Clayton Foundation Laboratories for Peptide Biology
"Peptides and metabolites have fundamental roles in human biology and disease but are difficult to measure using common biological methods. Therefore, we've developed innovative methods to detect physiological peptides and metabolites and have discovered new classes of peptides and metabolites that control disease biology.
We hope that someday this information may lead to insights that enable us to effectively treat important diseases, such as diabetes, cancer and autoimmune diseases."
Saghatelian's lab dives into the discovery and characterization of novel molecules associated with human disease, such as diabetes, cancer and autoimmune disease. What makes his lab unique in this endeavor is the focus on the biology of metabolites and peptides—two classes of molecules that are extremely important in biology but understudied because of technical challenges. Exploring this uncharted territory has enabled the Saghatelian lab to discover novel lipids that reduce inflammation and improve the symptoms of diabetes and identify a previously unknown cluster of human genes that produce peptides and small proteins that control fundamental cellular processes, such as DNA repair, highlighting their potential importance in cancer.
The discovery of novel molecules relies on the application and development of cutting-edge mass spectrometry methods, which enable the analysis of thousands of metabolites and peptides from biological samples to identify those which correlate with a particular disease. The technical advance in our work, Saghatelian says, is the development and application of new mass spectrometry methods that enable the lab to measure changes in molecules overlooked by traditional methods, which typically focus on genes and proteins. Saghatelian also plans to integrate these methods into the Salk through cross-disciplinary collaborations that could lead to many important discoveries.
Saghatelian hopes to use the knowledge gained from his lab's work to accelerate the development of novel medicines. By identifying how key metabolic hormones that control blood glucose levels are processed, for example, Saghatelian and his colleague developed a drug-like compound that improves blood glucose in mice. These initial studies indicate that this molecule might be able to treat diabetes in humans. Notably, this molecule works by a unique mechanism that is different from all approved anti-diabetic drugs, which means that it may be used to treat patients refractory to current therapies or used in combination with current drugs to get an even better effect.
"Metabolites and peptides are a group of molecules that are challenging to measure in the same ways we use to measure genes and proteins. Therefore, we don't have a good sense how important metabolites or peptides are in disease. Our work hopes to determine the importance of these molecules, and in cases where they are important, use that information to create novel therapeutics," he says.
Prior to joining the Salk Institute, Saghatelian was an associate professor at Harvard University, and pursued his graduate degree and postgraduate work at The Scripps Research Institute. He attended University of California, Los Angeles for his undergraduate work in chemistry.
Nazarian, A., Lawlor, K., Yi, S. S., Philip, J., Ghosh, M., Yaneva, M., Villanueva, J., Saghatelian, A., Assel, M., Vickers, A. J., Eastham, J. A., Scher, H. I., Carver, B. S., Lilja, H. & Tempst, P. Inhibition of Circulating Dipeptidyl Peptidase 4 Activity in Patients with Metastatic Prostate Cancer. Molecular & cellular proteomics : MCP, (2014).
Oliver, P. M., Crooks, J. A., Leidl, M., Yoon, E. J., Saghatelian, A. & Weibel, D. B. Localization of anionic phospholipids in Escherichia coli cells. Journal of bacteriology, (2014).
Maianti, J. P., McFedries, A., Foda, Z. H., Kleiner, R. E., Du, X. Q., Leissring, M. A., Tang, W. J., Charron, M. J., Seeliger, M. A., Saghatelian, A. & Liu, D. R. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature 511, 94-98, (2014).
Chin, R. M., Fu, X., Pai, M. Y., Vergnes, L., Hwang, H., Deng, G., Diep, S., Lomenick, B., Meli, V. S., Monsalve, G. C., Hu, E., Whelan, S. A., Wang, J. X., Jung, G., Solis, G. M., Fazlollahi, F., Kaweeteerawat, C., Quach, A., Nili, M., Krall, A. S., Godwin, H. A., Chang, H. R., Faull, K. F., Guo, F., Jiang, M., Trauger, S. A., Saghatelian, A., Braas, D., Christofk, H. R., Clarke, C. F., Teitell, M. A., Petrascheck, M., Reue, K., Jung, M. E., Frand, A. R. & Huang, J. The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510, 397-401, (2014).
Slavoff, S. A., Heo, J., Budnik, B. A., Hanakahi, L. A. & Saghatelian, A. A human short open reading frame (sORF)-encoded polypeptide that stimulates DNA end joining. The Journal of biological chemistry 289, 10950-10957, (2014). PMCID: PMC4036235.
Lone, A. M., Leidl, M., McFedries, A. K., Horner, J. W., Creemers, J. & Saghatelian, A. Deletion of PREPl causes growth impairment and hypotonia in mice. PloS one 9, e89160, (2014). PMCID: PMC3938459.
Ma, J., Ward, C. C., Jungreis, I., Slavoff, S. A., Schwaid, A. G., Neveu, J., Budnik, B. A., Kellis, M. & Saghatelian, A. Discovery of human sORF-encoded polypeptides (SEPs) in cell lines and tissue. Journal of proteome research 13, 1757-1765, (2014). PMCID: PMC3993966.
Pauli, A., Norris, M. L., Valen, E., Chew, G. L., Gagnon, J. A., Zimmerman, S., Mitchell, A., Ma, J., Dubrulle, J., Reyon, D., Tsai, S. Q., Joung, J. K., Saghatelian, A. & Schier, A. F. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science 343, 1248636, (2014). PMCID: PMC4107353.
Liu, S., Brown, J. D., Stanya, K. J., Homan, E., Leidl, M., Inouye, K., Bhargava, P., Gangl, M. R., Dai, L., Hatano, B., Hotamisligil, G. S., Saghatelian, A., Plutzky, J. & Lee, C. H. A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. Nature 502, 550-554, (2013).
Schwaid, A. G., Shannon, D. A., Ma, J., Slavoff, S. A., Levin, J. Z., Weerapana, E. & Saghatelian, A. Chemoproteomic discovery of cysteine-containing human short open reading frames. Journal of the American Chemical Society 135, 16750-16753, (2013). PMCID: PMC3868496.
Lopez-Sagaseta, J., Dulberger, C. L., McFedries, A., Cushman, M., Saghatelian, A. & Adams, E. J. MAIT recognition of a stimulatory bacterial antigen bound to MR1. Journal of immunology 191, 5268-5277, (2013). PMCID: PMC3819123.
Kim, Y. G., Lone, A. M. & Saghatelian, A. Analysis of the proteolysis of bioactive peptides using a peptidomics approach. Nature protocols 8, 1730-1742, (2013).
Mitchell, A. J., Lone, A. M., Tinoco, A. D. & Saghatelian, A. Proteolysis controls endogenous substance P levels. PloS one 8, e68638, (2013). PMCID: PMC3716696.
Tatematsu, S., Francis, S. A., Natarajan, P., Rader, D. J., Saghatelian, A., Brown, J. D., Michel, T. & Plutzky, J. Endothelial lipase is a critical determinant of high-density lipoprotein-stimulated sphingosine 1-phosphate-dependent signaling in vascular endothelium. Arteriosclerosis, thrombosis, and vascular biology 33, 1788-1794, (2013). PMCID: PMC3794714.
McFedries, A., Schwaid, A. & Saghatelian, A. Methods for the elucidation of protein-small molecule interactions. Chemistry & biology 20, 667-673, (2013).
Miraldi, E. R., Sharfi, H., Friedline, R. H., Johnson, H., Zhang, T., Lau, K. S., Ko, H. J., Curran, T. G., Haigis, K. M., Yaffe, M. B., Bonneau, R., Lauffenburger, D. A., Kahn, B. B., Kim, J. K., Neel, B. G., Saghatelian, A. & White, F. M. Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice. Integrative biology : quantitative biosciences from nano to macro 5, 940-963, (2013). PMCID: PMC3759823.
Lopez-Sagaseta, J., Dulberger, C. L., Crooks, J. E., Parks, C. D., Luoma, A. M., McFedries, A., Van Rhijn, I., Saghatelian, A. & Adams, E. J. The molecular basis for Mucosal-Associated Invariant T cell recognition of MR1 proteins. Proceedings of the National Academy of Sciences of the United States of America 110, E1771-1778, (2013). PMCID: PMC3651419.
Zhang, T. & Saghatelian, A. Emerging roles of lipids in BCL-2 family-regulated apoptosis. Biochimica et biophysica acta 1831, 1542-1554, (2013).
Lone, A. M., Kim, Y. G. & Saghatelian, A. Peptidomics methods for the identification of peptidase-substrate interactions. Current opinion in chemical biology 17, 83-89, (2013). PMCID: PMC3594040.
Cezairliyan, B., Vinayavekhin, N., Grenfell-Lee, D., Yuen, G. J., Saghatelian, A. & Ausubel, F. M. Identification of Pseudomonas aeruginosa phenazines that kill Caenorhabditis elegans. PLoS pathogens 9, e1003101, (2013). PMCID: PMC3536714.
Slavoff, S. A., Mitchell, A. J., Schwaid, A. G., Cabili, M. N., Ma, J., Levin, J. Z., Karger, A. D., Budnik, B. A., Rinn, J. L. & Saghatelian, A. Peptidomic discovery of short open reading frame-encoded peptides in human cells. Nature chemical biology 9, 59-64, (2013). PMCID: PMC3625679.
Slavoff, S. A. & Saghatelian, A. Discovering ligand-receptor interactions. Nature biotechnology 30, 959-961, (2012).
Du, Y., Yang, M., Wei, W., Huynh, H. D., Herz, J., Saghatelian, A. & Wan, Y. Macrophage VLDL receptor promotes PAFAH secretion in mother's milk and suppresses systemic inflammation in nursing neonates. Nature communications 3, 1008, (2012). PMCID: PMC3520613.
Du, Y., Yang, M., Lee, S., Behrendt, C. L., Hooper, L. V., Saghatelian, A. & Wan, Y. Maternal western diet causes inflammatory milk and TLR2/4-dependent neonatal toxicity. Genes & development 26, 1306-1311, (2012). PMCID: PMC3387658.
Kim, Y. G., Lone, A. M., Nolte, W. M. & Saghatelian, A. Peptidomics approach to elucidate the proteolytic regulation of bioactive peptides. Proceedings of the National Academy of Sciences of the United States of America 109, 8523-8527, (2012). PMCID: PMC3365226.
Tinoco, A. D., Thomas, H. R., Incarvito, C. D., Saghatelian, A. & Valentine, A. M. Cytotoxicity of a Ti(IV) compound is independent of serum proteins. Proceedings of the National Academy of Sciences of the United States of America 109, 5016-5021, (2012). PMCID: PMC3323991.
Guzman-Rojas, L., Rangel, R., Salameh, A., Edwards, J. K., Dondossola, E., Kim, Y. G., Saghatelian, A., Giordano, R. J., Kolonin, M. G., Staquicini, F. I., Koivunen, E., Sidman, R. L., Arap, W. & Pasqualini, R. Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment. Proceedings of the National Academy of Sciences of the United States of America 109, 1637-1642, (2012). PMCID: PMC3277167.
Kim, Y. G. & Saghatelian, A. Functional analysis of protein targets by metabolomic approaches. Topics in current chemistry 324, 137-162, (2012).
Vinayavekhin, N. & Saghatelian, A. Discovery of a protein-metabolite interaction between unsaturated fatty acids and the nuclear receptor Nur77 using a metabolomics approach. Journal of the American Chemical Society 133, 17168-17171, (2011).
Tinoco, A. D. & Saghatelian, A. Investigating endogenous peptides and peptidases using peptidomics. Biochemistry 50, 7447-7461, (2011). PMCID: PMC3418817.
Brown, J. D., Oligino, E., Rader, D. J., Saghatelian, A. & Plutzky, J. VLDL hydrolysis by hepatic lipase regulates PPARdelta transcriptional responses. PloS one 6, e21209, (2011). PMCID: PMC3130023.
Lone, A. M., Bachovchin, D. A., Westwood, D. B., Speers, A. E., Spicer, T. P., Fernandez-Vega, V., Chase, P., Hodder, P. S., Rosen, H., Cravatt, B. F. & Saghatelian, A. A substrate-free activity-based protein profiling screen for the discovery of selective PREPL inhibitors. Journal of the American Chemical Society 133, 11665-11674, (2011). PMCID: PMC3145007.
Homan, E. A., Kim, Y. G., Cardia, J. P. & Saghatelian, A. Monoalkylglycerol ether lipids promote adipogenesis. Journal of the American Chemical Society 133, 5178-5181, (2011).
Tinoco, A. D., Kim, Y. G., Tagore, D. M., Wiwczar, J., Lane, W. S., Danial, N. N. & Saghatelian, A. A peptidomics strategy to elucidate the proteolytic pathways that inactivate peptide hormones. Biochemistry 50, 2213-2222, (2011). PMCID: PMC3076939.
Kim, Y. G., Lou, A. C. & Saghatelian, A. A metabolomics strategy for detecting protein-metabolite interactions to identify natural nuclear receptor ligands. Molecular bioSystems 7, 1046-1049, (2011).
Scharf, L., Li, N. S., Hawk, A. J., Garzon, D., Zhang, T., Fox, L. M., Kazen, A. R., Shah, S., Haddadian, E. J., Gumperz, J. E., Saghatelian, A., Faraldo-Gomez, J. D., Meredith, S. C., Piccirilli, J. A. & Adams, E. J. The 2.5 A structure of CD1c in complex with a mycobacterial lipid reveals an open groove ideally suited for diverse antigen presentation. Immunity 33, 853-862, (2010). PMCID: PMC3010391.
Lone, A. M., Nolte, W. M., Tinoco, A. D. & Saghatelian, A. Peptidomics of the prolyl peptidases. The AAPS journal 12, 483-491, (2010). PMCID: PMC2976987.
Vinayavekhin, N. & Saghatelian, A. Untargeted metabolomics. Current protocols in molecular biology / edited by Frederick M. Ausubel ... [et al.] Chapter 30, Unit 30 31 31-24, (2010).
Tinoco, A. D., Tagore, D. M. & Saghatelian, A. Expanding the dipeptidyl peptidase 4-regulated peptidome via an optimized peptidomics platform. Journal of the American Chemical Society 132, 3819-3830, (2010). PMCID: PMC2842575.
Vinayavekhin, N., Homan, E. A. & Saghatelian, A. Exploring disease through metabolomics. ACS chemical biology 5, 91-103, (2010).
Nolte, W. M., Tagore, D. M., Lane, W. S. & Saghatelian, A. Peptidomics of prolyl endopeptidase in the central nervous system. Biochemistry 48, 11971-11981, (2009). PMCID: PMC2813186.
MacBeath, G. & Saghatelian, A. The promise and challenge of '-omic' approaches. Current opinion in chemical biology 13, 501-502, (2009).
Vinayavekhin, N. & Saghatelian, A. Regulation of alkyl-dihydrothiazole-carboxylates (ATCs) by iron and the pyochelin gene cluster in Pseudomonas aeruginosa. ACS chemical biology 4, 617-623, (2009).
Rodgers, M. A., Saghatelian, A. & Yang, P. L. Identification of an overabundant cholesterol precursor in hepatitis B virus replicating cells by untargeted lipid metabolite profiling. Journal of the American Chemical Society 131, 5030-5031, (2009).
Tagore, D. M., Nolte, W. M., Neveu, J. M., Rangel, R., Guzman-Rojas, L., Pasqualini, R., Arap, W., Lane, W. S. & Saghatelian, A. Peptidase substrates via global peptide profiling. Nature chemical biology 5, 23-25, (2009). PMCID: PMC2730040.
Tagore, R., Thomas, H. R., Homan, E. A., Munawar, A. & Saghatelian, A. A global metabolite profiling approach to identify protein-metabolite interactions. Journal of the American Chemical Society 130, 14111-14113, (2008).
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Awards and Honors
- Sloan Foundation Fellow (2011)
- Searle Scholars Program Award (2008)
- New Innovator Award, National Institutes of Health (2007)
- Burroughs Wellcome Fund Career Award in Biomedical Sciences (2005)