To date, a high-affinity binding of nitric oxide (*NO) to protein metal centers, such as in the case of guanylate cyclase (iron) and mitochondrial Cytochrome c oxidase (copper), has been attributed to the classical mechanism of its biological function. Alternatively, *NO may regulate cell signaling through post-translational modifications. One such well-characterized one is S-nitrosylation, which refers to covalent bond formation between a nitroso-moiety and the reduced thiol of a cysteine residue. Accumulated evidence suggests underlying mechanisms for nonenzymatic formation of S-nitrosylation via few possible routes of biochemical reactions. In addition, S-nitrosyation may be generated by enzyme-mediated process of transnitrosylation, which moves a *NO moiety from a SNO donor to a thiolate recipient. Removal of SNO group involved in signaling events is generally considered an enzymatic process catalyzed by a number of enzymes called denitrosylases.
SNO formation may occur in key enzymes regulating cell metabolism or critical modulators governing signal transduction. Interestingly, the reactive thiol group susceptible to S-nitrosylation is present in the active-site Cys of many enzymes identified so far. It has been also shown that a high degree of S-nitrosylation may promote the progression of human diseases exampled by development of neuronal degeneration, cerebral ischemia, cartilage loss and pancreas beta cells destruction. It is believed that autoimmune diabete (type 1) si mediate by adverse reaction of T cells against some auto-antigens in pancreas. Science has unequivocally proven that among the major culprits in beta cells demise there is nitric oxide. In in this settings, 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.
The researchers discovered a novel “carrier” enzyme (called SNO-CoA-assisted nitrosylase, or SCAN) that attaches nitric oxide to proteins, including the receptor for insulin action. They found that the SCAN enzyme was essential for normal insulin action, but also discovered heightened SCAN activity in diabetic patients and mice with diabetes. Insulin-stimulated S-nitrosylation of insulin receptor (INSR), its downstram adaptor (IRS-1) by SCAN reduces insulin signaling physiologically, whereas increased SCAN activity in obesity causes INSR/IRS1 hypernitrosylation of and insulin resistance. SCAN-deficient mice are thus protected from diabetes. In human skeletal muscle and adipose tissue, SCAN expression increases with BMI and correlates with INSR S-nitrosylation. Given the discovery, next steps could be to develop medications against the enzyme. Many human diseases, including Alzheimer’s, cancer, heart failure and diabetes, are thought to be caused or accelerated by nitric oxide excessive binding to key proteins.
Excessive nitric oxide has been implicated in many diseases, but the ability to treat has been limited because the molecule is reactive and can’t be targeted specifically. With this discovery, enzymes that attach the nitric oxide become a focus. With diabetes, the body often stops responding normally to insulin. The resulting increased blood sugar stays in the bloodstream and, over time, can cause serious health problems. Individuals with diabetes, the CDCs reports, are more likely to suffer such conditions as heart disease, macular disease (leading to blindness) and kidney disease. But the reason that insulin stops working isn’t well understood, though known to be dependent also with over-production of oxidative stress. Excessive nitric oxide has been implicated in many diseases, but the ability to treat has been limited because the molecule is reactive and can’t be targeted specifically. These new informations may inspire researchers to develop targeted compounds to modulate SCAN activity to treat diabetes and its correlated secondary complications.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
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