Alcohol dehydrogenase 5 (class III) (ADH5)

Alcohol dehydrogenase 5 (ADH5), also known as S-nitrosoglutathione reductase (GSNOR) or glutathione-dependent formaldehyde dehydrogenase, is a member of the alcohol dehydrogenase family that plays a dual role in cellular homeostasis [1, 3, 5]. It is the primary enzyme responsible for the detoxification of endogenous and exogenous formaldehyde by converting it to formate in a glutathione-dependent manner [1, 6, 17]. Additionally, ADH5 is a master regulator of nitric oxide (NO) signaling; it reduces S-nitrosoglutathione (GSNO), the major cellular reservoir of NO, thereby controlling the levels of protein S-nitrosylation [2, 3, 5]. Dysregulation of this enzyme is implicated in various pathologies, including respiratory diseases like asthma and COPD, where GSNOR overactivity leads to depleted NO levels and airway constriction [2, 5, 9]. Therapeutic targeting of ADH5 with GSNOR inhibitors, such as cavosonstat, aims to restore NO bioavailability and mitigate inflammatory responses [8, 11]. However, loss-of-function mutations in ADH5, particularly when combined with ALDH2 deficiency, result in severe developmental and hematopoietic disorders like AMeD syndrome due to the accumulation of DNA-damaging formaldehyde [6, 20].

Other names

S-nitrosoglutathione reductaseGSNORGlutathione-dependent formaldehyde dehydrogenaseFDHADHXADH-3Alcohol dehydrogenase class-3Alcohol dehydrogenase class III chi chain

GSNOR inhibition increases S-nitrosoglutathione (GSNO) levels, thereby enhancing nitric oxide bioavailability and modulating protein S-nitrosylation to promote bronchodilation and reduce inflammation.