Methylthioadenosine phosphorylase deficiency in tumors: A compelling therapeutic target

Abstract

The methionine salvage pathway is responsible for recycling sulfur-containing metabolites to methionine. This salvage pathway has been found to be implicated in cell apoptosis, proliferation, differentiation and inflammatory response. Methylthioadenosine phosphorylase (MTAP) catalyzes the reversible phosphorolysis of 5′-methylthioadenosine, a by-product produced from polyamine biosynthesis. The MTAP gene is located adjacent to the cyclin-dependent kinase inhibitor 2A gene and co-deletes with CDKN2A in nearly 15% of tumors. Moreover, MTAP-deleted tumor cells exhibit greater sensitivity to methionine depletion and to the inhibitors of purine synthesis. In this review, we first summarized the molecular structure and expression of MTAP in tumors. Furthermore, we discussed PRMT5 and MAT2A as a potential vulnerability for MTAP-deleted tumors. The complex and dynamic role of MTAP in diverse malignancies has also been discussed. Finally, we demonstrated the implications for the treatment of MTAP-deleted tumors.

5’-S-(3-aminophenyl)-5’-thioadenosine, a novel chemoprotective agent for reducing toxic side effects of fluorouracil in treatment of MTAP-deficient cancers

“…)phenyl]-5'-thioadenosine (6). Under an argon atmosphere, 4mercaptobenzyl alcohol (0.314 mmol) was dissolved in DMF (5 mL).…”

“…The grey solid was filtered out of the aqueous layer, washed with water, and dried in vacuo to afford the desired product as a clear, colorless oil in 44% yield. (6). Under an argon atmosphere, 4mercaptobenzyl alcohol (0.314 mmol) was dissolved in DMF (5 mL).…”

“…Deletion of the MTAP gene, as well as dysregulation of gene expression [5], leads to MTAP deficiency in human cancers. Although MTAP deficiency contributes to the tumor microenvironment that favors tumor progression, leading to poor disease outcome in multiple types of cancers [6][7][8][9], this functional loss of MTAP offers a unique opportunity for developing selective therapeutics. Various strategies have been pursued to exploit this unique opportunity, such as methionine deprivation therapy and de novo adenine synthesis inhibition.…”