New Targets Found for Diabetes, Inflammatory Diseases

Inhibiting newly classified enzymes may lead to treatments for type 2 diabetes, inflammation, and autoimmune disease.

Two enzymes have been discovered that in the future could be targeted for the treatment of type 2 diabetes and inflammatory disorders.

These 2 enzymes, androgen-induced gene 1 protein (AIG1) and ADTRP, shared zero resemblance in structure or amino-acid sequence to any other known class of enzymes. Researchers labeled these enzymes as “outlier” members of the serine/threonine hydrolase class.

“A huge fraction of the human 'proteome' 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,” said senior co-author Benjamin F. Cravatt.

The study published in Nature Chemical Biology looked to discover and characterize new serine/threonine hydrolases using fluorophosphonate (FP) probes that selectively find and label the active sites of the enzymes.

The FP-binding proteins were pulled out of the proteome test of cells and identified using mass spectrometry techniques. Researchers were able to match almost all of the known hydrolases besides the 2 outliers AIG1 and ADTRP, which after several different tests showed a unique way of conducting their enzymatic work.

Initial tests with panels of various enzyme inhibitors showed that AIG1 and ADTRP are moderately inhibited by lipases inhibitors.

“Neither of these proteins had been characterized as an enzyme, in fact, there had been little functional characterization of them at all,” said first study co-author, William H. Parsons. “It looks like they have an active site that is novel--it had never been described in the literature.”

The Saghatelian lab conducted an investigation of a class of lipids called fatty acid esters of hydroxy fatty acids (FAHFAs) discovered in 2014 that showed strong therapeutic potential.

When tested on diabetic mice, researchers increased the levels of 1 key FAHFA lipid. This boost normalized the glucose levels and reduced inflammation.

“Ben's lab was screening panels of lipids to find the ones that their new enzymes work on,” said senior co-author Alan Saghatelian. “We suggested they throw FAHFAs in there--and these turned out to be very good substrates.”

When the 2 labs began working together, they concluded that AIG1 and ADTRP seem to mainly break down FAHFAs instead of other major classes of lipids.

“Our prediction is that if FAHFAs do what we think they're 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,” Saghatelian said.

Currently, collaborations are underway for further studies on the potential benefits of inhibiting the new enzymes in mouse models of diabetes, inflammation, and autoimmune disease.

“One of the neat things this study shows 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,” Cravatt said.