Department of Chemistry
The Skaggs Institute for Chemical Biology
Faculty, Graduate Program
Our research group aims to understand the roles that mammalian enzymes play in physiological and pathological processes and to use this knowledge to identify novel therapeutic targets for the treatment of human disease. To achieve these goals, we develop and apply new technologies that bridge the fields of chemistry and biology, ascribing to the philosophy that the most significant biomedical problems require creative multidisciplinary approaches for their solution. Our technological innovations address fundamental challenges in systems biology that are beyond the scope of contemporary methods. For instance, enzymes are tightly regulated by post-translational events in vivo, meaning that their activity may not correlate with expression as measured by standard genomic and proteomic approaches. Considering that it is an enzyme's activity, rather than abundance that ultimately dictates its role in cell physiology and pathology, we have introduced a set of proteomic technologies that directly measures this parameter. These activity-based protein profiling (ABPP) methods exploit the power of chemistry to engender new tools and assays for the global analysis of enzyme activities. The enzyme activity profiles generated by ABPP constitute unique molecular portraits of cells and tissues that illuminate how metabolic and signaling networks are regulated in vivo. Additionally, by evaluating enzymes based on functional properties rather than mere abundance, ABPP acquires high-content proteomic information that is enriched in novel markers and targets for the diagnosis and treatment of human disease.
We complement these efforts in technology development with focused studies on individual enzymes. With particular interests in the nervous system and cancer, we select proteins, such as the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), for detailed investigation using a range of chemical, biochemical, genetic, and pharmacological techniques. This multidisciplinary approach ensures that we generate all of the tools and models required to assign molecular, cellular, and physiological functions to enzymes and, as an important corollary, assess their suitability as therapeutic targets. Notably, these basic discovery projects both benefit from and provide a fertile testing ground for our technological innovations. Thus, through the integration of two complementary research programs, one dedicated to methods development for functional proteomics, and the other to the characterization of key signaling enzymes, our group achieves a unique balance that cultivates the creation and rapid implementation of cutting-edge technologies that address unmet needs in experimental biology.
B.S., Biological Sciences, Stanford University, 1992
B.A., History, Stanford University, 1992
Ph.D., Macromolecular and Cellular Structure and Chemistry, The Scripps Research Institute, 1996
2007-present Professor and Chair, Department of Chemical Physiology, TSRI
2004 – 2007 Professor, Departments of Cell Biology and Chemistry, TSRI
2004-present Norton B. Gilula Chair in Chemical Biology, TSRI
2002-present Director, Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute
2001-2004 Associate Professor (with tenure), Departments of Cell Biology and Chemistry, TSRI
2000-2001 Assistant Professor, Department of Chemistry, TSRI
1996-2001 Assistant Professor, The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute (TSRI)
2009-10 Pfizer Fellowship for Creativity in Chemistry and Chemical Biology
2009 MERIT Award, National Cancer Institute
2008 Tetrahedron Young Investigator Award in Bioorganic and Medicinal Chemistry, Elsevier
2007 Irving Sigal Young Investigator Award, The Protein Society
2005 Young Investigator Award, International Cannabinoid Research Society
2004 Eli Lilly Award in Biological Chemistry, American Chemical Society
2002 Promega Award for Early Career Life Scientists, American Society for Cell Biology
2002 Technology Review’s TR100 Top 100 Young Innovators Award
Weerapana E*, Wang C*, Simon GM, Richter F, Khare S, Dillon MB, Bachovchin DA, Mowen K, Baker D, Cravatt BF. (2010) Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature. 468:790-5
Schlosburg JE*, Blankman JL*, Long JZ, Nomura DK, Pan B, Kinsey SG, Nguyen PT, Ramesh D, Booker L, Burston JJ, Thomas EA, Selley DE, Sim-Selley LJ, Liu QS, Lichtman AH, Cravatt BF. (2010) Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci. 13(9):1113-9
Nomura DK, Long JZ, Niessen S, Hoover HS, Ng S, Cravatt BF. (2010) Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer Pathogenesis. Cell. 140(1):49-61
Bachovchin DA, Brown SJ, Rosen H, Cravatt BF. (2009) Identification of selective inhibitors of uncharacterized enzymes by high-throughput screening with fluorescent activity-based probes. Nat Biotechnol. 27(4):387-94.
Martin BR, Cravatt BF. (2009) Large-scale profiling of protein palmitoylation in mammalian cells. Nat Methods. 6(2):135-8.
Long JZ, Li W, Booker L, Burston JJ, Kinsey SH, Schlosburg JE, Pavon FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF. (2009) Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 5(37):37-44.
Dix MM*, Simon GM*, Cravatt BF. (2008) Global mapping of the topography and magnitude of proteolytic events in apoptosis. Cell. 134(4):679-91.
Weerapana E, Simon GM, Cravatt BF. (2008) Disparate proteome reactivity profiles of carbon electrophiles. Nat Chem Biol. 4(7):405-407.
Carlson EE, Cravatt BF (2007) Chemoselective probes for metabolite enrichment and profiling. Nat Methods. 4(5):429-435.
Blankman JL, Simon GM, Cravatt BF. (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol. 14(12):1347-1356.
Chiang KP, Niessen S, Saghatelian A, Cravatt BF. (2006) An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling. Chem Biol. 13(10):1041-1050.
Sieber SA, Niessen S, Hoover HS, Cravatt BF. (2006) Proteomic profiling of metalloprotease activities withcocktails of active-site probes. Nat Chem Biol. 2(5):274-281
Evans MJ, Saghatelian A, Sorensen EJ, Cravatt BF (2005) Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling. Nat Biotechnol. 23(10):1303-1307.
Jessani N, Niessen S, Wei BQ, Nicolau M, Humphrey M, Ji Y, Han W, Noh DY, Yates JR 3rd, Jeffrey SS, CravattBF. (2005) A streamlined platform for high-content functional proteomics of primary human specimens. Nat Methods. 2(9):691-697.
Saghatelian A, Trauger SA, Want EJ, Hawkins EG, Siuzdak G, and Cravatt BF. (2004) Assignment of endogenoussubstrates to enzymes by global metabolite profiling. Biochemistry. 43(45):14332-14339
Saghatelian A, Jessani N, Joseph A, Humphrey M, Cravatt BF. (2004) Activity-based probes for the proteomic profiling of metalloproteases. Proc Natl Acad Sci USA. 101(27):10000-10005.
Speers AE, Adam GC, Cravatt BF. (2003) Activity-based protein profiling in vivo using a copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition. J Am Chem Soc. 125(16):4686-4687.
Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF. (2002) Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science. 298(5599):1793-1796.
Patricelli MP, Cravatt BF. (2001) Characterization and manipulation of the acyl chain selectivity of fatty acid amide hydrolase. Biochemistry. 40(20):6107-6115
Patricelli MP, Cravatt BF. (2000) Clarifying the catalytic roles of conserved residues in the amidase signature family. J. Biol. Chem. 275(25):19177-19184.
Liu Y, Patricelli MP, Cravatt BF. (1999) Activity-based protein profiling: The serine hydrolases. Proc. Natl. Acad. Sci. USA. 96(26):14694-14699.
Giang DK, Cravatt BF. (1998) A second mammalian N-myristoyltransferase. J Biol Chem. 273(12):6595-6598.
Giang DK, Cravatt BF. (1997) Molecular characterization of human and mouse fatty acid amide hydrolases. Proc. Natl. Acad. Sci. USA. 94(6):2238-2242.
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384(6604):83-87.
Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA. (1995) Chemical characterization of a family of brain lipids that induce sleep. Science 268(5216):1506-1509.