{"id":9330,"date":"2016-03-28T11:57:37","date_gmt":"2016-03-28T18:57:37","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=9330"},"modified":"2018-10-04T11:38:42","modified_gmt":"2018-10-04T18:38:42","slug":"tsri-salk-scientists-discover-outlier-enzymes-that-could-offer-new-targets-to-treat-diabetes-inflammation","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/es\/news-release\/tsri-salk-scientists-discover-outlier-enzymes-that-could-offer-new-targets-to-treat-diabetes-inflammation\/","title":{"rendered":"TSRI, Salk scientists discover \u2018outlier\u2019 enzymes that could offer new targets to treat diabetes, inflammation"},"content":{"rendered":"

LA JOLLA\u2014A team led by scientists at The Scripps Research Institute<\/a> (TSRI) and the Salk Institute for Biological Studies has discovered two enzymes that appear to play a role in metabolism and inflammation\u2014and might someday be targeted with drugs to treat type 2 diabetes and inflammatory disorders.<\/p>\n

The discovery is unusual because the enzymes do not bear a resemblance\u2014in their structures or amino-acid sequences\u2014to any known class of enzymes. The team of scientists nevertheless identified them as \u201coutlier\u201d members of the serine\/threonine hydrolase class, using newer techniques that detect biochemical activity.<\/p>\n

\u201cA huge fraction of the human \u2018proteome\u2019 remains uncharacterized, and this paper shows how chemical approaches can be used to uncover proteins of a given functionality that have eluded classification based on sequence or predicted structure,\u201d said co-senior author Benjamin F. Cravatt, chair of TSRI\u2019s Department of Chemical Physiology.<\/p>\n

\"Matthew
From left: Matthew Kolar, Siddhesh Kamat, Enrique Saez, Armand Cognetta, Alan Saghatelian and William Parsons <\/p>\n

Click here for a high-resolution image.<\/a><\/p>\n

Credit: Salk Institute<\/figcaption><\/figure>\n

\u201cIn this study, we found two genes that control levels of lipids with anti-diabetic and anti-inflammatory activity, suggesting exciting targets for diabetes<\/a> and inflammatory diseases,\u201d said co-senior author Alan Saghatelian<\/a>, who holds the Dr. Frederik Paulsen Chair at the Salk Institute.<\/p>\n

Into the Unknown<\/strong><\/p>\n

The study, which appears as a Nature Chemical Biology<\/em><\/a> Advance Online Publication on March 28, 2016, began as an effort in the Cravatt laboratory to discover and characterize new serine\/threonine hydrolases using fluorophosphonate (FP) probes\u2014molecules that selectively bind and, in effect, label the active sites of these enzymes.<\/p>\n

Pulling FP-binding proteins out of the entire proteome of test cells and identifying them using mass spectrometry techniques, the team matched nearly all to known hydrolases. The major outlier was a protein called androgen-induced gene 1 protein (AIG1). The only other one was a distant cousin in terms of sequence, a protein called ADTRP.<\/p>\n

\u201cNeither of these proteins had been characterized as an enzyme; in fact, there had been little functional characterization of them at all,\u201d said William H. Parsons, a research associate in the Cravatt laboratory who was co-first author of the study. Experiments on AIG1 and ADTRP revealed that they do their enzymatic work in a unique way. \u201cIt looks like they have an active site that is novel\u2014it had never been described in the literature,\u201d said Parsons.<\/p>\n

Initial tests with panels of different enzyme inhibitors showed that AIG1 and ADTRP are moderately inhibited by inhibitors of lipases\u2014enzymes that break down fats and other lipids. But on what specific lipids do these newly discovered outlier enzymes normally work?<\/p>\n

Regulators of FAHFAs<\/strong><\/p>\n

At the Salk Institute, the Saghatelian laboratory was investigating a class of lipids it had discovered in 2014. Known as fatty acid esters of hydroxy fatty acids (FAHFAs), these molecules showed strong therapeutic potential. Saghatelian and his colleagues had found that boosting the levels of one key FAHFA lipid normalizes glucose levels in diabetic mice and also reduces inflammation.<\/p>\n

\u201cBen\u2019s lab was screening panels of lipids to find the ones that their new enzymes work on,\u201d said Saghatelian, who is a former research associate in the Cravatt laboratory. \u201cWe suggested they throw FAHFAs in there\u2014and these turned out to be very good substrates.\u201d<\/p>\n

The Cravatt laboratory soon developed powerful inhibitors of the newly discovered enzymes, and the two labs began working together, using the inhibitors and genetic techniques to explore the enzymes\u2019 functions in vitro<\/em> and in cultured cells. Co-first author Matthew J. Kolar, an MD-PhD student, performed most of the experiments in the Saghatelian lab.<\/p>\n

The team concluded that AIG1 and ADTRP, at least in the cell types tested, appear to work mainly to break down FAHFAs and not any other major class of lipid.<\/p>\n

In principle, inhibitors of AIG1 and ADTRP could be developed into FAHFA-boosting therapies. \u201cOur prediction,\u201d said Saghatelian, \u201cis that if FAHFAs do what we think they\u2019re doing, then using an enzyme inhibitor to block their degradation would make FAHFA levels go up and should thus reduce inflammation as well as improve glucose levels and insulin sensitivity.\u201d<\/p>\n

The two labs are now collaborating on further studies of the new enzymes\u2014and the potential benefits of inhibiting them\u2014in mouse models of diabetes, inflammation and autoimmune disease.<\/p>\n

\u201cOne of the neat things this study shows,\u201d said Cravatt, \u201cis that even for enzyme classes as well studied as the hydrolases, there may still be hidden members that, presumably by convergent evolution, arrived at that basic enzyme mechanism despite sharing no sequence or structural homology.\u201d<\/p>\n

Other co-authors of the study were Siddhesh S. Kamat, Armand B. Cognetta III, Jonathan J. Hulce and Enrique Saez, of TSRI; and co-senior author Barbara B. Kahn of Beth Israel Deaconess Medical Center and Harvard Medical School.<\/p>\n

Funding was provided in part by the U.S. National Institutes of Health (DA033760, DK909810), The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002), National Cancer Institute Cancer Center Support (grant P30 [CA014195 MASS core]) and the Dr. Frederick Paulsen Chair\/Ferring Pharmaceuticals.<\/p>\n

Content provided by TSRI.<\/em><\/p>\n

About The Salk Institute for Biological Studies<\/strong><\/p>\n

The Salk Institute for Biological Studies is one of the world’s preeminent basic research institutions, where internationally renowned faculty probes fundamental life science questions in a unique, collaborative and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer’s, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.<\/p>\n

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, MD, the Institute is an independent nonprofit organization and architectural landmark.<\/p>\n

About The Scripps Research Institute<\/strong><\/p>\n

The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists\u2014including two Nobel laureates\u2014work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu<\/a>.<\/p>\n","protected":false},"featured_media":0,"template":"","faculty":[111],"disease-research":[165,123,331],"class_list":["post-9330","disclosure","type-disclosure","status-publish","hentry","faculty-alan-saghatelian","disease-research-diabetes-type-2","disease-research-metabolism-and-diabetes","disease-research-protein-interactions"],"acf":[],"yoast_head":"\nTSRI, Salk scientists discover \u2018outlier\u2019 enzymes that could offer new targets to treat diabetes, inflammation - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/es\/news-release\/tsri-salk-scientists-discover-outlier-enzymes-that-could-offer-new-targets-to-treat-diabetes-inflammation\/\" \/>\n<meta property=\"og:locale\" content=\"es_MX\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"TSRI, Salk scientists discover \u2018outlier\u2019 enzymes that could offer new targets to treat diabetes, inflammation - 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