University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Paul R. Ortiz de Montellano, PhD

Paul R. Ortiz de Montellano, PhD

Professor, Departments of Pharmaceutical Chemistry and Pharmacology, UCSF

Cancer Center Program Memberships

Affiliate Member

Research Summary

Heme-containing proteins are critical for the function of essentially all life forms. In humans, they are involved in respiration, the synthesis of hormones and other vital molecules, the elimination of drugs, and various signaling pathways. My laboratory has investigated the structure, mechanism, biochemistry and role of heme proteins for many years. We have focused particularly on the human cytochrome P450, peroxidase, and heme oxygenase enzymes. Our contributions in this area include crystal structures of bacterial P450 enzymes and the human heme oxygenase, clarification of the mechanism of cytochrome P450 enzymes, the development of methods for the mechanism-based inactivation of P450 enzymes, and more recently studies of human cytochrome P450 enzymes that are selectively expressed in cancer cells and are potentially useful in the activation of anticancer drugs. We currently also work on two classes of heme proteins in Mycobacterium tuberculosis, the causative agent of tuberculosis: (a) the twenty cytochrome P450 enzymes, some of which potential targets for anti-tuberculosis drugs, and (b) the gas sensor that initiates the dormant, persistent stage of tuberculosis that is difficult to eradicate and which can be reactivated when the immune system is compromised.

The studies in my laboratory employ a diversity of techniques, including organic synthesis, molecular biology, enzymology, and multiple spectroscopic techniques. We frequently collaborate with laboratories that have complementary expertise in organic synthesis, X-ray crystallography, NMR, or resonance Raman spectroscopy.


Mass. Institute of Technology (Cambridge, MA), B.S., 1964, Chemistry
Harvard University (Cambridge, MA), M.A., 1966, Chemistry
Harvard University (Cambridge, MA), Ph.D., 1968, Bioorganic Chemistry
Eidg. Tech. Hochschule (Zurich, Switzerland), Postdoc, 1968-1969, Bioorganic Chemistry

Professional Experience

  • 1969-1971
    Group Leader, Syntex Research Laboratories
  • 1972-1980
    Assistant/Associate Professor, University of California, San Francisco
  • 1980-present
    Professor of Chemistry, Pharmaceutical Chemistry, and Pharmacology, University of California, San Francisco
  • 1982-1994
    Vice Chairman, Department of Pharmaceutical Chemistry
  • 1978-1979
    Professeur Associe, Institut de Chimie, Universite Louis Pasteur, Strasbourg, France
  • 1985-1986
    Honorary Fellow, Department of Biochemistry, University College, London
  • 1993-1994
    Professeur Rhone Poulenc, Universite René Descartes (Paris V), Paris, France
  • 2000-2001
    Visiting Academic, Department of Biochemistry & Molec. Biol., University College, London

Honors & Awards

  • 1960-1964
    McDermott Scholar (MIT)
  • 1965-1968
    NIH Predoctoral Fellow (Harvard)
  • 1968-1969
    NATO Postdoctoral Fellow
  • 1988
    Alfred P. Sloan Foundation Research Science
  • 1989
    John Moffat Lecturer, University of British Columbia
  • 1989-1999
    NIH MERIT Award
  • 1989, 1996, 1997
    UCSF Long Foundation Award for Excellence in Teaching
  • 1991
    King/Chavez/Parks Visiting Professor, University of Michigan
  • 1991
    Distinguished University Lecturer, University of Utah
  • 1994
    Wellcome Visiting Professor, Washington State University
  • 1994
    B. B. Brodie Award in Drug Metabolism of the American Society of Pharmacology and Experimental Therapeutics
  • 1998
    Robert A. Welch Foundation Lecturer, University of Texas Campuses
  • 2000
    Chauncey Leake Lecturer, University of Texas Medical Branch Galveston
  • 2001
    Karcher Lecturer, University of Oklahoma

Selected Publications

  1. Yanev S, Stoyanova T, Valcheva V, Ortiz De Montellano PR. Xanthates: metabolism by flavoprotein-containing monooxygenases (FMO) and antimycobacterial activity. Drug Metab Dispos. 2018 May 18.
    View on PubMed
  2. Ortiz de Montellano PR. Potential drug targets in the Mycobacterium tuberculosis cytochrome P450 system. J Inorg Biochem. 2018 Mar; 180:235-245.
    View on PubMed
  3. Ortiz de Montellano PR. A New Step in the Treatment of Sickle Cell DiseasePublished as part of the Biochemistry series "Biochemistry to Bedside". Biochemistry. 2018 Feb 06; 57(5):470-471.
    View on PubMed
  4. Madrona Y, Waddling CA, Ortiz de Montellano PR. Crystal structures of the CO and NOBound DosS GAF-A domain and implications for DosS signaling in Mycobacterium tuberculosis. Arch Biochem Biophys. 2016 Dec 15; 612:1-8.
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  5. Basudhar D, Madrona Y, Yukl ET, Sivaramakrishnan S, Nishida CR, Moënne-Loccoz P, Ortiz de Montellano PR. Distal Hydrogen-bonding Interactions in Ligand Sensing and Signaling by Mycobacterium tuberculosis DosS. J Biol Chem. 2016 07 29; 291(31):16100-11.
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  6. Zhao Y, Wan D, Yang J, Hammock BD, Ortiz de Montellano PR. Catalytic Activities of Tumor-Specific Human Cytochrome P450 CYP2W1 Toward Endogenous Substrates. Drug Metab Dispos. 2016 May; 44(5):771-80.
    View on PubMed
  7. Frank DJ, Zhao Y, Wong SH, Basudhar D, De Voss JJ, Ortiz de Montellano PR. Cholesterol Analogs with Degradation-resistant Alkyl Side Chains Are Effective Mycobacterium tuberculosis Growth Inhibitors. J Biol Chem. 2016 Apr 01; 291(14):7325-33.
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  8. Frank DJ, Waddling CA, La M, Ortiz de Montellano PR. Cytochrome P450 125A4, the Third Cholesterol C-26 Hydroxylase from Mycobacterium smegmatis. Biochemistry. 2015 Nov 24; 54(46):6909-16.
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  9. Ortiz de Montellano PR. Heme and I. J Biol Chem. 2015 Sep 04; 290(36):21833-44.
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  10. Conner KP, Cruce AA, Krzyaniak MD, Schimpf AM, Frank DJ, Ortiz de Montellano P, Atkins WM, Bowman MK. Drug modulation of water-heme interactions in low-spin P450 complexes of CYP2C9d and CYP125A1. Biochemistry. 2015 Feb 10; 54(5):1198-207.
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  11. Frank DJ, Madrona Y, Ortiz de Montellano PR. Cholesterol ester oxidation by mycobacterial cytochrome P450. J Biol Chem. 2014 Oct 31; 289(44):30417-25.
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  12. Varfaj F, Zulkifli SN, Park HG, Challinor VL, De Voss JJ, Ortiz de Montellano PR. Carbon-carbon bond cleavage in activation of the prodrug nabumetone. Drug Metab Dispos. 2014 May; 42(5):828-38.
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  13. Conner KP, Schimpf AM, Cruce AA, McLean KJ, Munro AW, Frank DJ, Krzyaniak MD, Ortiz de Montellano P, Bowman MK, Atkins WM. Strength of axial water ligation in substrate-free cytochrome P450s is isoform dependent. Biochemistry. 2014 Mar 11; 53(9):1428-34.
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  14. Nishida CR, Everett S, Ortiz de Montellano PR. Specificity determinants of CYP1B1 estradiol hydroxylation. Mol Pharmacol. 2013 Sep; 84(3):451-8.
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  15. García-Fernández E, Frank DJ, Galán B, Kells PM, Podust LM, García JL, Ortiz de Montellano PR. A highly conserved mycobacterial cholesterol catabolic pathway. Environ Microbiol. 2013 Aug; 15(8):2342-59.
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  16. Ortiz de Montellano PR. Cytochrome P450-activated prodrugs. Future Med Chem. 2013 Feb; 5(2):213-28.
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  17. Meitzler JL, Hinde S, Bánfi B, Nauseef WM, Ortiz de Montellano PR. Conserved cysteine residues provide a protein-protein interaction surface in dual oxidase (DUOX) proteins. J Biol Chem. 2013 Mar 08; 288(10):7147-57.
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  18. Aicart-Ramos C, Valhondo Falcón M, Ortiz de Montellano PR, Rodriguez-Crespo I. Covalent attachment of heme to the protein moiety in an insect E75 nitric oxide sensor. Biochemistry. 2012 Sep 18; 51(37):7403-16.
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  19. Varfaj F, Lampe JN, Ortiz de Montellano PR. Role of cysteine residues in heme binding to human heme oxygenase-2 elucidated by two-dimensional NMR spectroscopy. J Biol Chem. 2012 Oct 12; 287(42):35181-91.
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  20. Johnston JB, Singh AA, Clary AA, Chen CK, Hayes PY, Chow S, De Voss JJ, Ortiz de Montellano PR. Substrate analog studies of the ?-regiospecificity of Mycobacterium tuberculosis cholesterol metabolizing cytochrome P450 enzymes CYP124A1, CYP125A1 and CYP142A1. Bioorg Med Chem. 2012 Jul 01; 20(13):4064-81.
    View on PubMed

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