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| | <StructureSection load='4ynb' size='340' side='right'caption='[[4ynb]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='4ynb' size='340' side='right'caption='[[4ynb]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ynb]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Campylobacter_pylori_j99 Campylobacter pylori j99]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YNB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YNB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ynb]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Helicobacter_pylori_J99 Helicobacter pylori J99]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YNB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YNB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4EH:(3R,4S)-1-[(4-AMINO-5H-PYRROLO[3,2-D]PYRIMIDIN-7-YL)METHYL]-4-[(PYRAZIN-2-YLSULFANYL)METHYL]PYRROLIDIN-3-OL'>4EH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4wkn|4wkn]], [[4wko|4wko]], [[4wkp|4wkp]], [[4ffs|4ffs]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4EH:(3R,4S)-1-[(4-AMINO-5H-PYRROLO[3,2-D]PYRIMIDIN-7-YL)METHYL]-4-[(PYRAZIN-2-YLSULFANYL)METHYL]PYRROLIDIN-3-OL'>4EH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mtnN, mtn, jhp_0082 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=85963 Campylobacter pylori J99])</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=4ynb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ynb OCA], [https://pdbe.org/4ynb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ynb RCSB], [https://www.ebi.ac.uk/pdbsum/4ynb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ynb 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=4ynb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ynb OCA], [http://pdbe.org/4ynb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ynb RCSB], [http://www.ebi.ac.uk/pdbsum/4ynb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ynb ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MQMTN_HELPJ MQMTN_HELPJ]] Catalyzes the direct conversion of aminodeoxyfutalosine (AFL) into dehypoxanthine futalosine (DHFL) and adenine via the hydrolysis of the N-glycosidic bond; this reaction seems to represent an essential step in the menaquinone biosynthesis pathway in Helicobacter species. Also catalyzes the hydrolysis of 5'-methylthioadenosine (MTA) to adenine and 5'-methylthioribose. Can also probably use S-adenosylhomocysteine (SAH) as substrate, leading to adenine and S-ribosylhomocysteine. These other activities highlight the tremendous versatility of the enzyme, which also plays key roles in S-adenosylmethionine recycling and in the biosynthesis of the quorum-sensing molecule autoinducer-2.<ref>PMID:20954236</ref> <ref>PMID:22891633</ref> | + | [https://www.uniprot.org/uniprot/MQMTN_HELPJ MQMTN_HELPJ] Catalyzes the direct conversion of aminodeoxyfutalosine (AFL) into dehypoxanthine futalosine (DHFL) and adenine via the hydrolysis of the N-glycosidic bond; this reaction seems to represent an essential step in the menaquinone biosynthesis pathway in Helicobacter species. Also catalyzes the hydrolysis of 5'-methylthioadenosine (MTA) to adenine and 5'-methylthioribose. Can also probably use S-adenosylhomocysteine (SAH) as substrate, leading to adenine and S-ribosylhomocysteine. These other activities highlight the tremendous versatility of the enzyme, which also plays key roles in S-adenosylmethionine recycling and in the biosynthesis of the quorum-sensing molecule autoinducer-2.<ref>PMID:20954236</ref> <ref>PMID:22891633</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Campylobacter pylori j99]] | + | [[Category: Helicobacter pylori J99]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Almo, S C]] | + | [[Category: Almo SC]] |
| - | [[Category: Cameron, S A]] | + | [[Category: Cameron SA]] |
| - | [[Category: Schramm, V L]] | + | [[Category: Schramm VL]] |
| - | [[Category: Wang, S]] | + | [[Category: Wang S]] |
| - | [[Category: Hydrolase-inhibitor complex]]
| + | |
| Structural highlights
Function
MQMTN_HELPJ Catalyzes the direct conversion of aminodeoxyfutalosine (AFL) into dehypoxanthine futalosine (DHFL) and adenine via the hydrolysis of the N-glycosidic bond; this reaction seems to represent an essential step in the menaquinone biosynthesis pathway in Helicobacter species. Also catalyzes the hydrolysis of 5'-methylthioadenosine (MTA) to adenine and 5'-methylthioribose. Can also probably use S-adenosylhomocysteine (SAH) as substrate, leading to adenine and S-ribosylhomocysteine. These other activities highlight the tremendous versatility of the enzyme, which also plays key roles in S-adenosylmethionine recycling and in the biosynthesis of the quorum-sensing molecule autoinducer-2.[1] [2]
Publication Abstract from PubMed
Helicobacter pylori is a Gram-negative bacterium that colonizes the gut of over 50% of the world's population. It is responsible for most peptic ulcers and is an important risk factor for gastric cancer. Antibiotic treatment for H. pylori infections is challenging as drug resistance has developed to antibiotics with traditional mechanisms of action. H. pylori uses an unusual pathway for menaquinone biosynthesis with 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzing an essential step. We validated MTAN as a target with a transition-state analogue of the enzyme [Wang, S.; Haapalainen, A. M.; Yan, F.; et al. Biochemistry 2012, 51, 6892-6894]. MTAN inhibitors will only be useful drug candidates if they can both include tight binding to the MTAN target and have the ability to penetrate the complex cell membrane found in Gram-negative H. pylori. Here we explore structural scaffolds for MTAN inhibition and for growth inhibition of cultured H. pylori. Sixteen analogues reported here are transition-state analogues of H. pylori MTAN with dissociation constants of 50 pM or below. Ten of these prevent growth of the H. pylori with IC90 values below 0.01 mug/mL. These remarkable compounds meet the criteria for potent inhibition and cell penetration. As a consequence, 10 new H. pylori antibiotic candidates are identified, all of which prevent H. pylori growth at concentrations 16-2000-fold lower than the five antibiotics, amoxicillin, metronidazole, levofloxacin, tetracyclin, and clarithromycin, commonly used to treat H. pylori infections. X-ray crystal structures of MTAN cocrystallized with several inhibitors show them to bind in the active site making interactions consistent with transition-state analogues.
New Antibiotic Candidates against Helicobacter pylori.,Wang S, Cameron SA, Clinch K, Evans GB, Wu Z, Schramm VL, Tyler PC J Am Chem Soc. 2015 Nov 18;137(45):14275-80. doi: 10.1021/jacs.5b06110. Epub 2015, Nov 9. PMID:26494017[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ronning DR, Iacopelli NM, Mishra V. Enzyme-ligand interactions that drive active site rearrangements in the Helicobacter pylori 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase. Protein Sci. 2010 Oct 15. PMID:20954236 doi:10.1002/pro.524
- ↑ Wang S, Haapalainen AM, Yan F, Du Q, Tyler PC, Evans GB, Rinaldo-Matthis A, Brown RL, Norris GE, Almo SC, Schramm VL. A Picomolar Transition State Analogue Inhibitor of MTAN as a Specific Antibiotic for Helicobacter pylori. Biochemistry. 2012 Sep 4;51(35):6892-4. Epub 2012 Aug 22. PMID:22891633 doi:http://dx.doi.org/10.1021/bi3009664
- ↑ Wang S, Cameron SA, Clinch K, Evans GB, Wu Z, Schramm VL, Tyler PC. New Antibiotic Candidates against Helicobacter pylori. J Am Chem Soc. 2015 Nov 18;137(45):14275-80. doi: 10.1021/jacs.5b06110. Epub 2015, Nov 9. PMID:26494017 doi:http://dx.doi.org/10.1021/jacs.5b06110
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