Paul R Ortiz de Montellano

Summary

Affiliation: University of California
Country: USA

Publications

  1. pmc Cytochrome P450-activated prodrugs
    Paul R Ortiz de Montellano
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94158 2517, USA
    Future Med Chem 5:213-28. 2013
  2. ncbi request reprint Mechanism and role of covalent heme binding in the CYP4 family of P450 enzymes and the mammalian peroxidases
    Paul R Ortiz de Montellano
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA
    Drug Metab Rev 40:405-26. 2008
  3. ncbi request reprint Oxidizing species in the mechanism of cytochrome P450
    Paul R Ortiz de Montellano
    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143 0446, USA
    Nat Prod Rep 19:477-93. 2002
  4. ncbi request reprint The mechanism of heme oxygenase
    P R Montellano
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, 94143 0446, USA
    Curr Opin Chem Biol 4:221-7. 2000
  5. ncbi request reprint Nitric oxide synthase structure and electron transfer
    P R Ortiz de Montellano
    Department of Pharmaceutical Chemistry, University of California, San Francisco 94143 0446, USA
    Drug Metab Dispos 26:1185-9. 1998
  6. ncbi request reprint EpoK, a cytochrome P450 involved in biosynthesis of the anticancer agents epothilones A and B. Substrate-mediated rescue of a P450 enzyme
    Hiroshi Ogura
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143 2280, USA
    Biochemistry 43:14712-21. 2004
  7. ncbi request reprint The Met-Tyr-Trp cross-link in Mycobacterium tuberculosis catalase-peroxidase (KatG): autocatalytic formation and effect on enzyme catalysis and spectroscopic properties
    Reza A Ghiladi
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 94143, USA
    J Biol Chem 280:22651-63. 2005
  8. ncbi request reprint Regiospecificity determinants of human heme oxygenase: differential NADPH- and ascorbate-dependent heme cleavage by the R183E mutant
    Jinling Wang
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143 2280, USA
    J Biol Chem 280:2797-806. 2005
  9. ncbi request reprint Aromatic stacking as a determinant of the thermal stability of CYP119 from Sulfolobus solfataricus
    Andrei V Puchkaev
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143 0446, USA
    Arch Biochem Biophys 409:52-8. 2003
  10. pmc Coupling of the distal hydrogen bond network to the exogenous ligand in substrate-bound, resting state human heme oxygenase
    Dungeng Peng
    Department of Chemistry, University of California, Davis, California 95616, USA
    Biochemistry 48:11231-42. 2009

Research Grants

  1. Oxygen Sensors and P450 Monooxygenases in Mycobacertium tuberculosis
    Paul R Ortiz de Montellano; Fiscal Year: 2010
  2. HEMOPROTEIN OXIDATION AND HEME CATABOLISM
    Paul Ortiz de Montellano; Fiscal Year: 2003
  3. SELECTIVE DESTRUCTION OF CYTOCHROME P450 BY DRUGS
    Paul Ortiz de Montellano; Fiscal Year: 2002
  4. BIOCHEMISTRY AND HEPATIC TOXICITY OF CARBON RADICALS
    Paul Ortiz de Montellano; Fiscal Year: 1999
  5. Mechanism, Specificity, and Inhibition of Cytochrome P450
    Paul R Ortiz de Montellano; Fiscal Year: 2010
  6. HEMOPROTEIN OXIDATION AND HEME CATABOLISM
    Paul R Ortiz de Montellano; Fiscal Year: 2010
  7. SELECTIVE DESTRUCTION OF CYTOCHROME P450 BY DRUGS
    Paul Ortiz de Montellano; Fiscal Year: 2007
  8. Oxygen Sensors and P450 Monooxygenases in Mycobacertium tuberculosis
    Paul Ortiz de Montellano; Fiscal Year: 2007
  9. HEMOPROTEIN OXIDATION AND HEME CATABOLISM
    Paul Ortiz de Montellano; Fiscal Year: 2007
  10. Mechanism, Specificity, and Inhibition of Cytochrome P450
    Paul Ortiz de Montellano; Fiscal Year: 2007

Collaborators

Detail Information

Publications86

  1. pmc Cytochrome P450-activated prodrugs
    Paul R Ortiz de Montellano
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94158 2517, USA
    Future Med Chem 5:213-28. 2013
    ..The activation of prodrugs by the cytochrome P450 system provides a highly versatile approach to prodrug design that is particularly adaptable for targeting drug activation to the liver, to tumors or to hypoxic tissues...
  2. ncbi request reprint Mechanism and role of covalent heme binding in the CYP4 family of P450 enzymes and the mammalian peroxidases
    Paul R Ortiz de Montellano
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA
    Drug Metab Rev 40:405-26. 2008
    ..The covalent heme bond in CYP4 enzymes contributes to their high preference for omega- over (omega-1)-hydroxylation...
  3. ncbi request reprint Oxidizing species in the mechanism of cytochrome P450
    Paul R Ortiz de Montellano
    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143 0446, USA
    Nat Prod Rep 19:477-93. 2002
    ..The focus of the review is on recent results, but earlier work is discussed as appropriate. The literature through to February 2002 is surveyed, and 175 referenced are cited...
  4. ncbi request reprint The mechanism of heme oxygenase
    P R Montellano
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, 94143 0446, USA
    Curr Opin Chem Biol 4:221-7. 2000
    ....
  5. ncbi request reprint Nitric oxide synthase structure and electron transfer
    P R Ortiz de Montellano
    Department of Pharmaceutical Chemistry, University of California, San Francisco 94143 0446, USA
    Drug Metab Dispos 26:1185-9. 1998
    ..Electron transfer from the flavin to the heme domain, and within the flavin and heme domains, is thus a critical determinant of the catalytic turnover of NOS...
  6. ncbi request reprint EpoK, a cytochrome P450 involved in biosynthesis of the anticancer agents epothilones A and B. Substrate-mediated rescue of a P450 enzyme
    Hiroshi Ogura
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143 2280, USA
    Biochemistry 43:14712-21. 2004
    ..Furthermore, the finding that the denatured enzyme is rescued by the substrate offers a potential paradigm for control of the P450 catalytic function...
  7. ncbi request reprint The Met-Tyr-Trp cross-link in Mycobacterium tuberculosis catalase-peroxidase (KatG): autocatalytic formation and effect on enzyme catalysis and spectroscopic properties
    Reza A Ghiladi
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 94143, USA
    J Biol Chem 280:22651-63. 2005
    ..The structure-function-spectroscopy relationship in KatG is discussed with relevance to the role that the Met-Tyr-Trp cross-link plays in the catalase-peroxidase mechanism...
  8. ncbi request reprint Regiospecificity determinants of human heme oxygenase: differential NADPH- and ascorbate-dependent heme cleavage by the R183E mutant
    Jinling Wang
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143 2280, USA
    J Biol Chem 280:2797-806. 2005
    ..Ascorbate may be able to reduce the R183E ferric and ferrous dioxygen complexes in active site conformations that cannot be reduced by NADPH-cytochrome P450 reductase...
  9. ncbi request reprint Aromatic stacking as a determinant of the thermal stability of CYP119 from Sulfolobus solfataricus
    Andrei V Puchkaev
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143 0446, USA
    Arch Biochem Biophys 409:52-8. 2003
    ..The extended aromatic cluster, but not the Arg154-Glu212 salt bridge, contributes to the thermal stability of CYP119...
  10. pmc Coupling of the distal hydrogen bond network to the exogenous ligand in substrate-bound, resting state human heme oxygenase
    Dungeng Peng
    Department of Chemistry, University of California, Davis, California 95616, USA
    Biochemistry 48:11231-42. 2009
    ..The effect of pH on the H-bonding network in human HO is much larger and transmitted much further from the iron than in a pathogenic bacterial HO. The implications for the HO mechanism of the H-bond of Tyr58 to Asp140 are discussed...
  11. ncbi request reprint Role of the Met-Tyr-Trp cross-link in Mycobacterium tuberculosis catalase-peroxidase (KatG) as revealed by KatG(M255I)
    Reza A Ghiladi
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143 2280, USA
    Biochemistry 44:15093-105. 2005
    ....
  12. ncbi request reprint The mechanism of Mycobacterium tuberculosis alkylhydroperoxidase AhpD as defined by mutagenesis, crystallography, and kinetics
    Aleksey Koshkin
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143 2280, USA
    J Biol Chem 278:29502-8. 2003
    ..The collective results strongly support the proposed catalytic mechanism for AhpD...
  13. ncbi request reprint Crystal structure of human heme oxygenase-1 in a complex with biliverdin
    Latesh Lad
    Department of Molecular Biology and Biochemistry, Program in Macromolecular Structure, University of California, Irvine, California 92697 3900, USA
    Biochemistry 43:3793-801. 2004
    ..Biliverdin adopts a more linear conformation and moves from the heme site to an internal cavity. These structural results provide insight into the rate-limiting step in HO-1 catalysis, which is product, biliverdin, release...
  14. pmc Alteration of the regiospecificity of human heme oxygenase-1 by unseating of the heme but not disruption of the distal hydrogen bonding network
    Jinling Wang
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143 2280, USA
    Biochemistry 45:61-73. 2006
    ....
  15. pmc Radical intermediates in the catalytic oxidation of hydrocarbons by bacterial and human cytochrome P450 enzymes
    Yongying Jiang
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143 2280, USA
    Biochemistry 45:533-42. 2006
    ..The results indicate that carbon hydroxylation is catalyzed exclusively by a P450 ferryl species via radical intermediates whose detailed properties are substrate- and enzyme-dependent...
  16. ncbi request reprint The Sulfolobus solfataricus electron donor partners of thermophilic CYP119: an unusual non-NAD(P)H-dependent cytochrome P450 system
    Andrei V Puchkaev
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, CA 94143 2280, USA
    Arch Biochem Biophys 434:169-77. 2005
    ..This first high-temperature in vitro catalytic system represents an important step in the development of industrially relevant catalysts...
  17. ncbi request reprint Crystal structures of ferrous and ferrous-NO forms of verdoheme in a complex with human heme oxygenase-1: catalytic implications for heme cleavage
    Latesh Lad
    Department of Molecular Biology and Biochemistry, University of California, 2206 Natural Sciences 1, Irvine, CA 92697 3900, USA
    J Inorg Biochem 98:1686-95. 2004
    ..A network of water molecules, which provide the required protons to activate the iron-oxy complex of heme-HO-1, is absent in both ferrous-verdoheme and the verdoheme-NO structure...
  18. ncbi request reprint Crystal structures of epothilone D-bound, epothilone B-bound, and substrate-free forms of cytochrome P450epoK
    Shingo Nagano
    Department of Molecular Biology and Biochemistry, University of California, Irvine, 92697 3900, USA
    J Biol Chem 278:44886-93. 2003
    ..Interestingly, there are strong parallels between the epothilone/P450epoK and paclitaxel/tubulin interactions. Based on structural similarities, a plausible epothilone tubulin-binding mode is proposed...
  19. ncbi request reprint Role of heme-protein covalent bonds in mammalian peroxidases. Protection of the heme by a single engineered heme-protein link in horseradish peroxidase
    Liusheng Huang
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA
    J Biol Chem 281:18983-8. 2006
    ..The results directly establish that one function of the covalent heme-protein bonds in mammalian peroxidases is to protect their prosthetic group from their highly reactive metabolic products...
  20. pmc Biochemical and structural characterization of CYP124: a methyl-branched lipid omega-hydroxylase from Mycobacterium tuberculosis
    Jonathan B Johnston
    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158 2517, USA
    Proc Natl Acad Sci U S A 106:20687-92. 2009
    ..The enzymatic specificity and structures reported here provide a scaffold for the design and testing of specific inhibitors of CYP124...
  21. ncbi request reprint Autoreduction of ferryl myoglobin: discrimination among the three tyrosine and two tryptophan residues as electron donors
    Olivier M Lardinois
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143 2280, USA
    Biochemistry 43:4601-10. 2004
    ..These results demonstrate that internal electron transfer is governed as much by the tyrosine pK(a) and oxidation potential as by its distance from the electron accepting iron atom...
  22. ncbi request reprint Steady-state kinetic investigation of cytochrome P450cam: interaction with redox partners and reaction with molecular oxygen
    Matthew M Purdy
    Department of Chemistry, University of California, Berkeley, CA 94720 1460, USA
    Biochemistry 43:271-81. 2004
    ..These data support a mechanism where Pdx acts as a shuttle for transport of electrons from PdR to P450cam, effectively ruling out the formation of a kinetically significant PdR/Pdx/P450cam complex...
  23. ncbi request reprint Catalytic activity and isoform-specific inhibition of rat cytochrome p450 4F enzymes
    Fengyun Xu
    Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143 0446, USA
    J Pharmacol Exp Ther 308:887-95. 2004
    ..These data support a significant role for CYP4F1 and CYP4F4 in the formation of 20-HETE and identify p450 inhibitors that can be used to understand the relative contribution of the CYP4A and CYP4F isoforms to renal 20-HETE formation...
  24. ncbi request reprint Intra- and intermolecular transfers of protein radicals in the reactions of sperm whale myoglobin with hydrogen peroxide
    Olivier M Lardinois
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143 2280, USA
    J Biol Chem 278:36214-26. 2003
    ..Intermolecular electron transfers that generate protein radicals on bystander proteins are likely to propagate the cellular damage initiated by the reaction of metalloproteins with H2O2...
  25. pmc 2.3 A X-ray structure of the heme-bound GAF domain of sensory histidine kinase DosT of Mycobacterium tuberculosis
    Larissa M Podust
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94158 2517, USA
    Biochemistry 47:12523-31. 2008
    ..Determination of the GAF(DosT) structure sets up a framework in which to address ligand recognition, discrimination, and signal propagation schemes in the heme-based GAF domains of biological sensors...
  26. ncbi request reprint The P450cam G248E mutant covalently binds its prosthetic heme group
    Julian Limburg
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143 0446, USA
    Biochemistry 44:4091-9. 2005
    ....
  27. ncbi request reprint Heme-protein covalent bonds in peroxidases and resistance to heme modification during halide oxidation
    Liusheng Huang
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, CA 94143 2280, USA
    Arch Biochem Biophys 446:77-83. 2006
    ..These results support the hypothesis that the covalent heme-protein links in the mammalian peroxidases protect the heme from modification during the oxidation of halide ions...
  28. pmc Efficient catalytic turnover of cytochrome P450(cam) is supported by a T252N mutation
    Donghak Kim
    Department of Pharmaceutical Chemistry, University of California, San Francisco, Genentech Hall, N572D, 600 16th Street, San Francisco, CA 94158 2517, USA
    Arch Biochem Biophys 474:150-6. 2008
    ....
  29. ncbi request reprint Correlation between isoniazid resistance and superoxide reactivity in mycobacterium tuberculosis KatG
    Reza A Ghiladi
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143 2280, USA
    J Am Chem Soc 127:13428-42. 2005
    ....
  30. pmc 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
    Hiroshi Ogura
    Department of Chemistry, University of California, Davis, California 95616, USA
    Biochemistry 48:3127-37. 2009
    ..The Asp140 --> Ala hHO mutant that abolishes activity retains the unusual WT azide complex spin/orbital ground state. The relevance of our findings for other HO complexes and the HO mechanism is discussed...
  31. ncbi request reprint 1H NMR detection of immobilized water molecules within a strong distal hydrogen-bonding network of substrate-bound human heme oxygenase-1
    Ray T Syvitski
    Department of Chemistry, University of California, Davis, California 95616, USA
    J Am Chem Soc 124:14296-7. 2002
    ..It is proposed that the role of the strong hydrogen-bonding network is to immobilize numerous water molecules which both stabilize the activated hydroperoxy species and funnel protons to the active site...
  32. pmc DevS oxy complex stability identifies this heme protein as a gas sensor in Mycobacterium tuberculosis dormancy
    Alexandra Ioanoviciu
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94158 2517, USA
    Biochemistry 48:5839-48. 2009
    ..Our results indicate that DevS is a gas sensor in vivo rather than a redox sensor and that the stability of its ferrous-oxy complex is enhanced by interdomain interactions...
  33. pmc Reaction of Mycobacterium tuberculosis cytochrome P450 enzymes with nitric oxide
    Hugues Ouellet
    Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94158 2517, USA
    Biochemistry 48:863-72. 2009
    ..Selective P450 inhibition may contribute to the inhibitory effects of (*)NO on Mtb growth...
  34. ncbi request reprint Intermolecular interactions in the AhpC/AhpD antioxidant defense system of Mycobacterium tuberculosis
    Aleksey Koshkin
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, CA 94143 2280, USA
    Arch Biochem Biophys 427:41-7. 2004
    ..Cys176 can also, to some extent, substitute for Cys174, providing a measure of redundancy that helps to maintain the efficiency of this antioxidant protective system...
  35. pmc Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis
    Xin He
    Department of Pharmaceutical Chemistry, University of California, 600 16 Street, San Francisco, California 94158 2517, USA
    J Med Chem 49:6308-23. 2006
    ..Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA...
  36. pmc Perturbed heme binding is responsible for the blistering phenotype associated with mutations in the Caenorhabditis elegans dual oxidase 1 (DUOX1) peroxidase domain
    Jennifer L Meitzler
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94518 2517, USA
    J Biol Chem 285:40991-1000. 2010
    ..This result argues that the CeDUOX peroxidase domain is primarily responsible for tyrosine cross-linking...
  37. pmc Reverse type I inhibitor of Mycobacterium tuberculosis CYP125A1
    Hugues Ouellet
    Department of Pharmaceutical Chemistry and Sandler Center for Drug Discovery, University of California, San Francisco, CA 94158, USA
    Bioorg Med Chem Lett 21:332-7. 2011
    ..These results provide an insight into the structural requirements for developing selective CYP125A1 inhibitors...
  38. pmc A novel intermediate in the reaction of seleno CYP119 with m-chloroperbenzoic acid
    Santhosh Sivaramakrishnan
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158 2517, United States
    Biochemistry 50:3014-24. 2011
    ....
  39. ncbi request reprint Oxidation of carboxylic acids by horseradish peroxidase results in prosthetic heme modification and inactivation
    Liusheng Huang
    Contribution from the Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, CA 94143 2280, USA
    J Am Chem Soc 126:12865-73. 2004
    ..The hemoprotein-mediated oxidation of carboxylic acids, ubiquitous natural constituents, may play other roles in biology...
  40. pmc Structural control of cytochrome P450-catalyzed ω-hydroxylation
    Jonathan B Johnston
    Department of Pharmaceutical Chemistry, University of California San Francisco, CA 94158 2517, United States
    Arch Biochem Biophys 507:86-94. 2011
    ..The evidence indicates that steric constraints are used to favor reaction at the ω-site rather than at the more reactive (ω-1)-site...
  41. pmc Substrate analog studies of the ω-regiospecificity of Mycobacterium tuberculosis cholesterol metabolizing cytochrome P450 enzymes CYP124A1, CYP125A1 and CYP142A1
    Jonathan B Johnston
    Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco 94158 2517, USA
    Bioorg Med Chem 20:4064-81. 2012
    ..The results are discussed in the context of the structure-activity relationships of the enzymes and how their active sites enforce ω-oxidation...
  42. pmc Inhibition of Mycobacterium tuberculosis AhpD, an element of the peroxiredoxin defense against oxidative stress
    Aleksey Koshkin
    University of California, Genentech Hall N572D, 600 16th Street, San Francisco, CA 94143 2280, USA
    Antimicrob Agents Chemother 48:2424-30. 2004
    ..This finding, and the low solubility of the inhibitor, explains its inability to suppress the growth of INH-resistant M. tuberculosis in infected mouse lungs...
  43. pmc Oxidative activation of thiacetazone by the Mycobacterium tuberculosis flavin monooxygenase EtaA and human FMO1 and FMO3
    Lian Qian
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143 2280, USA
    Chem Res Toxicol 19:443-9. 2006
    ..These reactions may contribute to the antitubercular activity and/or toxicity of TAZ...
  44. ncbi request reprint Interaction of nitric oxide with human heme oxygenase-1
    Jinling Wang
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 94143 0446, USA
    J Biol Chem 278:2341-7. 2003
    ..Inhibition of hHO-1 by NO may contribute to the pleiotropic responses to NO and CO...
  45. pmc Ligand-induced conformational heterogeneity of cytochrome P450 CYP119 identified by 2D NMR spectroscopy with the unnatural amino acid (13)C-p-methoxyphenylalanine
    Jed N Lampe
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158 2517, USA
    J Am Chem Soc 130:16168-9. 2008
    ..This general approach may be used to further illuminate the role that conformational dynamics plays in the complex enzymatic phenomena exhibited by P450 enzymes...
  46. pmc Caenorhabditis elegans and human dual oxidase 1 (DUOX1) "peroxidase" domains: insights into heme binding and catalytic activity
    Jennifer L Meitzler
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA
    J Biol Chem 284:18634-43. 2009
    ....
  47. ncbi request reprint CYP119 plus a Sulfolobus tokodaii strain 7 ferredoxin and 2-oxoacid:ferredoxin oxidoreductase constitute a high-temperature cytochrome P450 catalytic system
    Andrei V Puchkaev
    Department of Pharmaceutical Chemistry, University of California, San Francisco 94143 0446, USA
    J Am Chem Soc 124:12682-3. 2002
    ..This first in vitro high-temperature P450 catalytic system is a key step in the development of practical high-temperature monooxygenase systems...
  48. ncbi request reprint Thermophilic cytochrome P450 enzymes
    Clinton R Nishida
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, CA 94143 2280, USA
    Biochem Biophys Res Commun 338:437-45. 2005
    ..The structures and properties of two such enzymes, CYP119 and CYP175A1, have been investigated and provide the foundation for future work on thermophilic P450 enzymes...
  49. pmc Covalent heme attachment to the protein in human heme oxygenase-1 with selenocysteine replacing the His25 proximal iron ligand
    Yongying Jiang
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, CA 94158 2517, United States
    J Inorg Biochem 103:316-25. 2009
    ..Jiang, P.R. Ortiz de Montellano, Inorg. Chem. 47 (2008) 3480-3482 ], indicate that a selenyl radical is formed in the hHO-1 His25SeCys mutant that adds to a heme vinyl group...
  50. ncbi request reprint Enhanced electron transfer and lauric acid hydroxylation by site-directed mutagenesis of CYP119
    Laura S Koo
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94143 0446, USA
    J Am Chem Soc 124:5684-91. 2002
    ..As a result, the catalytic activity of the thermo- and barostable CYP119 has been incorporated into a catalytic system that hydroxylates fatty acids...
  51. ncbi request reprint Autocatalytic modification of the prosthetic heme of horseradish but not lactoperoxidase by thiocyanate oxidation products. A role for heme-protein covalent cross-linking
    Grzegorz Wojciechowski
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143 2280, USA
    J Am Chem Soc 127:15871-9. 2005
    ....
  52. ncbi request reprint Covalent attachment of the heme prosthetic group in the CYP4F cytochrome P450 family
    Laurie A LeBrun
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143 0446, USA
    Biochemistry 41:5931-7. 2002
    ..CYP4F proteins thus autocatalytically bind their heme groups covalently in a process that requires a glutamic acid both to generate a reactive (cationic) form of the heme methyl and to trap it to give the ester bond...
  53. ncbi request reprint The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase
    Tommaso A Vannelli
    Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143 0446, USA
    J Biol Chem 277:12824-9. 2002
    ....
  54. pmc Structural stability and heme binding potential of the truncated human dual oxidase 2 (DUOX2) peroxidase domain
    Jennifer L Meitzler
    Department of Pharmaceutical Chemistry, University of California, San Francisco, United States
    Arch Biochem Biophys 512:197-203. 2011
    ..A conformational difference in the full-length protein and/or a protein-protein interaction may be required to increase the heme binding affinity...
  55. pmc Reductive heme-dependent activation of the n-oxide prodrug AQ4N by nitric oxide synthase
    Clinton R Nishida
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94158 2517, USA
    J Med Chem 51:5118-20. 2008
    ..Here, we report that the N-oxide AQ4N is reduced by a nitric oxide synthase. This reduction involves interaction with the heme iron atom in the active site and is thus subject to specific protein constraints...
  56. pmc Proximal ligand electron donation and reactivity of the cytochrome P450 ferric-peroxo anion
    Santhosh Sivaramakrishnan
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94158 2517, USA
    J Am Chem Soc 134:6673-84. 2012
    ..These observations are consistent with an increase in the pK(a) of the ferric-peroxo anion, which favors its protonation and, therefore, Compound I formation...
  57. pmc Isocyanides inhibit human heme oxygenases at the verdoheme stage
    John P Evans
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94158 2517, USA
    Biochemistry 48:8920-8. 2009
    ..Much tighter binding of the inhibitor to the verdoheme intermediate differentiates it from inhibition of, for example, CYP3A4 and offers a possible route to more selective inhibitor design...
  58. ncbi request reprint Electron supply and catalytic oxidation of nitrogen by cytochrome P450 and nitric oxide synthase
    Clinton R Nishida
    Department of Pharmaceutical Chemistry, University of California, San Francisco 94143 0446, USA
    Drug Metab Rev 34:479-501. 2002
    ..Electron transfer from the flavins is controlled by the binding of calmodulin, the presence of peptide inserts in the flavin domain, the substrate structure, and phosphorylation of the enzyme...
  59. pmc Arthromyces ramosus peroxidase produces two chlorinating species
    Liusheng Huang
    Department of Pharmaceutical Chemistry, University of California San Francisco, 600 16th Street, San Francisco, CA 94158 2517, USA
    Biochem Biophys Res Commun 355:581-6. 2007
    ....
  60. ncbi request reprint Influence of the distal his in imparting imidazolate character to the proximal his in heme peroxidase: (1)h NMR spectroscopic study of cyanide-inhibited his42-->ala horseradish peroxidase
    Jeffrey S de Ropp
    Contribution from the Department of Chemistry and NMR Facility, University of California, Davis, California 95616, USA
    J Am Chem Soc 124:11029-37. 2002
    ....
  61. ncbi request reprint Prosthetic heme modification during halide ion oxidation. Demonstration of chloride oxidation by horseradish peroxidase
    Liusheng Huang
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143 2280, USA
    J Am Chem Soc 127:5345-53. 2005
    ..The results raise the question of how the prosthetic hemes of MPO and EPO, whose function is to produce oxidized halide species, escape modification...
  62. ncbi request reprint Autocatalytic radical reactions in physiological prosthetic heme modification
    Christophe Colas
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94143 0446, USA
    Chem Rev 103:2305-32. 2003
  63. ncbi request reprint Autocatalytic mechanism and consequences of covalent heme attachment in the cytochrome P4504A family
    Laurie A LeBrun
    Department of Pharmaceutical Chemistry, School of Pharmacy S 926, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143 0446, USA
    J Biol Chem 277:12755-61. 2002
    ....
  64. ncbi request reprint Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid omega-hydroxylase activity
    Fengyun Xu
    Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California 94143, USA
    Am J Physiol Regul Integr Comp Physiol 283:R710-20. 2002
    ..These results provide further evidence that 20-HETE plays an important role in the regulation of blood pressure in the spontaneously hypertensive rat...
  65. ncbi request reprint Solution NMR characterization of an unusual distal H-bond network in the active site of the cyanide-inhibited, human heme oxygenase complex of the symmetric substrate, 2,4-dimethyldeuterohemin
    Yiming Li
    Department of Chemistry, University of California, Davis, California 95616, USA
    J Biol Chem 277:33018-31. 2002
    ..2000) J. Biol. Chem. 275, 34501-34507). The potential role of this network in placing a water molecule to stabilize the hydroperoxy species and as a template for the condensation of the distal helix upon substrate binding are discussed...
  66. ncbi request reprint Comparison of the heme-free and -bound crystal structures of human heme oxygenase-1
    Latesh Lad
    Department of Molecular Biology and Biochemistry, Program in Macromolecular Structure, University of California, Irvine 92697, USA
    J Biol Chem 278:7834-43. 2003
    ..It thus appears that the binding of heme and a tightening of the structure around the heme stabilize the solvent H-bonded network required for proper catalysis...
  67. ncbi request reprint Asp-225 and glu-375 in autocatalytic attachment of the prosthetic heme group of lactoperoxidase
    Christophe Colas
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, CA 94143 0446, USA
    J Biol Chem 277:7191-200. 2002
    ..The results establish that a single covalent link suffices to achieve maximum catalytic activity and suggest that the 5-hydroxymethyl bond may form before the 1-hydroxymethyl bond...
  68. pmc Interaction of Mycobacterium tuberculosis CYP130 with heterocyclic arylamines
    Larissa M Podust
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA
    J Biol Chem 284:25211-9. 2009
    ..We suggest a role for the conserved Ala(Gly)(243)-Gly(244) motif in the I-helix in modulating both the binding affinity of the axial water ligand and the ligand selectivity of cytochrome P450 enzymes...
  69. pmc The Mycobacterium tuberculosis cytochrome P450 system
    Hugues Ouellet
    Department of Pharmaceutical Chemistry, University of California San Francisco, 600 16th Street, San Francisco, CA 94158 2517, USA
    Arch Biochem Biophys 493:82-95. 2010
    ..tuberculosis P450 enzymes and their putative redox partners is reviewed, with an emphasis on findings related to their physiological function(s) as well as their potential as drug targets...
  70. pmc Functional expression and characterization of cytochrome P450 52A21 from Candida albicans
    Donghak Kim
    Department of Pharmaceutical Chemistry, University of California, San Francisco, Genentech Hall, N572D, 600 16th Street, San Francisco, CA 94158 2517, USA
    Arch Biochem Biophys 464:213-20. 2007
    ..This constricted access, in contrast to that proposed for the CYP4A family of enzymes, does not involve covalent binding of the heme to the protein...
  71. ncbi request reprint Alpha- and beta-thujone radical rearrangements and isomerizations. A new radical clock
    Xiang He
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94143 2280, USA
    J Org Chem 69:5684-9. 2004
    ..Thujone therefore differentiates between radical and cation pathways and provides a measure of the radical lifetime...
  72. pmc Communication between the active sites and dimer interface of a herpesvirus protease revealed by a transition-state inhibitor
    Alan B Marnett
    Program in Chemistry and Chemical Biology, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 101:6870-5. 2004
    ....
  73. ncbi request reprint Expression and characterization of truncated human heme oxygenase (hHO-1) and a fusion protein of hHO-1 with human cytochrome P450 reductase
    A Wilks
    Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143 0446, USA
    Biochemistry 34:4421-7. 1995
    ....
  74. pmc Cooperative effects on radical recombination in CYP3A4-catalyzed oxidation of the radical clock beta-thujone
    Yongying Jiang
    Department of Pharmaceutical Chemistry, University of California San Francisco, 600 16th Street, San Francisco, CA 94158 2517, USA
    Chembiochem 10:650-3. 2009
    ..The results demonstrate that the apparent radical recombination rate in the CYP3A4 hydroxylation of beta-thujone is accelerated by the progesterone heterotropic cooperativity...
  75. pmc Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides
    Xin He
    Applied Technology Group, Incyte Corporation, Experimental Station, Wilmington, DE 19880, USA
    Bioorg Med Chem 15:6649-58. 2007
    ....
  76. ncbi request reprint Revisiting the mechanism of P450 enzymes with the radical clocks norcarane and spiro[2,5]octane
    Karine Auclair
    Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA
    J Am Chem Soc 124:6020-7. 2002
    ....
  77. ncbi request reprint Cytochrome P450 3A4-mediated oxidative conversion of a cyano to an amide group in the metabolism of pinacidil
    Zhoupeng Zhang
    Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    Biochemistry 41:2712-8. 2002
    ..This nucleophilic addition of an Fe(3+)-O-O(-) intermediate to a -C=N pi-bond in a P450 system resembles the analogous reaction catalyzed by the nitric oxide synthases...
  78. ncbi request reprint The crystal structure of Mycobacterium tuberculosis alkylhydroperoxidase AhpD, a potential target for antitubercular drug design
    Christine M Nunn
    Department of Biochemistry and Molecular Biology, University College, Gower Street, London WC1E 6BT, United Kingdom
    J Biol Chem 277:20033-40. 2002
    ..tuberculosis biology...
  79. ncbi request reprint Cyclopropyl containing fatty acids as mechanistic probes for cytochromes P450
    Max J Cryle
    Department of Chemistry, University of Queensland, St Lucia, Brisbane, Australia 4072
    J Org Chem 70:2455-69. 2005
    ..The effects of introduction of a cyclopropane ring into a fatty acid upon the regiochemistry of hydroxylation are discussed...
  80. ncbi request reprint Crystal structures of the ferric, ferrous, and ferrous-NO forms of the Asp140Ala mutant of human heme oxygenase-1: catalytic implications
    Latesh Lad
    Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, CA 92697 3900, USA
    J Mol Biol 330:527-38. 2003
    ..On the basis of these structures, we consider why the D140A mutant is inactive as a heme oxygenase but active as a peroxidase...
  81. ncbi request reprint The diagnostic substrate bicyclohexane reveals a radical mechanism for bacterial cytochrome P450 in whole cells
    Rachel N Austin
    Department of Chemistry, Bates College, Lewiston, ME 04240, USA
    Angew Chem Int Ed Engl 45:8192-4. 2006
  82. ncbi request reprint Cytochrome P450(cin) (CYP176A), isolation, expression, and characterization
    David B Hawkes
    Department of Chemistry, University of Queensland, Brisbane, Queensland 4067, Australia
    J Biol Chem 277:27725-32. 2002
    ..This constitutes the first characterization of an enzyme involved in this pathway...
  83. ncbi request reprint Cloning and expression of a heme binding protein from the genome of Saccharomyces cerevisiae
    Karine Auclair
    Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 2K6
    Protein Expr Purif 28:340-9. 2003
    ..Thus, YLR205c codes for a hemoprotein of unknown physiological function that exhibits peroxidase activity...
  84. ncbi request reprint Computer-assisted design of selective imidazole inhibitors for cytochrome p450 enzymes
    Andreas Verras
    Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, CA 94143 2280, USA
    J Med Chem 47:3572-9. 2004
    ....
  85. ncbi request reprint Solution NMR study of environmental effects on substrate seating in human heme oxygenase: influence of polypeptide truncation, substrate modification and axial ligand
    Wenfeng Zhu
    Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, United States
    J Inorg Biochem 100:97-107. 2006
    ....
  86. pmc Selenolate complexes of CYP101 and the heme-bound hHO-1/H25A proximal cavity mutant
    Yongying Jiang
    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158 2517, USA
    Inorg Chem 47:3480-2. 2008
    ..These results indicate that selenocysteine-coordinated heme proteins will not be stable species in the absence of a redox potential stabilizing effect...

Research Grants65

  1. Oxygen Sensors and P450 Monooxygenases in Mycobacertium tuberculosis
    Paul R Ortiz de Montellano; Fiscal Year: 2010
    ..The project thus encompasses two heme- and oxygen-dependent system of M. tuberculosis that offer new avenues to the development of drugs effective against the latent form of the disease. ..
  2. HEMOPROTEIN OXIDATION AND HEME CATABOLISM
    Paul Ortiz de Montellano; Fiscal Year: 2003
    ....
  3. SELECTIVE DESTRUCTION OF CYTOCHROME P450 BY DRUGS
    Paul Ortiz de Montellano; Fiscal Year: 2002
    ..abstract_text> ..
  4. BIOCHEMISTRY AND HEPATIC TOXICITY OF CARBON RADICALS
    Paul Ortiz de Montellano; Fiscal Year: 1999
    ..The results should help to clarify tic role of peroxidatively generated radicals in toxicological processes and to uncover mechanisms for the suppression of such processes. ..
  5. Mechanism, Specificity, and Inhibition of Cytochrome P450
    Paul R Ortiz de Montellano; Fiscal Year: 2010
    ..The ability to predict P-450 substrate and inhibitor specificity is central to all of these areas of P-450 involvement. ..
  6. HEMOPROTEIN OXIDATION AND HEME CATABOLISM
    Paul R Ortiz de Montellano; Fiscal Year: 2010
    ..At the same time, their antiapoptotic activity makes them targets for the design of inhibitors of potential utility in anticancer therapy. ..
  7. SELECTIVE DESTRUCTION OF CYTOCHROME P450 BY DRUGS
    Paul Ortiz de Montellano; Fiscal Year: 2007
    ..abstract_text> ..
  8. Oxygen Sensors and P450 Monooxygenases in Mycobacertium tuberculosis
    Paul Ortiz de Montellano; Fiscal Year: 2007
    ..The project thus encompasses two heme- and oxygen-dependent system of M. tuberculosis that offer new avenues to the development of drugs effective against the latent form of the disease. ..
  9. HEMOPROTEIN OXIDATION AND HEME CATABOLISM
    Paul Ortiz de Montellano; Fiscal Year: 2007
    ..abstract_text> ..
  10. Mechanism, Specificity, and Inhibition of Cytochrome P450
    Paul Ortiz de Montellano; Fiscal Year: 2007
    ..The ability to predict P-450 substrate and inhibitor specificity is central to all of these areas of P-450 involvement. ..
  11. BIOCHEMISTRY AND HEPATIC TOXICITY OF CARBON RADICALS
    Paul Ortiz de Montellano; Fiscal Year: 2007
    ....
  12. Structure Biology and Targeted Drug Design for AIDS
    Paul Ortiz de Montellano; Fiscal Year: 2006
    ....
  13. SELECTIVE DESTRUCTION OF CYTOCHROME P450 BY DRUGS
    Paul Ortiz de Montellano; Fiscal Year: 2006
    ....
  14. HEMOLYTIC ANEMIA AND ABNORMAL HEME CATABOLITES
    Paul Ortiz de Montellano; Fiscal Year: 1993
    ....
  15. SELECTIVE DESTRUCTION OF CYTOCHROME P450 BY DRUGS
    Paul Ortiz de Montellano; Fiscal Year: 1980
    ..These mechanistic studies involve structural analysis of the pigments which accumulate in the liver of animals treated with the agents, as well as a correlation of structure with activity...
  16. BIOCHEMISTRY AND HEPATIC TOXICITY OF CARBON RADICALS
    Paul Ortiz de Montellano; Fiscal Year: 1993
    ..The collective intent of these studies is to advance our understanding of the biochemistry of carbon radicals, particularly the mechanisms by which they are formed and quenched, and to clarify their toxicological potential...
  17. BIOCHEMISTRY AND HEPATIC TOXICITY OF CARBON RADICALS
    Paul Ortiz de Montellano; Fiscal Year: 1991
    ..The collective intent of these studies is to advance our understanding of the biochemistry of carbon radicals and to clarify their toxicological potential...