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==STRUCTURE OF HUMAN 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE COMPLEXED WITH 5'-METHYLTHIOTUBERCIDIN==
==STRUCTURE OF HUMAN 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE COMPLEXED WITH 5'-METHYLTHIOTUBERCIDIN==
<StructureSection load='1sd2' size='340' side='right' caption='[[1sd2]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='1sd2' size='340' side='right'caption='[[1sd2]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1sd2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SD2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1SD2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1sd2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SD2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1SD2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MTH:2-(4-AMINO-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-5-METHYLSULFANYLMETHYL-TETRAHYDRO-FURAN-3,4-DIOL'>MTH</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MTAP, MSAP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MTH:2-(4-AMINO-PYRROLO[2,3-D]PYRIMIDIN-7-YL)-5-METHYLSULFANYLMETHYL-TETRAHYDRO-FURAN-3,4-DIOL'>MTH</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/S-methyl-5'-thioadenosine_phosphorylase S-methyl-5'-thioadenosine phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.28 2.4.2.28] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1sd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1sd2 OCA], [https://pdbe.org/1sd2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1sd2 RCSB], [https://www.ebi.ac.uk/pdbsum/1sd2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1sd2 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1sd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1sd2 OCA], [http://pdbe.org/1sd2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1sd2 RCSB], [http://www.ebi.ac.uk/pdbsum/1sd2 PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/MTAP_HUMAN MTAP_HUMAN]] Defects in MTAP are the cause of diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH) [MIM:[http://omim.org/entry/112250 112250]]. An autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. Some patients show a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. Note=DMSMFH causing mutations found in MTAP exon 9 result in exon skipping and dysregulated alternative splicing of all MTAP isoforms (PubMed:22464254).<ref>PMID:22464254</ref>  Note=Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer.[HAMAP-Rule:MF_03155]  
[https://www.uniprot.org/uniprot/MTAP_HUMAN MTAP_HUMAN] Defects in MTAP are the cause of diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH) [MIM:[https://omim.org/entry/112250 112250]. An autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. Some patients show a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. Note=DMSMFH causing mutations found in MTAP exon 9 result in exon skipping and dysregulated alternative splicing of all MTAP isoforms (PubMed:22464254).<ref>PMID:22464254</ref>  Note=Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer.[HAMAP-Rule:MF_03155]
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/MTAP_HUMAN MTAP_HUMAN]] Catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S-adenosylmethionine. Has broad substrate specificity with 6-aminopurine nucleosides as preferred substrates.<ref>PMID:3091600</ref>
[https://www.uniprot.org/uniprot/MTAP_HUMAN MTAP_HUMAN] Catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S-adenosylmethionine. Has broad substrate specificity with 6-aminopurine nucleosides as preferred substrates.<ref>PMID:3091600</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/sd/1sd2_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/sd/1sd2_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1sd2 ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1sd2 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The development of new and effective antiprotozoal drugs has been a difficult challenge because of the close similarity of the metabolic pathways between microbial and mammalian systems. 5'-Methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase is thought to be an ideal target for therapeutic drug design as the enzyme is present in many microbes but not in mammals. MTA/AdoHcy nucleosidase (MTAN) irreversibly depurinates MTA or AdoHcy to form adenine and the corresponding thioribose. The inhibition of MTAN leads to a buildup of toxic byproducts that affect various microbial pathways such as quorum sensing, biological methylation, polyamine biosynthesis, and methionine recycling. The design of nucleosidase-specific inhibitors is complicated by its structural similarity to the human MTA phosphorylase (MTAP). The crystal structures of human MTAP complexed with formycin A and 5'-methylthiotubercidin have been solved to 2.0 and 2.1 A resolution, respectively. Comparisons of the MTAP and MTAN inhibitor complexes reveal size and electrostatic potential differences in the purine, ribose, and 5'-alkylthio binding sites, which account for the substrate specificity and reactions catalyzed. In addition, the differences between the two enzymes have allowed the identification of exploitable regions that can be targeted for the development of high-affinity nucleosidase-specific inhibitors. Sequence alignments of Escherichia coli MTAN, human MTAP, and plant MTA nucleosidases also reveal potential structural changes to the 5'-alkylthio binding site that account for the substrate preference of plant MTA nucleosidases.
Structural comparison of MTA phosphorylase and MTA/AdoHcy nucleosidase explains substrate preferences and identifies regions exploitable for inhibitor design.,Lee JE, Settembre EC, Cornell KA, Riscoe MK, Sufrin JR, Ealick SE, Howell PL Biochemistry. 2004 May 11;43(18):5159-69. PMID:15122881<ref>PMID:15122881</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1sd2" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[5'-deoxy-5'-methylthioadenosine phosphorylase|5'-deoxy-5'-methylthioadenosine phosphorylase]]
*[[5'-deoxy-5'-methylthioadenosine phosphorylase 3D structures|5'-deoxy-5'-methylthioadenosine phosphorylase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: S-methyl-5'-thioadenosine phosphorylase]]
[[Category: Large Structures]]
[[Category: Cornell, K A]]
[[Category: Cornell KA]]
[[Category: Ealick, S E]]
[[Category: Ealick SE]]
[[Category: Howell, P L]]
[[Category: Howell PL]]
[[Category: Lee, J E]]
[[Category: Lee JE]]
[[Category: Riscoe, M K]]
[[Category: Riscoe MK]]
[[Category: Settembre, E C]]
[[Category: Settembre EC]]
[[Category: Sufrin, J R]]
[[Category: Sufrin JR]]
[[Category: 5'-methylthiotubercidin]]
[[Category: Methylthioadenosine phosphorylase]]
[[Category: Mtt]]
[[Category: Purine nucleoside phosphorylase]]
[[Category: Purine salvage]]
[[Category: Sulfate]]
[[Category: Transferase]]

Latest revision as of 11:29, 14 February 2024

STRUCTURE OF HUMAN 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE COMPLEXED WITH 5'-METHYLTHIOTUBERCIDINSTRUCTURE OF HUMAN 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE COMPLEXED WITH 5'-METHYLTHIOTUBERCIDIN

Structural highlights

1sd2 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.1Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MTAP_HUMAN Defects in MTAP are the cause of diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH) [MIM:112250. An autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. Some patients show a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. Note=DMSMFH causing mutations found in MTAP exon 9 result in exon skipping and dysregulated alternative splicing of all MTAP isoforms (PubMed:22464254).[1] Note=Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer.[HAMAP-Rule:MF_03155]

Function

MTAP_HUMAN Catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S-adenosylmethionine. Has broad substrate specificity with 6-aminopurine nucleosides as preferred substrates.[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Camacho-Vanegas O, Camacho SC, Till J, Miranda-Lorenzo I, Terzo E, Ramirez MC, Schramm V, Cordovano G, Watts G, Mehta S, Kimonis V, Hoch B, Philibert KD, Raabe CA, Bishop DF, Glucksman MJ, Martignetti JA. Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. Am J Hum Genet. 2012 Apr 6;90(4):614-27. doi: 10.1016/j.ajhg.2012.02.024. Epub, 2012 Mar 29. PMID:22464254 doi:10.1016/j.ajhg.2012.02.024
  2. ↑ Della Ragione F, Carteni-Farina M, Gragnaniello V, Schettino MI, Zappia V. Purification and characterization of 5'-deoxy-5'-methylthioadenosine phosphorylase from human placenta. J Biol Chem. 1986 Sep 15;261(26):12324-9. PMID:3091600

1sd2, resolution 2.10Å

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