Adh5, also known as alcohol dehydrogenase 5 (class III), chi polypeptide, is the key enzyme metabolizing S-nitrosoglutathione (GSNO) to decrease cellular S-nitrosothiols (SNOs) [1]. It is involved in maintaining SNO homeostasis, which is crucial for innate immune responses, as it facilitates STING activation during oxidative burst [1]. It also plays a role in regulating the nitroso-redox status in brown adipose tissue (BAT), thus maintaining metabolic homeostasis [2].

In Adh5-deficient mice, there are defective STING-dependent immune responses upon microbial challenge, facilitating viral replication, indicating its importance in host defense [1]. In BAT, loss of Adh5 impairs cold-induced UCP1-dependent thermogenesis and worsens obesity-associated metabolic dysfunction [2]. In zebrafish, disruption of adh5 in fancd2 -/- zebrafish led to a body size reduction and a lower number of mature spermatozoa compared to wild-type or single knockout zebrafish [3].

In conclusion, Adh5 is essential for maintaining SNO homeostasis in innate immunity and nitroso-redox homeostasis in BAT metabolism. Gene knockout models in mice and zebrafish have revealed its critical roles in host defense against pathogens, adipose thermogenesis, and in the context of certain genetic disorders, providing insights into related disease mechanisms [1,2,3].

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/