S-methyl-5'-thioadenosine phosphorylase is an enzyme that in humans is encoded by the MTAP gene.
This gene encodes an enzyme that plays a major role in polyamine metabolism and is important for the salvage of both adenine and methionine. The encoded enzyme is deficient in many cancers because this gene and the tumor suppressor p16 gene are co-deleted. Multiple alternatively spliced transcript variants have been described for this gene, but their full-length natures remain unknown.

MTDIA hydrochloride


An overview of MTAP

S-methyl-5'-thioadenosine phosphorylase (MTAP) is an important metabolic enzyme in the adenine and methionine salvage pathways. MTAP encodes on human chromosome 9p21 and is adjacent to the p16INK4a and p14ARF tumor suppressor genes. MTAP is often co-deleted with p16INK4a in many cancers. S-methyl-5'-thioadenosine (MTA) is a product of polyamine synthesis cleaved by MTAP to produce adenine and methylthioribose-1-phosphate which is further recycled to methionine. MTAP is highly conserved across all Kingdoms, with nearly all organisms expressing either MTAP or 5’-Me-thylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN), both of which perform the conversion of MTA to adenine and methionine. But accumulation of MTA is toxic to cells due to feedback inhibition of spermidine synthase. Therefore, MTAP plays a key function in eliminating this toxic by-product of polyamine synthesis.

MTAP and diseases

Since MTAP is located on chromosome 9 and directly adjacent to the tumor suppressor, CDKN2a, it is frequently co-deleted in many human tumors, including glioma, non-small-cell lung cancer, acute nonlymphoid leukemia, melanoma, and mesothelioma. Because MTAP activity is present in all normal cells (including red blood cells and bone marrow stem/progenitor cells) in a relatively narrow range, the lack of MTAP in tumor cells provides a unique opportunity to develop selective treatment of tumors. Tumor cells without MTAP activity are unable to salvage adenine from MTA and therefore, are more dependent on the de novo synthesis of AMP. As a consequence, MTAP deficient tumor cells are more sensitive than normal cells to agents that block de novo AMP synthesis. Furthermore, normal cells abundant in MTAP can be rescued from the toxicity of inhibitors of de novo AMP synthesis by the provision of exogenous MTAP substrates that provide a source of adenine.

Inhibition of MTAP

Targeting MTAP deficient tumors with purine synthesis inhibitors in combination with MTAP substrates, such as MTA or 9-β-D-erythrofuranosyladenine (EFA), provide greater efficacy and a greater therapeutic window over chemotherapeutic regimens currently in clinical use. Besides, L-alanosine is apotent inhibitor of de novo AMP synthesis. The metabolite of L-alanosine, L-alanosinyl-5-amino-4-imidazole carboxylic acid ribonucleotide (L-alanosinyl-AICOR), is a strong inhibitor of adenylosuccinate synthase, which converts IMP to AMP. Thus, L-alanosine is an ideal candidate for MTAP-targeted therapy.


Juliana, R. T., José, B.-N., Ricardo, D., Humberto, D. P., (2016) Crystal Structure of Schistosoma mansoni Adenosine Phosphorylase/5’-Methylthioadenosine Phosphorylase and Its Importance on Adenosine Salvage Pathway. Plos Neglected Tropical Diseases, 10(12): 25