MTAP

Classification

This enzyme belongs to the family of glycosyltransferases, specifically the pentosyltransferases. The systematic name of this enzyme class is S-methyl-5-thioadenosine:phosphate S-methyl-5-thio-alpha-D-ribosyl-transferase. Other names in common use include 5'-methylthioadenosine nucleosidase, 5'-deoxy-5'-methylthioadenosine phosphorylase, MTA phosphorylase, MeSAdo phosphorylase, MeSAdo/Ado phosphorylase, methylthioadenosine phosphorylase, methylthioadenosine nucleoside phosphorylase, 5'-methylthioadenosine:phosphate methylthio-D-ribosyl-transferase, and S-methyl-5-thioadenosine phosphorylase. This enzyme participates in methionine metabolism.

Gene

The MTAP gene location is 9p21.3 which is chromosome 9, p arm, band 2, sub-band1, and sub-sub-band 3. The MTAP gene has seven isomers which are created when mRNA's of the same locus have different transcription start sites. Due to the nature of the MTAP gene and the surrounding genes of chromosome 9, deletion of the genes around p21, and gene p21 are common. Particularly the deletion of the gene p16 in conjunction with the whole or partial deletion of MTAP has been indicated in some cancer types. Genes p15 and p16 of chromosome nine are closely linked to the MTAP gene, because of this, MTAP is commonly cross-deleted. This deletion is found in many cancerous tissues.

Structure

MTAP is a trimer enzyme that shares a similar structure and functions with mammalian purine nucleoside phosphorylases (PNPs) which are also trimeric enzymes. MTAP's subunits are identical in structure and composed of 283 amino acid residues that form to the size of about 32 kDa each. The main structure of an MTAP subunit consists of eleven beta-sheets with six alpha-helices intermixed. The active site of the enzyme is made up of beta-sheets five and 11, as well as alpha-helix 5, and four separate residue loop structures. Within MTAP, helix six is a 12-residue C-terminal helix that arranges for the leucine residue 279 of one subunit to be a part of the active site of another subunit. The active site of each subunit includes two residues (His137 and Leu279) from a neighboring subunit, relying on the interactions between the subunits for proper enzymatic activity. MTAP contains an active site with three regions that correspond to a base, methylthioribose, and sulfate/phosphate binding site.

Function

S-methyl-5'-thioadenosine phosphorylase, MTAP, primarily functions to salvage adenine and methionine from molecule methylthioadenosine (MTA), a byproduct of the polyamine pathway. MTAP is a phosphorylase, which is an enzyme that catalyzes the addition of an inorganic phosphate to another molecule. MTAP is responsible for the cleaving of its substrate, MTA, into adenine and 5-methylthioribose-1-phosphate by the addition of the inorganic phosphate to the 1-prime carbon of the ribose sugar unit MTA. The 5-methylthioribose-1-phosphate is then cycled into the salvage pathway and metabolized into methionine. The MTAP enzyme is responsible for nearly all the adenine synthesis in the human body. Adenine is one of the purine bases of nucleic acids, which build both DNA and RNA. Through the recovery of adenine, MTAP plays an indirect role in the synthesis of DNA and RNA.

Cancer

In recent years a connection between tumor growth, cancer developments, and the enzyme MTAP. Research studies show that tumor cells have lower expression of MTAP enzymes and a higher concentration of the MTA molecule. This trend can be easily understood through the polyamine pathway where MTAP functions to cleave its substrate MTA. In healthy cells, the molecule MTA is believed to have tumor suppressing properties and regulate cell proliferation. However, when MTA levels were recorded above optimal working conditions, these MTA molecules appeared to have an inverse relation, promoting tumor growth and significantly increasing the proliferation of tumor cells. These increased levels of MTA in tumor cells is in direct correlation to a down regulation or complete deletion of the gene encoding the MTAP enzyme.

References

References

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