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Reactivity of HNO‐Induced Modifications and Its Relevance to Phospholamban Function
Author(s) -
Keceli Gizem,
Toscano John
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb207
Subject(s) - chemistry , reactivity (psychology) , phospholamban , cysteine , nitroxyl , hydrolysis , thiol , chemical modification , combinatorial chemistry , endoplasmic reticulum , biochemistry , organic chemistry , enzyme , medicine , alternative medicine , pathology
HNO, a potential heart failure therapeutic, is known to post‐translationally modify cysteine residues. Among reactive nitrogen oxide species, the modification of cysteine residues to sulfinamides [RS(O)NH 2 ] is unique to HNO. Because this modification can alter protein structure and function, we have examined the reactivity of sulfinamides in several systems, including small organic molecules, peptides, and a protein. At physiological pH and temperature, relevant reactions of sulfinamides involve reduction to free thiols in the presence of excess thiol and hydrolysis to form sulfinic acids [RS(O)OH]. In addition to utilizing ESI‐MS and other spectroscopic methods to study sulfinamide reduction, we have applied 15 N‐edited 1 H‐NMR techniques to sulfinamide detection and used this method to explore sulfinamide hydrolysis. We have also investigated the effect of local environment on the reactivity of HNO with C‐terminal cysteines. Our findings indicate that the nature of HNO‐derived modifications of C‐terminal cysteines is influenced by the C‐terminal carboxylate. HNO has been shown to enhance cardiac sarcoplasmic reticulum Ca 2+ cycling independent of the β‐adrenergic pathway. In a collaborative project, the effects of HNO on the cardiac protein, phospholamban (PLN) are investigated using 15 N‐edited NMR methods and biochemistry protocols.This research was supported by the National Science Foundation (CHE‐1213438) and Cardioxyl Pharmaceuticals.