Tyw1-KO Mouse

Tyw1 is a radical S-adenosyl-l-methionine (SAM) enzyme. It catalyzes the condensation of pyruvate and N-methylguanosine-containing tRNAPhe, forming 4-demethylwyosine-containing tRNAPhe, which is involved in tRNA modification [1,2,5,7]. Homologues of Tyw1 are present in both archaea and eukarya, with eukaryal homologues containing a flavin binding domain in addition to the radical SAM domain [1].

Loss-of-function studies of Tyw1 have shown significant impacts. In humans, loss of function of Tyw1 led to cerebral palsy with severe intellectual disability through reduced neural proliferation [3,4]. Tyw1 loss also blocked the formation of OHyW in tRNAphe, affected the translation efficiency of UUU codon, impaired neuron differentiation, and up-regulated human-specific endogenous retrovirus-K (HERVK/HML2) in human embryonic stem cells (hESCs) [3]. In yeast, deletion of Tyw1 increased iron sensitivity in a Δccc1 strain, while overexpression of Tyw1 resulted in decreased cell growth and induction of the iron regulon [6].

In conclusion, Tyw1 is essential for tRNA modification, which is crucial for normal neural development and function in humans. Its loss-of-function is associated with severe neurological disorders like cerebral palsy and intellectual disability. In yeast, it also plays a role in iron-related processes. Studies of Tyw1, especially through loss-of-function models, provide insights into biological processes and disease mechanisms, potentially guiding future therapeutic strategies for related diseases.

References:

1. Young, Anthony P, Bandarian, Vahe. 2021. Eukaryotic TYW1 Is a Radical SAM Flavoenzyme. In Biochemistry, 60, 2179-2185. doi:10.1021/acs.biochem.1c00349. https://pubmed.ncbi.nlm.nih.gov/34184886/

2. Young, Anthony P, Bandarian, Vahe. 2018. TYW1: A Radical SAM Enzyme Involved in the Biosynthesis of Wybutosine Bases. In Methods in enzymology, 606, 119-153. doi:10.1016/bs.mie.2018.04.024. https://pubmed.ncbi.nlm.nih.gov/30097090/

3. Sun, Chuanbo, Guo, Ruirui, Ye, Xiangyan, Xu, Kaishou, Hu, Hao. 2024. Wybutosine hypomodification of tRNAphe activates HERVK and impairs neuronal differentiation. In iScience, 27, 109748. doi:10.1016/j.isci.2024.109748. https://pubmed.ncbi.nlm.nih.gov/38706838/

4. Li, Na, Zhou, Pei, Tang, Hongmei, Xu, Kaishou, Hu, Hao. . In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy. In Brain : a journal of neurology, 145, 119-141. doi:10.1093/brain/awab209. https://pubmed.ncbi.nlm.nih.gov/34077496/

5. Young, Anthony P, Bandarian, Vahe. 2022. Insertion of 4-Demethylwyosine in tRNAPhe Catalyzed by the Radical S-Adenosyl-l-methionine Enzyme TYW1 Entails Oxidative Cleavage of Pyruvate to Form CO2. In Biochemistry, 61, 2643-2647. doi:10.1021/acs.biochem.2c00519. https://pubmed.ncbi.nlm.nih.gov/36326713/

6. Li, Liangtao, Jia, Xuan, Ward, Diane M, Kaplan, Jerry. 2011. Yap5 protein-regulated transcription of the TYW1 gene protects yeast from high iron toxicity. In The Journal of biological chemistry, 286, 38488-38497. doi:10.1074/jbc.M111.286666. https://pubmed.ncbi.nlm.nih.gov/21917924/

7. Grell, Tsehai A J, Young, Anthony P, Drennan, Catherine L, Bandarian, Vahe. 2018. Biochemical and Structural Characterization of a Schiff Base in the Radical-Mediated Biosynthesis of 4-Demethylwyosine by TYW1. In Journal of the American Chemical Society, 140, 6842-6852. doi:10.1021/jacs.8b01493. https://pubmed.ncbi.nlm.nih.gov/29792696/