PYCR2, pyrroline-5-carboxylate reductase 2, is a key enzyme in proline synthesis, specifically catalyzing the last step of converting pyrroline-5-carboxylate (P5C) to proline [5,6]. It is involved in multiple biological pathways such as amino acid metabolism and oxidative stress response [1]. Genetic models, like mouse models, are valuable for studying its functions [5].

In mice, knocking out Pycr2 phenocopies the human disorder of postnatal degenerative microcephaly with hypomyelination, depletes PYCR1 levels in neural lineages, and increases cerebral glycine levels due to upregulation of SHMT2 [4]. Pycr2 knockdown in mouse colorectal cancer cells inhibits epithelial-mesenchymal transition (EMT), as well as the progression of subcutaneous and intraperitoneal metastatic tumors in a proline-independent manner [3]. In human liver cancer, silencing PYCR2 in cell lines and mouse xenograft models inhibits cell viability, glycolysis, AKT activation, and tumor growth, while overexpression promotes these processes [1]. In glioblastoma multiforme (GBM) cells, ALKBH5 and PYCR2 form a positive feedback loop involved in proline synthesis, promoting cell proliferation, migration, invasion, and proneural-mesenchymal transition (PMT) [2].

In conclusion, PYCR2 is crucial in proline synthesis and impacts various biological processes. Model-based research, especially Pycr2 knockout mouse models, has revealed its roles in neurodegenerative diseases, cancer progression including liver, colorectal, and glioma cancers. Understanding PYCR2 functions provides potential therapeutic targets for these disease areas [2-5].

References:

1. Wang, Shaoyan, Yi, Wenyan, Xu, Zhenyu, Shi, Minyu. 2023. PYCR2 promotes growth and aerobic glycolysis in human liver cancer by regulating the AKT signaling pathway. In Biochemical and biophysical research communications, 680, 15-24. doi:10.1016/j.bbrc.2023.09.007. https://pubmed.ncbi.nlm.nih.gov/37708598/

2. Li, Li, Yang, Mengting, Pu, Xufeng, Ren, Caifang, Gong, Aihua. 2023. ALKBH5-PYCR2 Positive Feedback Loop Promotes Proneural-Mesenchymal Transition Via Proline Synthesis In GBM. In Journal of Cancer, 14, 1579-1591. doi:10.7150/jca.84213. https://pubmed.ncbi.nlm.nih.gov/37325047/

3. Zhang, Qi, Luo, Hai, Xun, Jing, Yu, Xiangyang, Wang, Botao. 2022. Targeting PYCR2 inhibits intraperitoneal metastatic tumors of mouse colorectal cancer in a proline-independent approach. In Cancer science, 114, 908-920. doi:10.1111/cas.15635. https://pubmed.ncbi.nlm.nih.gov/36308281/

4. Escande-Beillard, Nathalie, Loh, Abigail, Saleem, Sahar N, Shiratori, Hidetaka, Reversade, Bruno. 2020. Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2. In Neuron, 107, 82-94.e6. doi:10.1016/j.neuron.2020.03.028. https://pubmed.ncbi.nlm.nih.gov/32330411/

5. Stum, Morgane G, Tadenev, Abigail L D, Seburn, Kevin L, John, Simon W M, Burgess, Robert W. . Genetic analysis of Pycr1 and Pycr2 in mice. In Genetics, 218, . doi:10.1093/genetics/iyab048. https://pubmed.ncbi.nlm.nih.gov/33734376/

6. Meng, Linyan, Donti, Taraka, Xia, Fan, Yang, Yaping, Elsea, Sarah H. 2016. Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy. In American journal of medical genetics. Part A, 173, 460-470. doi:10.1002/ajmg.a.38049. https://pubmed.ncbi.nlm.nih.gov/27860360/