Acmsd-KO Mouse

Acmsd, or α -amino-β -carboxymuconate-ε -semialdehyde decarboxylase, is a key enzyme in the kynurenine pathway which is responsible for the catalytic breakdown of tryptophan into NAD+ [2]. It limits the spontaneous cyclization of α -amino-β -carboxymuconate-ε -semialdehyde in the de novo NAD+ synthesis pathway, thus controlling cellular NAD+ levels [4]. Its activity is also regulated by its quaternary structure, forming homodimers, tetramers, and higher-order structures [5].

In mouse models of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH), inhibiting Acmsd with a novel specific pharmacological inhibitor promotes de novo NAD+ synthesis, reduces DNA damage, and reverses MASLD/MASH, mitigating fibrosis, inflammation, and DNA damage [1]. In diabetic cardiomyopathy, increased expression of Acmsd in myocardial endothelial cells of diabetic mice leads to impaired de novo NAD+ synthesis. Inhibition of Acmsd could increase de novo NAD+ synthesis, improve endothelial cell function, and potentially improve diabetic cardiomyopathy [3].

In conclusion, Acmsd is a crucial modulator of de novo NAD+ synthesis. Genetic and pharmacological inhibition of Acmsd in mouse models has revealed its potential role in treating diseases such as MASLD/MASH and diabetic cardiomyopathy by enhancing NAD+ levels, maintaining genomic stability, and improving cellular function [1,3].

References:

1. Liu, Yasmine J, Kimura, Masaki, Li, Xiaoxu, Takebe, Takanori, Auwerx, Johan. 2024. ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH. In Journal of hepatology, 82, 174-188. doi:10.1016/j.jhep.2024.08.009. https://pubmed.ncbi.nlm.nih.gov/39181211/

2. Thirtamara-Rajamani, Keerthi, Li, Peipei, Escobar Galvis, Martha L, Brundin, Patrik, Brundin, Lena. . Is the Enzyme ACMSD a Novel Therapeutic Target in Parkinson's Disease? In Journal of Parkinson's disease, 7, 577-587. doi:10.3233/JPD-171240. https://pubmed.ncbi.nlm.nih.gov/29103054/

3. Zeng, Fangfang, Zhou, Peng, Wang, Meng, Gong, Wei, Wang, Yi. 2023. ACMSD mediated de novo NAD+ biosynthetic impairment in cardiac endothelial cells as a potential therapeutic target for diabetic cardiomyopathy. In Diabetes research and clinical practice, 206, 111014. doi:10.1016/j.diabres.2023.111014. https://pubmed.ncbi.nlm.nih.gov/37977551/

4. Katsyuba, Elena, Mottis, Adrienne, Zietak, Marika, Pellicciari, Roberto, Auwerx, Johan. 2018. De novo NAD+ synthesis enhances mitochondrial function and improves health. In Nature, 563, 354-359. doi:10.1038/s41586-018-0645-6. https://pubmed.ncbi.nlm.nih.gov/30356218/

5. Yang, Yu, Davis, Ian, Matsui, Tsutomu, Rubalcava, Ivan, Liu, Aimin. 2019. Quaternary structure of α-amino-β-carboxymuconate-ϵ-semialdehyde decarboxylase (ACMSD) controls its activity. In The Journal of biological chemistry, 294, 11609-11621. doi:10.1074/jbc.RA119.009035. https://pubmed.ncbi.nlm.nih.gov/31189654/