ADH5

Official Full Name

alcohol dehydrogenase 5 (class III), chi polypeptide

Organism

Homo sapiens

GeneID

128

Background

This gene encodes a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. The encoded protein forms a homodimer. It has virtually no activity for ethanol oxidation, but exhibits high activity for oxidation of long-chain primary alcohols and for oxidation of S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione. This enzyme is an important component of cellular metabolism for the elimination of formaldehyde, a potent irritant and sensitizing agent that causes lacrymation, rhinitis, pharyngitis, and contact dermatitis. The human genome contains several non-transcribed pseudogenes related to this gene. [provided by RefSeq, Oct 2008]

Synonyms

FDH; ADHX; ADH-3; AMEDS; BMFS7; FALDH; GSNOR; GSH-FDH; HEL-S-60p;

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Detailed Information

GSNOR, officially named alcohol dehydrogenase 5 (ADH5), is an enzyme belonging to the class III alcohol dehydrogenase family. The encoded protein functions as a homodimer and exhibits distinct substrate preferences compared with major ethanol-metabolizing ADHs such as ADH1, showing negligible ethanol-oxidizing activity, which makes it a minor player in ethanol metabolism. Its unique biological role derives from its high catalytic efficiency toward two endogenous substrates: long-chain primary alcohols and ω-hydroxy fatty acids, and more importantly, S-hydroxymethylglutathione (HMGSH). HMGSH is a conjugate formed spontaneously between the toxic aldehyde formaldehyde and the antioxidant glutathione, making GSNOR a core component of the cellular formaldehyde detoxification system, converting harmful HMGSH into harmless formate to maintain cellular homeostasis.

Additionally, GSNOR functions as a S-nitrosoglutathione reductase, catalyzing the NADH-dependent reduction of S-nitrosoglutathione (GSNO), a key regulator of protein S-nitrosylation, an important post-translational modification involved in diverse cellular signaling processes.

Biological Significance

GSNOR's biological importance spans two interconnected core functions: cellular detoxification and signal transduction regulation. Formaldehyde is a potent genotoxic metabolite produced endogenously during processes such as histone and DNA demethylation. GSNOR, through its HMGSH dehydrogenase activity, drives the glutathione-dependent formaldehyde detoxification pathway, converting toxic formaldehyde into harmless formate. Loss or reduction of this function can result in formaldehyde accumulation, genomic instability, and increased cancer risk.

Figure 1. Endogenous formaldehyde metabolism. Endogenous formaldehyde is mainly detoxified via the ADH5 pathway. (Nakamura J, et al., 2020)

GSNOR's GSNO reductase activity positions it as a key negative regulator of nitric oxide (NO) signaling. NO and its reactive derivatives generate GSNO, which serves as a reservoir for protein S-nitrosylation, a post-translational modification akin to phosphorylation that regulates protein function. By degrading GSNO, GSNOR reduces global S-nitrosylation, modulating NO-driven signaling pathways. This regulation is critical for maintaining redox balance and preventing excessive nitrosative stress. In neurons and cardiovascular cells, GSNOR influences neurotransmitter release, vascular tone, and myocardial contractility through its control of GSNO levels, highlighting its role as a central hub linking metabolic homeostasis and redox signaling.

Clinical Relevance

GSNOR has growing clinical significance across cancer, respiratory, neurodegenerative, and cardiovascular diseases.

Cancer: Its role in formaldehyde detoxification and genomic stability suggests that loss of GSNOR function may contribute to tumorigenesis. Moreover, abnormal protein S-nitrosylation in cancer cells promotes survival and proliferation, making GSNOR activation a potential therapeutic strategy to counteract tumor growth through "denitrosylation".

Respiratory diseases: In asthma and chronic obstructive pulmonary disease, elevated airway S-nitrosylation contributes to hyperreactivity and inflammation. Preclinical studies show that GSNOR-deficient mice exhibit increased airway S-nitrosylation and steroid-insensitive asthma-like phenotypes, prompting development of GSNOR activators to restore S-nitrosylation homeostasis and reduce airway inflammation. Early clinical trials are ongoing.

Neurodegenerative diseases: Pathological protein aggregation in Alzheimer's and Parkinson's diseases often accompanies nitrosative/oxidative stress. Impaired GSNOR activity may exacerbate protein misfolding, suggesting that enhancing neuronal GSNOR activity could be neuroprotective.

Cardiovascular diseases: By regulating NO signaling, GSNOR affects vascular dilation and cardiac function, with dysregulation linked to pulmonary hypertension and heart failure.

References

Staab CA, Hellgren M, Höög JO. Medium- and short-chain dehydrogenase/reductase gene and protein families: dual functions of alcohol dehydrogenase 3: implications with focus on formaldehyde dehydrogenase and S-nitrosoglutathione reductase activities. Cell Mol Life Sci. 2008;65(24):3950–3960.
Liu L, Hausladen A, Zeng M, Que L, Heitman J, Stamler JS. A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans. Nature. 2001;410(6827):490–494.
Que LG, Liu L, Yan Y, et al. Protection from experimental asthma by an endogenous bronchodilator. Science. 2005;308(5728):1618–1621.
Nakamura J, Holley DW, Kawamoto T, et al. The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice. Genes Environ. 2020 Jun 3;42:21.

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