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Oxford-Harrington Rare Disease Scholar Award

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December 05, 2023

An Enzyme that Selectively S-nitrosylates Proteins to Regulate Insulin Signaling

Researchers at Case Western Reserve University and University Hospitals have identified an enzyme that blocks insulin produced in the body—a discovery that could provide a new target to treat diabetes.

Their study, published Dec. 5 in the journal Cell, focuses on nitric oxide, a compound that dilates blood vessels, improves memory, fights infection and stimulates the release of hormones, among other functions. How nitric oxide performs these activities had long been a mystery.

Highlights

  • SCAN catalyzes protein S-nitrosylation using S-nitroso-CoA as a cofactor
  • S-nitrosylation of insulin receptor and IRS1 by SCAN regulates insulin signaling
  • Hypernitrosylation of INSR and IRS1 by SCAN causes diabetes
  • SCAN expression correlates with human BMI and INSR S-nitrosylation

Summary

Acyl-coenzyme A (acyl-CoA) species are cofactors for numerous enzymes that acylate thousands of proteins. Here, we describe an enzyme that uses S-nitroso-CoA (SNO-CoA) as its cofactor to S-nitrosylate multiple proteins (SNO-CoA-assisted nitrosylase, SCAN). Separate domains in SCAN mediate SNO-CoA and substrate binding, allowing SCAN to selectively catalyze SNO transfer from SNO-CoA to SCAN to multiple protein targets, including the insulin receptor (INSR) and insulin receptor substrate 1 (IRS1). Insulin-stimulated S-nitrosylation of INSR/IRS1 by SCAN reduces insulin signaling physiologically, whereas increased SCAN activity in obesity causes INSR/IRS1 hypernitrosylation and insulin resistance. SCAN-deficient mice are thus protected from diabetes. In human skeletal muscle and adipose tissue, SCAN expression increases with body mass index and correlates with INSR S-nitrosylation. S-nitrosylation by SCAN/SNO-CoA thus defines a new enzyme class, a unique mode of receptor tyrosine kinase regulation, and a revised paradigm for NO function in physiology and disease.

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About the Scholar

Jonathan Stamler

Cardiovascular

Jonathan Stamler, MD

University Hospitals - Cleveland
Harrington Investigators

More about Jonathan Stamler