Impdh1-KO Mouse

IMPDH1, inosine monophosphate dehydrogenase 1, is a key regulatory enzyme in the de novo synthesis of the purine base guanine [1]. It is involved in purine nucleotide biosynthesis and GTP metabolic reprogramming, playing an essential role in various biological processes [1,2]. IMPDH1 also dynamically assembles filaments in response to metabolic demand changes [3].

Mutations in IMPDH1 are causative for RP10 autosomal dominant retinitis pigmentosa (adRP), presenting most frequently in the first decade of life with early macular involvement [1]. IMPDH1 is highly upregulated in colorectal cancer (CRC) and promotes CRC growth both in vitro and in vivo. The c-Myc-IMPDH1/2 axis promotes tumorigenesis by regulating GTP metabolic reprogramming, suggesting IMPDH1 inhibition as a cancer treatment option [2]. In clear cell renal cell carcinoma (ccRCC), IMPDH1 forms a positive feedback loop with YB-1, assembles cytoophidia, and is associated with tumor metastasis, making the IMPDH1/YB-1 axis a potential target for metastatic renal cancer treatment [4]. A lower ratio of IMPDH1 to IMPDH2 sensitizes gliomas to chemotherapy, indicating it as a novel prognostic indicator for glioma clinical diagnosis [5].

In conclusion, IMPDH1 is crucial for purine nucleotide and GTP synthesis. Its study in disease models has revealed its significant roles in retinal diseases like adRP, and in cancers such as CRC, ccRCC, and gliomas, offering potential therapeutic targets for these diseases.

References:

1. Sakti, Dhimas H, Cornish, Elisa E, Nash, Benjamin M, Jamieson, Robyn V, Grigg, John R. 2023. IMPDH1-associated autosomal dominant retinitis pigmentosa: natural history of novel variant Lys314Gln and a comprehensive literature search. In Ophthalmic genetics, 44, 437-455. doi:10.1080/13816810.2023.2215310. https://pubmed.ncbi.nlm.nih.gov/37259572/

2. Zhang, Qiang, Cui, Kaisa, Yang, Xiaoya, He, Zhen, Lan, Ping. . c-Myc-IMPDH1/2 axis promotes tumourigenesis by regulating GTP metabolic reprogramming. In Clinical and translational medicine, 13, e1164. doi:10.1002/ctm2.1164. https://pubmed.ncbi.nlm.nih.gov/36629054/

3. Burrell, Anika L, Nie, Chuankai, Said, Meerit, Peterson, Jeffrey R, Kollman, Justin M. 2022. IMPDH1 retinal variants control filament architecture to tune allosteric regulation. In Nature structural & molecular biology, 29, 47-58. doi:10.1038/s41594-021-00706-2. https://pubmed.ncbi.nlm.nih.gov/35013599/

4. Ruan, Hailong, Song, Zhengshuai, Cao, Qi, Zhang, Xiaoping, Chen, Ke. 2020. IMPDH1/YB-1 Positive Feedback Loop Assembles Cytoophidia and Represents a Therapeutic Target in Metastatic Tumors. In Molecular therapy : the journal of the American Society of Gene Therapy, 28, 1299-1313. doi:10.1016/j.ymthe.2020.03.001. https://pubmed.ncbi.nlm.nih.gov/32209435/

5. Ruan, Xiaoyu, Xiong, Yundong, Li, Xiaoman, Yang, Ence, Wang, Jiadong. 2024. Lower ratio of IMPDH1 to IMPDH2 sensitizes gliomas to chemotherapy. In Cancer gene therapy, 31, 1081-1089. doi:10.1038/s41417-024-00793-5. https://pubmed.ncbi.nlm.nih.gov/38871858/