个人简介

B.A., University of California, San Diego Ph.D., University of Minnesota, Minneapolis Helen Hay Whitney Fellow, Harvard Medical School

研究领域

Biological chemistry, bioinorganic chemistry, enzymology, inhibitor design and drug discovery

Significance: Biochemistry is a fascinating and challenging discipline at the interface of biology and chemistry. Our research group utilizes enzymology, site directed mutagenesis, molecular biology and spectroscopy to investigate the biological function of enzymes from a rigorous chemical perspective. Specifically, we study the biological function of lipoxygenase (LOX). Soybean LOX is directly involved in soybean germination and senescence, while human LOX has been implicated in a variety of human diseases, such as asthma, heart disease, stroke and diabetes, to name a few. Therefore, LOX is a critically important enzyme in human health and the Holman laboratory endeavors to understand its enzymatic mechanism, discover novel inhibitors and investigate the role of LOX in human health. Allosteric Regulation: There are six LOX isozymes and seven significant fatty acid substrates in the human body. The substrate specificity of each of the LOX isozymes varies from one to another, resulting in a complex array of LOX products being formed in human tissue. However, the Holman laboratory recently discovered that LOX products bind to an allosteric site on LOX, which changes the isozymes substrate specificity. This result is significant because it indicates that the distribution of LOX products can be modified, depending on the enzymatic activity of the six LOX isozymes and the available fatty acid substrates. The Holman laboratory is currently investigating the biochemical properties of the allosteric site and how it may be utilized to increase the production of beneficial LOX products. Inhibitor Discovery: Our lab is also interested in the discovery and characterization of novel inhibitors to lipoxygenase. We currently have discovered over 50 unique lipoxygenase inhibitors through screening the marine natural products library of our collaborator, Prof. Phil Crews and the NIH library with our collaborators at the NCGC (Dr. D. Maloney, Dr. A. Simeonov and Dr. A. Jadhav). We have screened these libraries with our high throughput lipoxygenase assay, which has increased our inhibitor discovery dramatically. These inhibitors are then investigated with biochemical and spectroscopic methods to determine how they bind and inhibit lipoxygenase. Biological Relevance: The Holman laboratory utilizes the knowledge gained from their biochemical and inhibitory studies to probe LOX in human disease. Currently, the Holman laboratory investigates the role of LOX in Type-1 diabetes (Dr. J. Nadler), blood coagulation (Dr. M. Holinstat), stroke (Dr. K. van Leyen) and fungal-derived inflammation (Dr. S. Kelly). With these collaborations, the Holman laboratory hopes to contribute to the understanding of these important human diseases and possibly identify potent therapeutics.

近期论文

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2-Lipoxygenase and Islet β cell Dysfunction in Diabetes. Tersey SA, Bolanis E, Holman TR, Maloney DJ, Nadler JL, Mirmira RG. Mol Endocrinol. 2015 Mar 24:me20151041. [Epub ahead of print] PMID: 25803446 Related citations Select item 25712042 A high-throughput mass spectrometric assay for discovery of human lipoxygenase inhibitors and allosteric effectors. Jameson JB 2nd, Kenyon V, Holman TR. Anal Biochem. 2015 Feb 21;476:45-50. doi: 10.1016/j.ab.2015.02.011. [Epub ahead of print] PMID: 25712042 Related citations Select item 25506969 Discovery of ML355, a Potent and Selective Inhibitor of Human 12-Lipoxygenase. Luci D, Jameson JB, Yasgar A, Diaz G, Joshi N, Kantz A, Markham K, Perry S, Kuhn N, Yeung J, Schultz L, Holinstat M, Nadler J, Taylor-Fishwick DA, Jadhav A, Simeonov A, Holman TR, Maloney DJ. Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. 2013 Apr 12 [updated 2014 Sep 18]. PMID: 25506969 Free Books Documents Related citations Select item 25495979 The potential of 12/15-lipoxygenase inhibitors in stroke therapy. van Leyen K, Holman TR, Maloney DJ. Future Med Chem. 2014;6(17):1853-5. doi: 10.4155/fmc.14.129. No abstract available. PMID: 25495979 Related citations Select item 25417214 Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction. Taylor-Fishwick DA, Weaver J, Glenn L, Kuhn N, Rai G, Jadhav A, Simeonov A, Dudda A, Schmoll D, Holman TR, Maloney DJ, Nadler JL. Diabetologia. 2015 Mar;58(3):549-57. doi: 10.1007/s00125-014-3452-0. Epub 2014 Nov 23. PMID: 25417214 Related citations Select item 25359714 Enzymatic Studies of Isoflavonoids as Selective and Potent Inhibitors of Human Leukocyte 5-Lipo-Oxygenase. Mascayano C, Espinosa V, Sepúlveda-Boza S, Hoobler EK, Perry S, Diaz G, Holman TR. Chem Biol Drug Des. 2014 Oct 30. doi: 10.1111/cbdd.12469. [Epub ahead of print] PMID: 25359714 Related citations Select item 25111178 A high throughput screen identifies potent and selective inhibitors to human epithelial 15-lipoxygenase-2. Jameson JB 2nd, Kantz A, Schultz L, Kalyanaraman C, Jacobson MP, Maloney DJ, Jadhav A, Simeonov A, Holman TR. PLoS One. 2014 Aug 11;9(8):e104094. doi: 10.1371/journal.pone.0104094. eCollection 2014. PMID: 25111178 Free PMC Article Related citations Select item 25100742 Platelet 12-LOX is essential for FcγRIIa-mediated platelet activation. Yeung J, Tourdot BE, Fernandez-Perez P, Vesci J, Ren J, Smyrniotis CJ, Luci DK, Jadhav A, Simeonov A, Maloney DJ, Holman TR, McKenzie SE, Holinstat M. Blood. 2014 Oct 2;124(14):2271-9. doi: 10.1182/blood-2014-05-575878. Epub 2014 Aug 6. PMID: 25100742 Related citations Select item 24924423 Inhibitory and mechanistic investigations of oxo-lipids with human lipoxygenase isozymes. Armstrong MM, Diaz G, Kenyon V, Holman TR. Bioorg Med Chem. 2014 Aug 1;22(15):4293-7. doi: 10.1016/j.bmc.2014.05.025. Epub 2014 May 21. PMID: 24924423 Related citations Select item 24893149 ATP allosterically activates the human 5-lipoxygenase molecular mechanism of arachidonic acid and 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid. Smyrniotis CJ, Barbour SR, Xia Z, Hixon MS, Holman TR. Biochemistry. 2014 Jul 15;53(27):4407-19. doi: 10.1021/bi401621d. Epub 2014 Jul 2. PMID: 24893149 Related citations Select item 24684213 Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies. Rai G, Joshi N, Jung JE, Liu Y, Schultz L, Yasgar A, Perry S, Diaz G, Zhang Q, Kenyon V, Jadhav A, Simeonov A, Lo EH, van Leyen K, Maloney DJ, Holman TR. J Med Chem. 2014 May 22;57(10):4035-48. doi: 10.1021/jm401915r. Epub 2014 May PMID: 24684213 Free PMC Article Related citations Select item 24672829 Discovery of ML351, a Potent and Selective Inhibitor of Human 15-Lipoxygenase-1. Rai G, Joshi N, Perry S, Yasgar A, Schultz L, Jung JE, Liu Y, Terasaki Y, Diaz G, Kenyon V, Jadhav A, Simeonov A, van Leyen K, Holman TR, Maloney DJ. Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. 2013 Apr 15 [updated 2014 Jan 13]. PMID: 24672829 Free Books Documents Related citations Select item 24430802 Gene-environment interaction models to unmask susceptibility mechanisms in Parkinson's disease. Chou VP, Ko N, Holman TR, Manning-Boğ AB. J Vis Exp. 2014 Jan 7;(83):e50960. doi: 10.3791/50960. PMID: 24430802 Related citations Select item 24393039 Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase. Luci DK, Jameson JB 2nd, Yasgar A, Diaz G, Joshi N, Kantz A, Markham K, Perry S, Kuhn N, Yeung J, Kerns EH, Schultz L, Holinstat M, Nadler JL, Taylor-Fishwick DA, Jadhav A, Simeonov A, Holman TR, Maloney DJ. J Med Chem. 2014 Jan 23;57(2):495-506. doi: 10.1021/jm4016476. Epub 2014 Jan 6. PMID: 24393039 Free PMC Article Related citations Select item 24171444 Kinetic and structural investigations into the allosteric and pH effect on the substrate specificity of human epithelial 15-lipoxygenase-2. Joshi N, Hoobler EK, Perry S, Diaz G, Fox B, Holman TR. Biochemistry. 2013 Nov 12;52(45):8026-35. doi: 10.1021/bi4010649. Epub 2013 Oct PMID: 24171444 Free PMC Article Related citations Select item 23826084 Discovery of a novel dual fungal CYP51/human 5-lipoxygenase inhibitor: implications for anti-fungal therapy. Hoobler EK, Rai G, Warrilow AG, Perry SC, Smyrniotis CJ, Jadhav A, Simeonov A, Parker JE, Kelly DE, Maloney DJ, Kelly SL, Holman TR. PLoS One. 2013 Jun 24;8(6):e65928. doi: 10.1371/journal.pone.0065928. Print 2013. PMID: 23826084 Free PMC Article Related citations Select item 23784669 12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity. Yeung J, Apopa PL, Vesci J, Stolla M, Rai G, Simeonov A, Jadhav A, Fernandez-Perez P, Maloney DJ, Boutaud O, Holman TR, Holinstat M. Thromb Haemost. 2013 Sep;110(3):569-81. doi: 10.1160/TH13-01-0014. Epub 2013 Jun 20. Erratum in: Thromb Haemost. 2014 Aug;112(2):426. PMID: 23784669 Free PMC Article Related citations Select item 23669189 Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases. Hoobler EK, Holz C, Holman TR. Bioorg Med Chem. 2013 Jul 1;21(13):3894-9. doi: 10.1016/j.bmc.2013.04.016. Epub 2013 Apr 18. PMID: 23669189 Free PMC Article Related citations Select item 23192915