Jonathan S. Stamler, MD
President and co-Founder, Harrington Discovery Institute; Distinguished University Professor; Robert S. and Sylvia K. Reitman Family Foundation Chair of Cardiovascular Innovation; Professor of Medicine and of Biochemistry; Founding Director, Institute for Transformative Molecular Medicine Case Western Reserve University; University Hospitals Health System
The Stamler lab has pioneered the field of S-nitrosylation-mediated protein control, a fundamental mechanism of cellular regulation and signaling that operates across phylogeny and cell type. S-nitrosylation subserves physiology essential for mammalian life and has been implicated in diverse diseases, ranging from heart and lung disorders to neurodegenerative diseases and cancer.
The process of S-nitrosylation entails an oxidative modification of cysteine (Cys) residues by nitric oxide (NO) to form S-nitrosothiols (SNOs) that regulate the activity, interactions, stability or subcellular localization of proteins in all functional categories. S-nitrosylation is carried out by a multiplex machinery involving three classes of enzymes: (1) NO synthases that generate NO, (2) SNO synthases that conjugate NO to Cys, and (3) transnitrosylases that transfer the NO group to protein substrates. Additional enzymes, termed denitrosylases, mediate SNO removal from proteins and thereby serve as major determinants of steady-state levels of S-nitrosylation.
Denitrosylases are categorized as low-molecular-weight (including S-nitroso-glutathione and S-nitroso-CoA reductases) or high-molecular weight (e.g. thioredoxin-related proteins), reflecting mechanism-based denitrosylation by small molecules and proteins, respectively. Identification of novel S-nitrosylases and denitrosylases across model systems, animals, and humans is a key focus of the lab, with the aim of delineating SNO-regulated pathways and therapeutic targets.
We are currently developing first-in-class agents that modulate S-nitrosylation in a tissue- and target-specific manner, promising new treatments for human disease.
STAR Protocols, 2023
Detailed lab protocol for preparing the specific thiopropyl-Sepharose resin required for capturing S-nitrosylated proteins from biological samples, for identification using either Western blot or mass spectrometry
Read PaperCell, 2023
We identified a new enzyme that uses S-nitroso-coenzyme A to S-nitrosylate protein partners at specific sites, analogous to a protein kinase. Prominent SCAN substrates include the insulin receptor and IRS1, resulting in insulin resistance in diabetes
Read PaperAntioxidants and Redox Signaling, 2023
Each of the 3 nitric oxide synthase isoforms interacts with and lead to S-nitrosylation of distinct sets of proteins, providing functional evidence for the specificity of S-nitrosylation as a signaling mechanism that is driven by nitrosylase enzymes
Read PaperJournal of Medicinal Chemistry, 2023
Starting with a known inhibitor of AKR1B1 that also inhibits AKR1A1/SCoR2, Imirestat, we identified derivative that selectively inhibits AKR1A1. Mice treated with JSD26 are protected from acute kidney injury, in agreement with the AKR1A1 knockout
Read PaperProceedings of the National Academy of Science USA, 2023
In mice and humans, reactive hyperemic responses are dependent on S-nitroso-Hemoglobin. In healthy subjects and patients with microcirculatory disorders, limb reoxygenation rates following occlusion correlated with arterial SNO-Hb levels
Read PaperCell Reports, 2023
Mice lacking the denitrosylase SCoR2 have low serum cholesterol, resulting from elevated S-nitrosylation of LDL receptor regulator PCSK9. A transnitrosylase cascade involving exocytotic vesicle proteins inhibits SNO-PCSK9 secretion from the liver
Read PaperMolecular Cell, 2022
The β2-adrenergic receptor activates NO production leading to its S-nitrosylation, which promotes desensitization. Mice with point mutant β2AR unable to be S-nitrosylated exhibit prolonged signaling, and are resistant to developing allergic asthma
Read PaperJCI Insight, 2022
Mice bearing human hemoglobin unable to be S-nitrosylated at β-globin Cys93 exhibit defects in hypoxic vasodilation (reactive hyperemia) and develop heart dysfunction due to chronically elevated pulmonary blood pressure when breathing low oxygen
Read PaperSTAR Protocols, 2021
Detailed lab protocol for capturing S-nitrosylated proteins from C. elegans to identify specific proteins with altered S-nitrosylation under differing conditions, using either Western blot or mass spectrometry
Read PaperJournal of Biological Chemistry, 2019
Purification of NADPH-dependent activity to reduce S-nitroso-glutathione (GSNO) identified AKR1A1, which was previously found to be a NADPH-dependent denitrosylase for S-nitroso-coenzyme A (SCoR2). SCoR2 is thus a dual specificity denitrosylase.
Read PaperCell, 2019
The nematode C. elegans lacks nitric oxide synthase enzymes, yet exhibits protein S-nitrosylation. The NO needed is produced instead by their bacterial food within the gut. Feeding C. elegans on bacteria that cannot make NO alters worm function.
Read PaperJournal of Biological Chemistry, 2019
SCoR2 is a denitrosylase that acts on S-nitroso-coenzyme A. We define the kinetics of this reaction, identify the enzyme active site and model its structure to clarify the enzyme mechanism.
Read PaperNature, 2019
Mice lacking the denitrosylase SCOR2 are protected from acute kidney injury, resulting from elevated S-nitrosylation of pyruvate kinase M2 that reprograms post-injury kidney metabolism from glycolysis to the antioxidant pentose phosphate pathway
Read PaperMolecular Cell, 2018
S-nitrosylation of β-arrestins (βArrs) by NO produced by nNOS or iNOS suppresses canonical βArr function during G protein-coupled receptor signaling, providing a general mechanism to bias GPCR signaling toward G proteins
Read PaperMolecular Cell, 2018
E. coli grown anaerobically use nitrate as electron acceptor in respiration, producing NO and protein S-nitrosylation. We identify the first cascade of enzymes converting NO to S-nitrosothiol and then placing SNO on specific sites on target proteins
Read PaperJournal of Clinical Investigation, 2016
Mice bearing human hemoglobin unable to be S-nitrosylated at β-globin Cys93 exhibit worsened heart function in models of myocardial infarction and heart failure, resulting from poor S-nitrosothiol-mediated vasodilation and oxygen delivery
Read PaperProceedings of the National Academy of Science USA, 2015
Mice bearing human hemoglobin unable to be S-nitrosylated at β-globin Cys93 exhibit defects in hypoxic vasodilation responses to breathing low oxygen, and heart dysfunction that worsens as inspired oxygen level decreases
Read Paper