Agmat-KO Mouse

AGMAT, also known as agmatinase, is an enzyme involved in the polyamine synthesis pathway. In this pathway, arginine can be converted to agmatine by arginine decarboxylase (ADC), and then AGMAT hydrolyzes agmatine to form putrescine, which is further converted to spermidine and spermine [3]. Polyamines are essential for processes like cell division, gene expression, DNA and protein synthesis, and apoptosis regulation, highlighting the importance of AGMAT in maintaining normal cellular functions [3].

In a study on sheep during the peri-implantation period of pregnancy, morpholino antisense oligonucleotides were used to inhibit the translation of ODC1 and AGMAT mRNAs. The results showed that in vivo knockdown of translation of both genes increased the expression of genes related to polyamine synthesis and transport in ovine conceptuses. Also, the pregnancy rate was significantly lower in ewes with inhibited ODC1 and AGMAT translation compared to control ewes [5].

In rats, overexpression of AGMAT in the ventral hippocampus of a chronic restraint stress (CRS) animal model of depression elicited depressive-and anxiety-like behaviors, while knockdown of AGMAT had antidepressant and anxiolytic effects. Blockage of AGMAT increased excitatory synaptic transmission in the hippocampal CA1 region [8].

In colorectal carcinoma cells, miR-151a-5p was found to promote cell proliferation, migration, and invasion by targeting AGMAT, suggesting that the miR-151a-5p/AGMAT axis may play a crucial role in CRC regulation [2].

In esophageal adenocarcinoma, AGMAT was overexpressed at the protein level compared to adjacent normal tissues, with a proposed EAC-selective, post-transcriptional mechanism of regulation of protein abundance [4].

In pancreatic adenocarcinoma, AGMAT was overexpressed and positively associated with a poor prognosis. Overexpression of AGMAT led to increased cell proliferation and metastasis through activation of the TGFβ/Smad pathway [7].

In a multi-omics study related to blood pressure, integration analysis illuminated that 4-guanidinobutanoate, a metabolite related to AGMAT, was a downstream effector of a kidney blood pressure-related gene AGMAT [1].

In a study on colorectal cancer metabolic subtypes, AGMAT combined with oxaliplatin showed the best efficacy in vivo, potentially associated with the inhibition of SFRP2 + cancer-associated fibroblast infiltration [6].

In conclusion, AGMAT plays a vital role in multiple biological processes, especially those related to polyamine synthesis, which impacts cell functions. Through in vivo studies in models like sheep, rats, and in the context of various human diseases such as different types of cancers and potentially blood pressure-related conditions, AGMAT has been shown to have significant implications. These findings not only help understand the normal physiological functions of AGMAT but also its potential as a therapeutic target in disease treatment.

References:

1. Xu, Xiaoguang, Khunsriraksakul, Chachrit, Eales, James M, Charchar, Fadi J, Tomaszewski, Maciej. 2024. Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets. In Nature communications, 15, 2359. doi:10.1038/s41467-024-46132-y. https://pubmed.ncbi.nlm.nih.gov/38504097/

2. Xie, Yaya, Zhang, Yue, Liu, Xianju, Chen, Jinlian, Zhang, Xingxing. 2023. miR‑151a‑5p promotes the proliferation and metastasis of colorectal carcinoma cells by targeting AGMAT. In Oncology reports, 49, . doi:10.3892/or.2023.8487. https://pubmed.ncbi.nlm.nih.gov/36704851/

3. Lenis, Yasser Y, Elmetwally, Mohammed A, Maldonado-Estrada, Juan G, Bazer, Fuller W. 2017. Physiological importance of polyamines. In Zygote (Cambridge, England), 25, 244-255. doi:10.1017/S0967199417000120. https://pubmed.ncbi.nlm.nih.gov/28587687/

4. O'Neill, J Robert, Yébenes Mayordomo, Marcos, Mitulović, Goran, Hupp, Ted, Alfaro, Javier Antonio. 2024. Multi-Omic Analysis of Esophageal Adenocarcinoma Uncovers Candidate Therapeutic Targets and Cancer-Selective Posttranscriptional Regulation. In Molecular & cellular proteomics : MCP, 23, 100764. doi:10.1016/j.mcpro.2024.100764. https://pubmed.ncbi.nlm.nih.gov/38604503/

5. Lenis, Yasser Y, Elmetwally, Mohammed A, Tang, Wanjin, Wu, Guoyao, Bazer, Fuller W. 2017. Functional roles of agmatinase during the peri-implantation period of pregnancy in sheep. In Amino acids, 50, 293-308. doi:10.1007/s00726-017-2515-1. https://pubmed.ncbi.nlm.nih.gov/29196820/

6. Wang, Youpeng, Qiu, Xingfeng, Li, Qinghai, Di, Yuqin, Zhou, Qi. 2025. Single-cell and spatial-resolved profiling reveals cancer-associated fibroblast heterogeneity in colorectal cancer metabolic subtypes. In Journal of translational medicine, 23, 175. doi:10.1186/s12967-025-06103-3. https://pubmed.ncbi.nlm.nih.gov/39934919/

7. Zhang, Yue, Cao, Lijun, Xie, Yaya, Zhang, Xingxing, Chen, Jinlian. 2022. Agmatinase facilitates the tumorigenesis of pancreatic adenocarcinoma through the TGFβ/Smad pathway. In Experimental and therapeutic medicine, 24, 490. doi:10.3892/etm.2022.11417. https://pubmed.ncbi.nlm.nih.gov/35837051/

8. Yan, Shi, Xu, Chang, Yang, Mengli, Tong, Zhiqian, Cai, Xiang. 2023. The expression of agmatinase manipulates the affective state of rats subjected to chronic restraint stress. In Neuropharmacology, 229, 109476. doi:10.1016/j.neuropharm.2023.109476. https://pubmed.ncbi.nlm.nih.gov/36849038/