ADH5

ADH5 Full Name

alcohol dehydrogenase 5 (class III), chi polypeptide

ADH5 Introduction

ADH5 (alcohol dehydrogenase 5, also known as ADH3, class III alcohol dehydrogenase, or glutathione-dependent formaldehyde dehydrogenase) is a unique member of the alcohol dehydrogenase family. The gene encoding ADH5 is located on human chromosome 4q23, within the same cluster as other ADH genes. ADH5 produces a protein of approximately 374 amino acids that functions as a homodimer. Unlike other alcohol dehydrogenases that primarily metabolize ethanol, ADH5 has a much broader substrate specificity and plays essential roles in the metabolism of formaldehyde, S-nitrosoglutathione (GSNO), and other endogenous and exogenous alcohols. ADH5 is ubiquitously expressed in virtually all human tissues, with the highest levels found in the liver, kidney, and brain. Its evolutionary conservation across species and its constitutive expression pattern suggest that ADH5 performs critical physiological functions beyond simple alcohol detoxification. Importantly, ADH5 has been implicated in cardiovascular health, neurodegenerative diseases, and cancer biology.

Figure 1. Strcuture of ADH5.

Enzymatic Functions: Formaldehyde Detoxification and Beyond
ADH5 serves as the primary enzyme responsible for formaldehyde detoxification in humans. Formaldehyde is a highly reactive and toxic aldehyde that is generated endogenously during normal metabolism (e.g., from demethylation of histones and DNA, metabolism of methanol, and breakdown of serine and glycine) and is also encountered exogenously in the environment. Accumulation of formaldehyde leads to protein and DNA crosslinking, cellular toxicity, and carcinogenesis. ADH5 catalyzes the glutathione-dependent oxidation of formaldehyde to S-formylglutathione, which is then converted to formate and glutathione by S-formylglutathione hydrolase (esterase D). This detoxification pathway is essential for maintaining cellular homeostasis. Additionally, ADH5 metabolizes other medium-chain alcohols, omega-hydroxy fatty acids, and various aliphatic and aromatic alcohols. The enzyme also exhibits significant activity toward long-chain primary alcohols and is involved in the metabolism of leukotrienes and other bioactive lipids, suggesting broader roles in lipid signaling and inflammation.

Role in Nitric Oxide Signaling and Cardiovascular Health
One of the most important physiological functions of ADH5 is its role in the metabolism of S-nitrosoglutathione (GSNO), a key reservoir and transporter of nitric oxide (NO) in the body. ADH5 catalyzes the reduction of GSNO to glutathione, releasing free NO in the process. This activity regulates local NO bioavailability, which is critical for vasodilation, blood pressure control, platelet aggregation, and immune function. Mice lacking ADH5 (Adh5 knockout mice) exhibit elevated levels of GSNO and reduced NO signaling, leading to impaired vasodilation, hypertension, and increased susceptibility to thrombosis. In humans, genetic variants in ADH5 have been associated with altered blood pressure and cardiovascular disease risk. The enzyme's dual functions in formaldehyde detoxification and GSNO reduction connect ADH5 to both metabolic and vascular health, making it an important target for understanding cardiovascular pathophysiology.

Alternate Names for ADH5

ADH5; alcohol dehydrogenase 5 (class III), chi polypeptide; FDH, formaldehyde dehydrogenase; alcohol dehydrogenase class-3; ADH 3; ADHX; formaldehyde dehydrogenase; alcohol dehydrogenase class-III; alcohol dehydrogenase class chi chain; S-(hydroxymethyl)glutathione dehydrogenase