TSRI/Salk team finds two enzymes that may control diabetes, inflammation

Scientists hailing from The Scripps Research Institute (TSRI) and the Salk Institute have flagged two novel "outlier" enzymes and their role in metabolism and inflammation. The discovery may point toward a new therapeutic angle on the increasingly prevalent Type 2 diabetes and inflammatory disorders.

The team headed up by co-author Alan Saghatelian and Benjamin Cravatt published their work online earlier this week in the journal Nature Chemical Biology.

They used a new technique to mine the potential protein structures present in the sample, making use of fluorophosphonate (FP) probes to label the active sites of these proteins. More specifically, the FP-binding proteins can recognize a class of proteins in the serine/threonine hydrolase family.

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The human proteome--the catalog of all known proteins--is largely uncharacterized and represents potential drug targets as we pull out new proteins involved in health and disease.

To examine the kind of proteins they pull out using this technique they applied mass spectrometry and identified two outliers to the hydrolase family--androgen-induced gene 1 protein (AIG1) and a related protein called ADTRP.

"Neither of these proteins had been characterized as an enzyme; in fact, there had been little functional characterization of them at all. It looks like they have an active site that is novel--it had never been described in the literature," said Parsons, referring to the newly discovered AIG1 and ADTRP proteins. 

The team found both were moderately inhibited by lipase inhibitors. A class of lipids called fatty acid esters of hydroxy fatty acids (FAHFAs) were already described by Saghatelian's lab and boosting one FAHFA lipid was sufficient to normalize glucose levels in diabetic mice while reducing inflammation.

"[Ben Cravatt's] lab was screening panels of lipids to find the ones that their new enzymes work on," said Saghatelian. "We suggested they throw FAHFAs in there--and these turned out to be very good substrates."

From this they found AIG1 and ADTRP break down FAHFAs specifically while leaving other major classes of lipids untouched. If the findings are accurate, then blocking their degradation may increase FAHFA levels, which should have a protective effect in diabetic mice and reduce inflammation associated with the sustained elevation of blood glucose.

"One of the neat things this study shows," said Cravatt, "is 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."

The teams next plan to carry out this experiment in mice using a larger number of AIG1/ADTRP lipid inhibitors with the goal to find an effective drug that targets metabolic disease.

- here's the release
- read the journal abstract

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