Adh5, also known as alcohol dehydrogenase 5 (class III), chi polypeptide and S-nitrosoglutathione reductase (GSNOR), is a key enzyme that metabolizes S-nitrosoglutathione (GSNO) to regulate cellular S-nitrosothiol (SNO) levels. It is involved in multiple biological pathways, including innate immune responses, metabolic homeostasis, and nitroso-redox regulation. Its functions are crucial for maintaining normal physiological states in the body, and genetic models such as gene knockout mice can help in understanding its roles in detail [1,2].

In innate immunity, Adh5 deficiency leads to defective STING-dependent immune responses upon microbial challenge and facilitates viral replication, as Adh5 normally facilitates STING activation by inhibiting its S-nitrosylation [1]. In brown adipose tissue, loss of Adh5 impairs cold-induced UCP1-dependent thermogenesis and worsens obesity-associated metabolic dysfunction, indicating its importance in metabolic homeostasis [2]. In a zebrafish model of Fanconi anemia, disruption of Adh5 in fancd2 -/- zebrafish led to a reduction in body size and a lower number of mature spermatozoa, while overexpression of human ADH5 partially recovered spermatogenesis progress, suggesting its potential role in treating Fanconi anemia [3].

In conclusion, Adh5 plays essential roles in innate immune responses, metabolic regulation, and may be involved in the pathophysiology of diseases like Fanconi anemia. Gene knockout models, such as Adh5-deficient mice and zebrafish, have significantly contributed to understanding its functions in these specific biological processes and disease conditions, providing insights into potential therapeutic targets for related diseases.

References:

1. Jia, Mutian, Chai, Li, Wang, Jie, Jia, Jihui, Zhao, Wei. 2024. S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens. In Nature communications, 15, 1750. doi:10.1038/s41467-024-46212-z. https://pubmed.ncbi.nlm.nih.gov/38409248/

2. Sebag, Sara C, Zhang, Zeyuan, Qian, Qingwen, Bartelt, Alexander, Yang, Ling. . ADH5-mediated NO bioactivity maintains metabolic homeostasis in brown adipose tissue. In Cell reports, 37, 110003. doi:10.1016/j.celrep.2021.110003. https://pubmed.ncbi.nlm.nih.gov/34788615/

3. Mu, Anfeng, Cao, Zimu, Huang, Denggao, Maegawa, Shingo, Takata, Minoru. 2023. Effects of the major formaldehyde catalyzer ADH5 on phenotypes of fanconi anemia zebrafish model. In Molecular biology reports, 50, 8385-8395. doi:10.1007/s11033-023-08696-8. https://pubmed.ncbi.nlm.nih.gov/37615925/