Biochemistry 47:10428-39
Mukherjee, Arnab; Smirnov, Valeriy V; Lanci, Michael P et al. (2008) Inner-sphere mechanism for molecular oxygen reduction catalyzed by copper amine oxidases. J Am Chem Soc 130:9459-73

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