Prps2, or phosphoribosyl pyrophosphate synthetase 2, is a rate-limiting enzyme in purine and pyrimidine nucleotide synthesis [5]. It transfers pyrophosphate groups from ATP to ribose-5-phosphate to produce 5-phosphate ribose-1-pyrophosphate (PRPP), a key intermediate in the biosynthesis of several metabolites like nucleotides, dinucleotides, and some amino acids [2]. Among the three PRPS isoforms encoded in the human genome, Prps2, along with Prps1, is expressed in most tissues [2].

In childhood acute lymphoblastic leukemia (ALL), Prps2 mutations were identified only in relapsed cases with thiopurine therapy. These mutations influenced Prps1/2 hexamer stability, mediated purine metabolism, reduced nucleotide feedback inhibition of Prps activity, and enhanced thiopurine resistance [1]. In non-small cell lung cancer (NSCLC), elevated Prps2 was correlated with cisplatin (DDP) resistance and poor prognosis. Prps2 silencing enhanced DDP-resistant cells' sensitivity to DDP treatment, and exosomal Prps2 mediated M2 macrophage polarization to promote DDP resistance [3]. In osteosarcoma (OS), higher Prps2 protein level was related to tumour proliferation and higher tumour recurrence, indicating it as an independent prognostic marker and potential therapeutic target [4]. In male infertility-related conditions, Prps2 depletion in mouse models led to increased apoptosis of spermatogenic cells and was associated with hypospermatogenesis [5], while in Sertoli-cell only syndrome, Prps2 expression was increased and over-expression inhibited apoptosis of TM4 Sertoli cells [6]. In lung cancer, Prps2 knockdown hindered cell migratory, invasive, and proliferative abilities, accelerated apoptosis, and blocked the growth of transplanted tumours [7].

In conclusion, Prps2 plays a crucial role in nucleotide synthesis and is involved in multiple disease processes. Its functions in diseases such as ALL, NSCLC, OS, and male infertility-related conditions have been revealed through various in vivo and in vitro studies. These findings highlight Prps2 as a potential biomarker and therapeutic target in these diseases.

References:

1. Song, Lili, Li, Peifeng, Sun, Huiying, Feng, Haizhong, Li, Yanxin. 2022. PRPS2 mutations drive acute lymphoblastic leukemia relapse through influencing PRPS1/2 hexamer stability. In Blood science (Baltimore, Md.), 5, 39-50. doi:10.1097/BS9.0000000000000139. https://pubmed.ncbi.nlm.nih.gov/36742181/

2. Lu, Guang-Ming, Hu, Huan-Huan, Chang, Chia-Chun, Yin, Boqi, Liu, Ji-Long. 2023. Structural basis of human PRPS2 filaments. In Cell & bioscience, 13, 100. doi:10.1186/s13578-023-01037-z. https://pubmed.ncbi.nlm.nih.gov/37248548/

3. Liu, Gaohua, Luo, Yang, Hou, Peifeng. 2021. PRPS2 Enhances Resistance to Cisplatin via Facilitating Exosomes-mediated Macrophage M2 Polarization in Non-small Cell Lung Cancer. In Immunological investigations, 51, 1423-1436. doi:10.1080/08820139.2021.1952217. https://pubmed.ncbi.nlm.nih.gov/34251965/

4. Luo, Yanli, Yuan, Junqing, Huang, Jin, Huang, Wentao, Zhang, Huizhen. 2021. Role of PRPS2 as a prognostic and therapeutic target in osteosarcoma. In Journal of clinical pathology, 74, 321-326. doi:10.1136/jclinpath-2020-206505. https://pubmed.ncbi.nlm.nih.gov/33589531/

5. Lei, Bin, Xie, Li-Xia, Zhang, Shou-Bo, Mao, Xiang-Ming, Shu, Fang-Peng. . Phosphoribosyl-pyrophosphate synthetase 2 (PRPS2) depletion regulates spermatogenic cell apoptosis and is correlated with hypospermatogenesis. In Asian journal of andrology, 22, 493-499. doi:10.4103/aja.aja_122_19. https://pubmed.ncbi.nlm.nih.gov/31736475/

6. Lei, Bin, Wan, Bo, Peng, Jian, Wu, Huayan, Mao, Xiangming. 2015. PRPS2 Expression Correlates with Sertoli-Cell Only Syndrome and Inhibits the Apoptosis of TM4 Sertoli Cells. In The Journal of urology, 194, 1491-7. doi:10.1016/j.juro.2015.04.116. https://pubmed.ncbi.nlm.nih.gov/26004865/

7. Meng, Ying, Zhang, Hua, Xu, Mingling, Chen, Zhenzhen, Wei, Lei. 2024. Regulatory mechanism and expression level of PRPS2 in lung cancer. In Thoracic cancer, 15, 1410-1418. doi:10.1111/1759-7714.15302. https://pubmed.ncbi.nlm.nih.gov/38736292/