S-methyl-5'-thioadenosine phosphorylase (MTAP) is an
enzyme in humans responsible for
polyaminemetabolism. It is encoded by the methylthioadenosine phosphorylase (MTAP) gene on
chromosome 9.[5] Multiple alternatively spliced
transcript variants have been described for this gene, but their full-length natures remain unknown.[6]
This gene encodes an enzyme that plays a major role in polyamine metabolism and is important for the salvage of both
adenine and
methionine. It is responsible for the first step in this pathway, where it catalyzes the reversible
phosphorylation of
MTA to adenine and 5-methylthioribose-1-phosphate. This takes place after MTA is generated from
S-adenosylmethionine.[5]
MTAP was identified for the first time and characterized likely as a
phosphorylase in 1969 by Pegg and Williams-Ashman.[7] The first purification that allowed characterization was by a group in 1986.[8] This purification allowed researchers to investigate why there is the lower expression of MTAP in some types of cancer.
Increased levels of MTA in tumor cells along with lower expression of MTAP.[9] The enzyme is deficient in many cancers because this gene and the tumor-suppressive p16 gene are co-deleted.[9][10][11][12][13]
Gene
The MTAP
gene location is 9p21.3 which is
chromosome 9,
p arm, band 2, sub-band1, and sub-sub-band 3.[14][15] The MTAP gene has seven
isomers which are created when
mRNA’s of the same
locus have different
transcription start sites.[16] 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.[17] Particularly the deletion of the gene p16 in conjunction with the whole or partial deletion of MTAP has been indicated in some cancer types.[17] Genes p15 and p16 of chromosome nine are closely linked to the MTAP gene, because of this, MTAP is commonly cross-deleted.[10][11][17] This deletion is found in many cancerous tissues.[10][11]
Structure
MTAP is a trimer
enzyme that shares a similar structure and functions with
mammalianpurine nucleoside phosphorylases (PNPs) which are also trimeric enzymes.[18] MTAP’s
subunits are identical in structure and composed of 283
amino acid residues that form to the size of about 32 kDa each.[8][18] The main structure of an MTAP subunit consists of eleven
beta-sheets with six
alpha-helices intermixed.[18] 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.[18] 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.[18] 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.[18] MTAP contains an active site with three regions that correspond to a base, methylthioribose, and sulfate/phosphate
binding site.[18]
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.[18] The 5-methylthioribose-1-phosphate is then cycled into the
salvage pathway and
metabolized into methionine.[20][21] The MTAP enzyme is responsible for nearly all the adenine synthesis in the human body.[18]Adenine is one of the
purine bases of
nucleic acids, which build both
DNA and
RNA. Through the recovery of adenine, MTAP plays a highly critical 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.[9] This trend can be easily understood through the polyamine pathway where MTAP functions to cleave its substrate MTA.[9][22] In healthy cells, the molecule MTA is believed to have tumor suppressing properties and regulate
cell proliferation.[22] 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.[9] 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.[9]
Della Ragione F, Takabayashi K, Mastropietro S, Mercurio C, Oliva A, Russo GL, et al. (June 1996). "Purification and characterization of recombinant human 5'-methylthioadenosine phosphorylase: definite identification of coding cDNA". Biochemical and Biophysical Research Communications. 223 (3): 514–519.
doi:
10.1006/bbrc.1996.0926.
PMID8687427.
Gursky S, Olopade OI, Rowley JD (September 2001). "Identification of a 1.2 Kb cDNA fragment from a region on 9p21 commonly deleted in multiple tumor types". Cancer Genetics and Cytogenetics. 129 (2): 93–101.
doi:
10.1016/S0165-4608(01)00444-7.
PMID11566337.
Christopher SA, Diegelman P, Porter CW, Kruger WD (November 2002). "Methylthioadenosine phosphorylase, a gene frequently codeleted with p16(cdkN2a/ARF), acts as a tumor suppressor in a breast cancer cell line". Cancer Research. 62 (22): 6639–6644.
PMID12438261.