Heme oxygenase oxidizes heme to biliverdin, CO, and iron. This is the only physiological mechanism for heme, degradation, although pathological heme degradation processes exist that do not yield biliverdin. All three heme oxygenase products are now thought to have important physiological roles: biliverdin as an antioxidant, CO as a signaling molecule akin to NO, and iron as a source of the metal for new heme synthesis and, under pathological conditions, as a catalyst of oxidative damage. Heme oxygenase thus fills a pivotal role in physiological and pathological processes. The long-term goal of this project is to elucidate the mechanisms of normal and abnormal heme degradation and their consequences. The immediate goal is to determine the structure, mechanism, and function of heme oxygenase. The investigator proposes to: (a) complete determination of the crystal structure of human heme oxygenase-1 and its substrate, product, and ligand complexes; (b) elucidate the catalytic mechanism of heme oxygenase-1 with emphasis on identifying all the reaction intermediates, establishing the kinetic mechanism, and identifying the catalytic residues; (c) clarify the mechanisms of the individual steps in the transformation catalyzed by heme oxygenases and the mechanistic relationship of the heme oxygenases to other catalytic hemoproteins, notably to the peroxidases and cytochrome P450 enzymes; (d) explore the mechanism of the abnormal H2O2 -dependent degradation of heme groups to monopyrrole and dipyrrole products; and (e) develop non-porphyrin, inhibitors of the heme oxygenases that do not inhibit the nitric oxide synthases or guanylyl cyclase. The results should help to clarify the molecular aspects of normal and abnormal heme catabolism, shed light on the physiological roles of the heme oxygenase products, and advance our fundamental understanding of hemoprotein structure and function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK030297-19
Application #
6177063
Study Section
Biochemistry Study Section (BIO)
Program Officer
Badman, David G
Project Start
1982-01-01
Project End
2004-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
19
Fiscal Year
2000
Total Cost
$156,967
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Meitzler, Jennifer L; Hinde, Sara; Bánfi, Botond et al. (2013) Conserved cysteine residues provide a protein-protein interaction surface in dual oxidase (DUOX) proteins. J Biol Chem 288:7147-57
Peng, Dungeng; Ogura, Hiroshi; Ma, Li-Hua et al. (2013) Solution NMR characterization of magnetic/electronic properties of azide and cyanide-inhibited substrate complexes of human heme oxygenase: implications for steric ligand tilt. J Inorg Biochem 121:179-86
Varfaj, Fatbardha; Lampe, Jed N; Ortiz de Montellano, Paul R (2012) Role of cysteine residues in heme binding to human heme oxygenase-2 elucidated by two-dimensional NMR spectroscopy. J Biol Chem 287:35181-91
Nishida, Clinton R; Ortiz de Montellano, Paul R (2011) Bioactivation of antituberculosis thioamide and thiourea prodrugs by bacterial and mammalian flavin monooxygenases. Chem Biol Interact 192:21-5
Meitzler, Jennifer L; Ortiz de Montellano, Paul R (2011) Structural stability and heme binding potential of the truncated human dual oxidase 2 (DUOX2) peroxidase domain. Arch Biochem Biophys 512:197-203
Jiang, Yongying; Trnka, Michael J; Medzihradszky, Katalin F et al. (2009) Covalent heme attachment to the protein in human heme oxygenase-1 with selenocysteine replacing the His25 proximal iron ligand. J Inorg Biochem 103:316-25
Peng, Dungeng; Ogura, Hiroshi; Zhu, Wenfeng et al. (2009) Coupling of the distal hydrogen bond network to the exogenous ligand in substrate-bound, resting state human heme oxygenase. Biochemistry 48:11231-42
Evans, John P; Kandel, Sylvie; Ortiz de Montellano, Paul R (2009) Isocyanides inhibit human heme oxygenases at the verdoheme stage. Biochemistry 48:8920-8
Ogura, Hiroshi; Evans, John P; Peng, Dungeng et al. (2009) The orbital ground state of the azide-substrate complex of human heme oxygenase is an indicator of distal H-bonding: implications for the enzyme mechanism. Biochemistry 48:3127-37
Meitzler, Jennifer L; Ortiz de Montellano, Paul R (2009) Caenorhabditis elegans and human dual oxidase 1 (DUOX1) ""peroxidase"" domains: insights into heme binding and catalytic activity. J Biol Chem 284:18634-43

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