研究领域

Analytical Chemistry Bioanalytical Chemistry Bioorganic Chemistry Chemical Biology Sensor Science

Our group aims to explore the function and physiological role of novel enzymes and lipids involved in the development of neurological diseases and cancer. To achieve these goals, we propose to bridge chemical, analytical, and biological approaches to identify novel disease targets and develop chemical approaches for therapeutic intervention. Our expertise in cell and molecular biology, chemical probes, mass spectrometry, and imaging technologies presents a unique opportunity for broad training in chemical biology. This multidisciplinary approach will rely on technological innovation focused on unexplored biochemical pathways and their links to human disease. Cysteine residues in proteins have pKa values close to neutral and are often in their reactive thiolate form in cells, making them nucleophilic and targets of distinct post-translational modifications. One such modification, termed protein S-palmitoylation describes the thioester linkage of palmitic acid and cysteine in proteins, and is required for membrane association and spatial regulation of diverse cellular pathways involved in cell growth and signaling. In many cases, palmitoylation is thought to be dynamically regulated, although the mechanisms that control this lipid modification remain poorly characterized. In order to understand the processes regulating dynamic palmitoylation, we have developed a quantitative chemo-proteomic platform for global comparative analysis of palmitoylated proteins, and used this platform to interrogate the population of palmitoylated proteins regulated by both palmitoyl transferases and thioesterases implicated in cancer and neurological diseases. Additionally, using competitive activity-based high throughput screening, we identified a new class of mechanism-based in vivo potent and highly selective inhibitors to enzymes proposed to regulate protein palmitoylation. In combination with novel activity-based probes, we identified a unique subset of enzymatically regulated, dynamically palmitoylated proteins in cells. Understanding the functional role of dynamic palmitoylation in disease will be explored through the application of new inhibitors and genetic models to test the importance of potential therapeutic targets in vitro and in vivo. Additionally, these methodologies will be used to assign substrates to palmitoyl transferases and thioesterases, as well as the introduction of new fluorescence microscopy approaches for visualizing the spatial and temporal control of membrane compartmentalization. Furthermore, through the development of an expanded suite of chemical probes, we will explore the enzymology, regulation, interactions, and function of novel enzymes involved in the biosynthesis and degradation of unique lipids altered in specific disease states.

近期论文

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Jia L, Chisari M, Maktabi MH, Sobieski C, Zhou H, Konopko AM, Martin BR, Mennerick SJ, Blumer KJ. A mechanism regulating G protein-coupled receptor signaling that requires cycles of protein palmitoylation and depalmitoylation. J. Biol. Chem. published online January 2, 2014. "Selected Paper of the Week", reserved for the top ~1% of accepted manuscripts. Link Davda D., Martin BR. Acyl protein thioesterase inhibitors as probes of dynamic S-palmitoylation. MedChemComm, 2013, In Press. (Review) link Davda D, El Azzouny MA, Tom CTMB, Hernandez JL, Majmudar JD, Kennedy RT, and Martin BR. Profiling targets of the irreversible palmitoylation inhibitor 2-bromopalmitate. ACS Chemical Biology, 2013, Sep 20;8(9):1912-7. link, issue podcast Martin BR. Nonradioactive analysis of dynamic protein palmitoylation. Current Protocols in Protein Science, 2013, 14.15.1-14.15.9, Supplement 73. link Martin, BR. The next frontier of post-translational modifications. Biopolymers. 2013. In Press (Review). link Majmudar JD and Martin BR. Strategies for profiling native S-nitrosylation. Biopolymers. 2013, In Press. (Review). link Martin, BR. Chemical approaches for profiling dynamic palmitoylation. Biochemical Society Transactions. 2013. 41,43-19. (Review) link Hernandez JL*, Majmudar JD*, Martin BR. Profiling and inhibiting reversible palmitoylation. Current Opinion in Chemical Biology. 2013, Feb;17(1):20-6. (Review). (*Equal contribution) link Tom CTMB, Martin BR. Fat chance! Getting a grip on a slippery modification. ACS Chemical Biology. 2013. Jan 18;8(1):46-57. (Revew) link Ivaldi C, Martin BR, Kieffer-Jaquinod S, Chapel A, Levade T, Garin J, Journet A. Proteomic Analysis of S-Acylated Proteins in Human B Cells Reveals Palmitoylation of the Immune Regulators CD20 and CD23. PLoS One, 2012, 7, May 17. link Adibekian A*, Martin BR*, Chang JW, Hsu KL, Tsuboi K, Bachovchin DA, Speers AE, Brown SJ, Spicer T, Fernandez-Vega V, Ferguson J, Hodder PS, Rosen H, Cravatt BF. Confirming target engagement for reversible inhibitors in vivo by kinetically tuned activity-based probes. J Am Chem Soc. 2012, Jun 27;134(25):10345-8. (*Equal Contribution). link Adibekian A, Martin BR, Speers AE, Brown SJ, Spicer T, Fernandez-Vega V, Ferguson J, Cravatt BF, Hodder P, Rosen H. Optimization and characterization of a triazole urea dual inhibitor for lysophospholipase 1 (LYPLA1) and lysophospholipase 2 (LYPLA2). Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-2011 Feb 25. link Li Y, Martin BR, Cravatt BF, and Hofmann SL. DHHC5 palmitoylates flotillin-2 and is rapidly degraded on induction of neuronal differentiation in cultured cells. J. Biol. Chem., 2012, 287, 523-530. link Martin BR*, Wang C, Adibekian A, Tully SE, and Cravatt BF*. Global Profiling of Dynamic Protein Palmitoylation. Nature Methods, 2012, 9, 84-89. *Corresponding authors. link Adibekian A, Martin BR, Wang C, Hsu KL, Bachovchin DA, Niessen S, Hoover H, and Cravatt BF. Click-generated triazole ureas as ultrapotent, in vivo-active serine hydrolase inhibitors. Nature Chemical Biology, 2011, 7, 469-478. link Ladygina N, Martin BR, Altman A. T-cell responsiveness and energy by reversible palmitoylation. Adv. Immunology, 2011, 109:1-44. link Martin BR, Cravatt BF. Large-scale profiling of protein palmitoylation in mammalian cells. Nature Methods. 2009, 6, 135-138. link Martin BR, Deerinck TJ, Ellisman MH, Taylor SS, Tsien RY. Isoform-specific PKA dynamics revealed by dye-triggered aggregation and DAKAP1-alpha-mediated localization in living cells. Chemistry & Biology. 2007, 14, 1031-1042. link Martin BR, Giepmans BN, Adams SR, Tsien RY. Mammalian cell-based optimization of the biarsenical-binding tetracysteine motif for improved fluorescence and affinity. Nature Biotechnology, 2005, 23, 1308-1314. link Adams SR, Campbell RE, Gross LA, Martin BR, Walkup GK, Yao Y, Llopis J, Tsien RY. New biarsenical ligands and tetracysteine motifs for protein labeling in vitro and in vivo: synthesis and biological applications. J Am Chem Soc. 2002, 124, 6063-6076. link