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User:Hstuhlma/MTAP

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S-methyl-5'-thioadenosine phosphorylase (MTAP) is an enzyme in humans responsible for polyamine metabolism. It is encoded by the methylthioadenosine phosphorylase (MTAP) gene on chromosome 9.[1]

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.[1]

MTAP was identified for the first time and characterized likely as a phosphorylase in 1969 by Pegg and Williams-Ashman.[2] The first purification that allowed characterization was by a group in 1986.[3] This purification allowed researchers to investigate why there is the lower expression of MTAP in some types of cancer.

Current research is looking at the connection between MTAP and cancer.[4][5][6][7][8] Researchers have found increased levels of MTA in tumor cells along with lower expression of MTAP.[4] The enzyme is deficient in many cancers because this gene and the tumor-suppressive p16 gene are co-deleted.

Multiple alternatively spliced transcript variants have been described for this gene, but their full-length natures remain unknown.[9]

 
A summary of the reaction that MTAP catalyzes.[1] Created via ChemDraw.

Function

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Methionine Salvage Pathway and Polyamine Pathways of the MTAP enzyme.[10]

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.[11] 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.[12] The 5-methylthioribose-1-phosphate is then cycled into the salvage pathway and metabolized into methionine.[10][13] The MTAP enzyme is responsible for nearly all the adenine synthesis in the human body.[12] Adenine is one of the purine bases of nucleic acids, which build both DNA and RNA.[14] Through the recovery of adenine, MTAP plays a highly critical indirect role in the synthesis of DNA and RNA.

Structure

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MTAP Subunit Secondary Structure with active site indicated in purple.[12]
 
MTAP quaternary structure with different subunits indicated by different colors (red, blue, and green).[15] Generated using PyMol.

MTAP is a trimer enzyme that shares a similar structure and functions with mammalian purine nucleoside phosphorylases (PNPs) which are also trimeric enzymes.[12] MTAP’s subunits are identical in structure and comprised of 283 amino acid residues that form to the size of about 32 kDa each.[3][12] The main structure of an MTAP subunit is comprised of eleven beta-sheets with six alpha-helices intermixed.[12] 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.[12] 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.[12] 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.[12] MTAP contains an active site with three regions that correspond to a base, methylthioribose, and sulfate/phosphate binding site.[12]

MTAP Gene

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The MTAP gene location is 9p21.3 which is chromosome 9, p arm, band 2, sub-band1, and sub-sub-band 3.[16][17] The MTAP gene has seven isomers which are created when mRNA’s of the same locus have different transcription start sites.[18] 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.[19] Particularly the deletion of the gene p16 in conjunction with the whole or partial deletion of MTAP has been indicated in some cancer types.[19] Genes p15 and p16 of chromosome nine are closely linked to the MTAP gene, because of this, MTAP is commonly cross-deleted.[5][6][19] This deletion is found in many cancerous tissues.[5][6]

MTAP and Cancer

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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.[20] This trend can be easily understood through the polyamine pathway where MTAP functions to cleave its substrate MTA.[20][21] In healthy cells, the molecule MTA is believed to have tumor suppressing properties and regulate cell proliferation.[21] 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.[20] 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.[20]

References

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  1. ^ a b c "MTAP - S-methyl-5'-thioadenosine phosphorylase - Homo sapiens (Human) - MTAP gene & protein". www.uniprot.org. Retrieved 2021-12-03.
  2. ^ Pegg, A. E.; Williams-Ashman, H. G. (1969). "Phosphate-stimulated breakdown of 5′-methylthioadenosine by rat ventral prostate". Biochemical Journal. 115 (2): 241–247. ISSN 0264-6021. PMC 1185095. PMID 5378381.
  3. ^ a b Della Ragione, F; Cartenì-Farina, M; Gragnaniello, V; Schettino, M I; Zappia, V (1986-09-15). "Purification and characterization of 5'-deoxy-5'-methylthioadenosine phosphorylase from human placenta". Journal of Biological Chemistry. 261 (26): 12324–12329. doi:10.1016/S0021-9258(18)67242-4. ISSN 0021-9258.
  4. ^ a b Kirovski, Georgi; Stevens, Axel P.; Czech, Barbara; Dettmer, Katja; Weiss, Thomas S.; Wild, Peter; Hartmann, Arndt; Bosserhoff, Anja K.; Oefner, Peter J.; Hellerbrand, Claus (2011). "Down-Regulation of Methylthioadenosine Phosphorylase (MTAP) Induces Progression of Hepatocellular Carcinoma via Accumulation of 5′-Deoxy-5′-Methylthioadenosine (MTA)". The American Journal of Pathology. 178 (3): 1145–1152. doi:10.1016/j.ajpath.2010.11.059. ISSN 0002-9440. PMC 3069916. PMID 21356366.
  5. ^ a b c Barekatain, Yasaman; Ackroyd, Jeffrey J.; Yan, Victoria C.; Khadka, Sunada; Wang, Lin; Chen, Ko-Chien; Poral, Anton H.; Tran, Theresa; Georgiou, Dimitra K.; Arthur, Kenisha; Lin, Yu-Hsi (2021-07-09). "Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine". Nature Communications. 12: 4228. doi:10.1038/s41467-021-24240-3. ISSN 2041-1723. PMC 8270912. PMID 34244484.
  6. ^ a b c de Menezes, Weder Pereira; Silva, Viviane Aline Oliveira; Gomes, Izabela Natália Faria; Rosa, Marcela Nunes; Spina, Maria Luisa Corcoll; Carloni, Adriana Cruvinel; Alves, Ana Laura Vieira; Melendez, Matias; Almeida, Gisele Caravina; da Silva, Luciane Sussuchi; Clara, Carlos (2020-02-20). "Loss of 5′-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness". Cells. 9 (2): 492. doi:10.3390/cells9020492. ISSN 2073-4409. PMC 7072758. PMID 32093414.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ Xu, Jihao; Chang, Wen-Hsin; Fong, Lon Wolf R.; Weiss, Robert H.; Yu, Sung-Liang; Chen, Ching-Hsien (2019-01-25). "Targeting the insulin-like growth factor-1 receptor in MTAP-deficient renal cell carcinoma". Signal Transduction and Targeted Therapy. 4: 2. doi:10.1038/s41392-019-0035-z. ISSN 2095-9907. PMC 6345872. PMID 30701095.
  8. ^ Hansen, Landon J.; Sun, Ran; Yang, Rui; Singh, Simranjit X.; Chen, Lee H.; Pirozzi, Christopher J.; Moure, Casey J.; Hemphill, Carlee; Carpenter, Austin B.; Healy, Patrick; Ruger, Ryan C. (2019-07-01). "MTAP loss promotes stemness in glioblastoma and confers unique susceptibility to purine starvation". Cancer research. 79 (13): 3383–3394. doi:10.1158/0008-5472.CAN-18-1010. ISSN 0008-5472. PMC 6810595. PMID 31040154.
  9. ^ "MTAP methylthioadenosine phosphorylase [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-12-03.
  10. ^ a b Subhi, Ahmad L.; Diegelman, Paula; Porter, Carl W.; Tang, Baiqing; Lu, Zichun J.; Markham, George D.; Kruger, Warren D. (2003-12-12). "Methylthioadenosine Phosphorylase Regulates Ornithine Decarboxylase by Production of Downstream Metabolites*". Journal of Biological Chemistry. 278 (50): 49868–49873. doi:10.1074/jbc.M308451200. ISSN 0021-9258.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ "Phosphorylase", Wikipedia, 2020-12-29, retrieved 2021-12-02
  12. ^ a b c d e f g h i j Appleby, Todd C; Erion, Mark D; Ealick, Steven E (1999-06-15). "The structure of human 5′-deoxy-5′-methylthioadenosine phosphorylase at 1.7 Å resolution provides insights into substrate binding and catalysis". Structure. 7 (6): 629–641. doi:10.1016/S0969-2126(99)80084-7. ISSN 0969-2126.
  13. ^ Bertino, Joseph R; Waud, William R; Parker, William B; Lubin, Martin (2011-04-01). "Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity". Cancer Biology & Therapy. 11 (7): 627–632. doi:10.4161/cbt.11.7.14948. ISSN 1538-4047. PMC 3084968. PMID 21301207.
  14. ^ "Adenine", Wikipedia, 2021-11-09, retrieved 2021-12-02
  15. ^ Bank, RCSB Protein Data. "RCSB PDB - 3OZE: Crystal Structure of human 5'-deoxy-5'-methyladenosine phosphorylase". www.rcsb.org. Retrieved 2021-12-02.
  16. ^ "MTAP Gene". www.genecards.org. Retrieved 2021-10-06.{{cite web}}: CS1 maint: url-status (link)
  17. ^ "MLA CE Course Manual: Molecular Biology Information Resources (Genetics Review: Chromosome Band Numbers)". www.ncbi.nlm.nih.gov. Retrieved 2021-10-06.
  18. ^ "UniProtKB - Q13126 (MTAP_Human)". UniProt. Retrieved October 5, 2021.{{cite web}}: CS1 maint: url-status (link)
  19. ^ a b c Nobori, T; Takabayashi, K; Tran, P; Orvis, L; Batova, A; Yu, A L; Carson, D A (1996-06-11). "Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers". Proceedings of the National Academy of Sciences of the United States of America. 93 (12): 6203–6208. ISSN 0027-8424. PMID 8650244.
  20. ^ a b c d Kirovski, Georgi; Stevens, Axel P.; Czech, Barbara; Dettmer, Katja; Weiss, Thomas S.; Wild, Peter; Hartmann, Arndt; Bosserhoff, Anja K.; Oefner, Peter J.; Hellerbrand, Claus (2011). "Down-Regulation of Methylthioadenosine Phosphorylase (MTAP) Induces Progression of Hepatocellular Carcinoma via Accumulation of 5′-Deoxy-5′-Methylthioadenosine (MTA)". The American Journal of Pathology. 178 (3): 1145–1152. doi:10.1016/j.ajpath.2010.11.059. ISSN 0002-9440. PMC 3069916. PMID 21356366.
  21. ^ a b Li, Yaofeng; Wang, Yubo; Wu, Ping (2019-01-29). "5'-Methylthioadenosine and Cancer: old molecules, new understanding". Journal of Cancer. 10 (4): 927–936. doi:10.7150/jca.27160. ISSN 1837-9664. PMC 6400808. PMID 30854099.
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