Faculty

Brent R. Martin

William R. Roush Assistant Professor of Chemistry

Ph.D., UC San Diego
Postdoctoral Fellow, The Scripps Research Institute

Research Focus: Chemical proteomics, fluorescent probes, post-translational modifications, inhibitors.

Office: 4541 Chemistry
Phone: 734.615.2867
E-mail: brentrm@umich.edu

Our group aims to explore the function and physiological role of novel enzymes and post-translational modifications 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. We have developed new chemistries to selectively tag and enrich native sites of protein palmitoylation for mass spectrometry analysis. Using activity-based high throughput screening, we also identified and optimized several small molecule inhibitors to selectively inhibit palmitoyl thioesterases, blocking the turnover of palmitoylation in cells and mice. With these tools, we have identified a novel interaction network regulating cell polarity. Efforts are underway to optimize these new inhibitors using rational design from co-crystal structures, as well as extend these studies to characterize new scaffolding proteins in growth signaling. Finally, we have expanded these studies to profile the interplay of palmitoylation and other oxidative modifications. This inspired our design of new small molecule affinity probes for a series of other cysteine oxidative modifications for fluorescent imaging and affinity enrichment for mass spectrometry.

Finally, a major focus of our lab is the development and application of transformative mass spectrometry methods for the in-depth annotation and quantification of proteins and post-translational modifications.  Future goals include leveraging new instrumentation and data acquisition methods to develop new algorithms and approaches for the de novo sequencing of peptides and the discovery of novel post-translational modifications

Martin Research Group

 

Awards

2014 NIH Director's New Innovator Award
2010-2014
Howard Temin Pathway to Independence Award in Cancer Research, K99/R00, National Cancer Institute
2007-2010
Ruth L. Kirschstein National Research Service Award Postdoctoral Fellowship, National Institute of Neurological Disorders and Stroke

 

Representative Publications

  1. Foe IT*, Child MA*, Majmudar JD*, Krishnamurthy S, Van der Linden WA, Ward GE, Martin BR^, Bogyo M^. Global analysis of palmitoylated proteins in Toxoplasma gondii. Cell Host & Microbe. 2015, 18, 501–511. (*Co-first authors, ^Corresponding authors)

  2. Xu H, Majmudar JD, Davda D, Ghanakota P, Kim KH, Carlson HA, Showalter HD, Martin BR*, Amidon GL*. Substrate-competitive activity-based profiling of ester prodrug activating enzymes. Molecular Pharmaceutics. 2015, Sep 8;12(9):3399-407 (*Corresponding authors) 

  3. Davda D, Martin BR. Acyl protein thioesterase inhibitors as probes of dynamic S-palmitoylation. Med. Chem. Commun.,5, 268-276 (2014).

  4. Davda D, El Azzouny MA, Tom CT, Hernandez JL, Majmudar JD, Kennedy RT, Martin BR. Profiling targets of the irreversible palmitoylation inhibitor 2-bromopalmitate. ACS Chemical Biology. 2013 Sep 20;8(9):1912-7.

  5. Tom CTMB and Martin BR. Fat chance! Getting a grip on a slippery modification. ACS Chemical Biology, Jan 18;8(1):46-57 (2013).

  6. Adibekian A*, Martin BR*, Chang JW, Hsu K-L, Bachovchin DA, Speers AE, Brown SJ, Spicer T, Fernandez-Vega V, Ferguson J, Rosen H, Cravatt BF. Confirming Target Engagement of Reversible Inhibitors In Vivo by Kinetically-tuned Activity-Based Probes. J. Am. Chem. Soc. 2012, Jun 27;134(25):10345-8. (*Equal Contribution).

  7. Martin BR, Wang C, Adibekian A, Tully SE, Cravatt BF. Global Profiling of Dynamic Protein Palmitoylation. Nature Methods. 2011 Nov 6;9(1):84-9.

  8. Adibekian A, Martin BR, Wang C, Hsu KL, Bachovchin DA, Niessen S, Hoover H, Cravatt BF. Click-generated triazole ureas as ultrapotent in vivo-active serine hydrolase inhibitors. Nature Chemical Biology. 2011 May 15;7(7):469-78.

  9. Martin BR, Cravatt BF. Large-scale profiling of protein palmitoylation in mammalian cells. Nature Methods. 2009 Feb;6(2):135-8.

  10. Martin BR, Deerinck TJ, Ellisman MH, Taylor SS, Tsien RY. Isoform-specific PKA dynamics revealed by dye-triggered aggregation and DAKAP1alpha-mediated localization in living cells. Chemistry & Biology. 2007 Sep;14(9):1031-42

  11. 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 Oct;23(10):1308-14.

 

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