Lawrence J. Marnett, Ph.D.

Mary Geddes Stahlman Professor of Cancer Research

Professor of Biochemistry and Chemistry

Director of the A. B. Hancock, Jr. Memorial Laboratory for Cancer Research

Director of the Vanderbilt Institute of Chemical Biology

Ph.D., Duke University, 1973 (Chemistry)

This laboratory is interested in the structure, mutagenicity, and repair of adducts derived from lipid oxidation products such as malondialdehyde. Adducts of defined structure are engineered site-specifically into viral DNA molecules that are introduced into bacterial and mammalian cells for evaluation of their mutagenic potential and repair. NMR and X-ray crystallographic experiments are performed in parallel to determine the three-dimensional structure of oligonucleotides bearing the chemical adduct. A second interest in this laboratory is the structure and function of fatty acid oxygenases. Enzymes such as cyclooxygenase (COX) and lipoxygenase catalyze the committed step in the metabolism of polyunsaturated fatty acids to bioactive lipids. Mechanistic studies, affinity labeling, and site-directed mutagenesis experiments are used to define critical amino acid residues and substrate and inhibitor binding sites. Particular attention is being focused on the design and synthesis of novel COX-2 inhibitors that are anti-inflammatory but not ulcerogenic and on the characterization of the chemistry and biology of COX-2-selective substrates.

Recent Publications

Felts AS, Ji C, Stafford JB, Crews BC, Kingsley PJ, Rouzer CA, Washington MK, Subbaramaiah K, Siegel BS, Young SM, Dannenberg AJ, Marnett LJ. Desmethyl Derivatives of Indomethacin and Sulindac as Probes for Cyclooxygenase-Dependent Biology. ACS Chem Biol. 2007 2:479-483.

Rouzer CA, Ivanova PT, Byrne MO, Brown HA, Marnett LJ. Lipid profiling reveals glycerophospholipid remodeling in zymosan-stimulated macrophages. Biochemistry. 2007 46:6026-42.

Blobaum AL, Marnett LJ. Molecular determinants for the selective inhibition of cyclooxygenase-2 by lumiracoxib. J Biol Chem. 2007 282:16379-90.

Trostchansky A, O'Donnell VB, Goodwin DC, Landino LM, Marnett LJ, Radi R, Rubbo H. Interactions between nitric oxide and peroxynitrite during prostaglandin endoperoxide H synthase-1 catalysis: a free radical mechanism of inactivation. Free Radic Biol Med. 2007 42:1029-38.

Blobaum AL, Marnett LJ. Structural and functional basis of cyclooxygenase inhibition. J Med Chem. 2007 50:1425-41.

Knutson CG, Akingbade D, Crews BC, Voehler M, Stec DF, Marnett LJ. Metabolism in vitro and in vivo of the DNA base adduct, M1G. Chem Res Toxicol. 2007 20:550-7.

Wang H, Xie H, Sun X, Kingsley PJ, Marnett LJ, Cravatt BF, Dey SK. Differential regulation of endocannabinoid synthesis and degradation in the uterus during embryo implantation. Prostaglandins Other Lipid Mediat. 2007 83:62-74.

Rouzer CA, Ivanova PT, Byrne MO, Milne SB, Marnett LJ, Brown HA. Lipid profiling reveals arachidonate deficiency in RAW264.7 cells: Structural and functional implications. Biochemistry. 2006 45:14795-808.

Wang H, Kozekov ID, Kozekova A, Tamura PJ, Marnett LJ, Harris TM, Rizzo CJ. Site-specific synthesis of oligonucleotides containing malondialdehyde adducts of deoxyguanosine and deoxyadenosine via a postsynthetic modification strategy. Chem Res Toxicol. 2006 19:1467-74.

Yu Y, Fan J, Hui Y, Rouzer CA, Marnett LJ, Klein-Szanto AJ, FitzGerald GA, Funk CD. Targeted cyclooxygenase gene (ptgs) exchange reveals discriminant isoform functionality. J Biol Chem. 2007 282:1498-506.

Adams TB, McGowen MM, Williams MC, Cohen SM, Feron VJ, Goodman JI, Marnett LJ, Munro IC, Portoghese PS, Smith RL, Waddell WJ. The FEMA GRAS assessment of aromatic substituted secondary alcohols, ketones, and related esters used as flavor ingredients. Food Chem Toxicol. 2007 45:171-201.

Druckova A, Marnett LJ. Characterization of the amino acid adducts of the enedial derivative of teucrin A. Chem Res Toxicol. 2006 19:1330-40.

Anning PB, Coles B, Morton J, Wang H, Uddin J, Morrow JD, Dey SK, Marnett LJ, O'Donnell VB. Nitric oxide deficiency promotes vascular side effects of cyclooxygenase inhibitors. Blood. 2006 108:4059-62.

Wang H, Xie H, Guo Y, Zhang H, Takahashi T, Kingsley PJ, Marnett LJ, Das SK, Cravatt BF, Dey SK. Fatty acid amide hydrolase deficiency limits early pregnancy events. J Clin Invest. 2006 116:2122-31.

Feng Z, Hu W, Marnett LJ, Tang MS. Malondialdehyde, a major endogenous lipid peroxidation product, sensitizes human cells to UV- and BPDE-induced killing and mutagenesis through inhibition of nucleotide excision repair. Mutat Res. 2006 601:125-36.

Rouzer CA, Tranguch S, Wang H, Zhang H, Dey SK, Marnett LJ. Zymosan-induced glycerylprostaglandin and prostaglandin synthesis in resident peritoneal macrophages: roles of cyclo-oxygenase-1 and -2. Biochem J. 2006 399:91-9.

Otteneder MB, Knutson CG, Daniels JS, Hashim M, Crews BC, Remmel RP, Wang H, Rizzo C, Marnett LJ. In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M1dG. Proc Natl Acad Sci U S A. 2006 103:6665-9.

West JD, Marnett LJ. Endogenous reactive intermediates as modulators of cell signaling and cell death. Chem Res Toxicol. 2006 19:173-94. Review.

Muthian G, Raikwar HP, Johnson C, Rajasingh J, Kalgutkar A, Marnett LJ, Bright JJ. COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis. J Clin Immunol. 2006 26:73-85.

Related Links
Marnett Research Laboratory