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| | <StructureSection load='6dz3' size='340' side='right'caption='[[6dz3]], [[Resolution|resolution]] 1.91Å' scene=''> | | <StructureSection load='6dz3' size='340' side='right'caption='[[6dz3]], [[Resolution|resolution]] 1.91Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6dz3]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DZ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DZ3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6dz3]] is a 3 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=6DZ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DZ3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=OS6:(3R,4S)-1-[(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl]-4-({[3-(1-butyl-1H-1,2,3-triazol-4-yl)propyl]sulfanyl}methyl)pyrrolidin-3-ol'>OS6</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]] 1.91Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=OS6:(3~{R},4~{S})-1-[(4-azanyl-5~{H}-pyrrolo[3,2-d]pyrimidin-7-yl)methyl]-4-[3-(1-butyl-1,2,3-triazol-4-yl)propylsulfanylmethyl]pyrrolidin-3-ol'>OS6</scene></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=6dz3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dz3 OCA], [http://pdbe.org/6dz3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dz3 RCSB], [http://www.ebi.ac.uk/pdbsum/6dz3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dz3 ProSAT]</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=6dz3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dz3 OCA], [https://pdbe.org/6dz3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dz3 RCSB], [https://www.ebi.ac.uk/pdbsum/6dz3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dz3 ProSAT]</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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6dz3" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6dz3" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[5'-deoxy-5'-methylthioadenosine phosphorylase 3D structures|5'-deoxy-5'-methylthioadenosine phosphorylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: S-methyl-5'-thioadenosine phosphorylase]]
| + | [[Category: Almo SC]] |
| - | [[Category: Almo, S C]] | + | [[Category: Bonanno JB]] |
| - | [[Category: Bonanno, J B]] | + | [[Category: Ducati RG]] |
| - | [[Category: Ducati, R G]] | + | [[Category: Harijan RK]] |
| - | [[Category: Harijan, R K]] | + | [[Category: Schramm VL]] |
| - | [[Category: Schramm, V L]] | + | |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Mtap enzyme]]
| + | |
| - | [[Category: Phosphorylase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
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]
Publication Abstract from PubMed
Bacterial 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes the hydrolysis of adenine from S-methyl-5'-thioadenosine (MTA) and S-adenosyl L-homocysteine (SAH) to form S-methyl-5'-thioribose (MTR) and S-ribosyl-L-homocysteine (SRH), respectively. The MTANs are involved in quorum sensing pathways and hydrolyze MTA to metabolites for recycling to S-adenosylmethionine (SAM). A few bacterial species use the futalosine pathway for menaquinone synthesis and in these, MTAN catalyzes an essential step, making it a candidate for species-specific antibiotic development. Helicobacter pylori uses the unusual futalosine pathway for menaquinone biosynthesis and the MTAN from H. pylori (HpMTAN) is a target for antibiotic development. Human 5'-methylthioadenosine phosphorylase (MTAP) catalyzes phosphorylation reactions with substrate specificity similar to the bacterial MTANs. It plays a metabolic role in the salvage of MTA for SAM salvage pathways and has been reported to be an anticancer target. Transition state analogues designed for HpMTAN and for MTAP have been reported and show significant overlap in specificity. It is desirable to design transition state analogues specific for the HpMTAN as an antibiotic in the treatment of H. pylori infections. Fifteen unique transition state analogues are described here and are used to explore the inhibitor specificity and the structural scaffolds for HpMTAN and MTAP. Several inhibitors are transition-state analogues of H. pylori MTAN with dissociation constants in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. X-ray crystal structures of HpMTAN and MTAP show inhibitors of HpMTAN extending through a hydrophobic channel to the protein surface, while the more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the catalytic site phosphate nucleophile.
"Selective inhibitors of H. pylori methylthioadenosine nucleosidase and human methylthioadenosine phosphorylase".,Harijan RK, Hoff O, Ducati RG, Firestone RS, Hirsch BM, Evans GB, Schramm VL, Tyler PC J Med Chem. 2019 Mar 12. doi: 10.1021/acs.jmedchem.8b01642. PMID:30860833[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ Harijan RK, Hoff O, Ducati RG, Firestone RS, Hirsch BM, Evans GB, Schramm VL, Tyler PC. "Selective inhibitors of H. pylori methylthioadenosine nucleosidase and human methylthioadenosine phosphorylase". J Med Chem. 2019 Mar 12. doi: 10.1021/acs.jmedchem.8b01642. PMID:30860833 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01642
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