Alcohol dehydrogenase 5 (ADH5) (ADH5)

Alcohol dehydrogenase 5 (ADH5), also known as S-nitrosoglutathione reductase (GSNOR), is a cytosolic enzyme that plays a pivotal role in regulating nitric oxide signaling by controlling the levels of S-nitrosoglutathione (GSNO) [UniProt P11766]. Unlike other members of the alcohol dehydrogenase family, ADH5 has a high specificity for GSNO and is the primary enzyme responsible for its catabolism, thereby acting as a master regulator of protein S-nitrosylation [NCBI Gene ID 128]. This post-translational modification is essential for various physiological processes, including airway smooth muscle relaxation and immune response modulation [PubMed 22403438]. In diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, ADH5 activity is often dysregulated, contributing to pathology through the depletion of protective GSNO levels [PubMed 25643943]. Pharmacological inhibitors like N6022 and Cavosonstat have been developed to increase GSNO concentrations, which can lead to bronchodilation and improved folding of the cystic fibrosis transmembrane conductance regulator (CFTR) protein [ClinicalTrials.gov NCT01315275]. However, because ADH5 is also required for the detoxification of formaldehyde, its inhibition may result in the accumulation of this toxic metabolite, presenting a significant therapeutic challenge [PubMed 21835145].

Other names

S-nitrosoglutathione reductaseGSNORAlcohol dehydrogenase class IIIAlcohol dehydrogenase class-3Chi polypeptideGlutathione-dependent formaldehyde dehydrogenaseFDHADH-3S-nitrosoglutathione reductase / alcohol dehydrogenase 5, chi polypeptide

Inhibition of S-nitrosoglutathione reductase (GSNOR) to increase levels of S-nitrosoglutathione (GSNO), thereby enhancing protein S-nitrosylation and improving the function of proteins such as CFTR and beta-2 adrenergic receptors.