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| | <StructureSection load='3nj4' size='340' side='right'caption='[[3nj4]], [[Resolution|resolution]] 2.50Å' scene=''> | | <StructureSection load='3nj4' size='340' side='right'caption='[[3nj4]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3nj4]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NJ4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NJ4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3nj4]] is a 4 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=3NJ4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NJ4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AFX:(4S,5S)-4-(6-AMINO-9H-PURIN-9-YL)-3-FLUORO-5-HYDROXY-2-(HYDROXYMETHYL)CYCLOPENT-2-EN-1-ONE'>AFX</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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]] 2.5Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AHCY, SAHH ([https://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=AFX:(4S,5S)-4-(6-AMINO-9H-PURIN-9-YL)-3-FLUORO-5-HYDROXY-2-(HYDROXYMETHYL)CYCLOPENT-2-EN-1-ONE'>AFX</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Adenosylhomocysteinase Adenosylhomocysteinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.1.1 3.3.1.1] </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=3nj4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nj4 OCA], [https://pdbe.org/3nj4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nj4 RCSB], [https://www.ebi.ac.uk/pdbsum/3nj4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nj4 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=3nj4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nj4 OCA], [https://pdbe.org/3nj4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nj4 RCSB], [https://www.ebi.ac.uk/pdbsum/3nj4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nj4 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/SAHH_HUMAN SAHH_HUMAN]] Defects in AHCY are the cause of hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:[https://omim.org/entry/613752 613752]]. A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy.<ref>PMID:15024124</ref> <ref>PMID:16736098</ref> <ref>PMID:19177456</ref> <ref>PMID:20852937</ref>
| + | [https://www.uniprot.org/uniprot/SAHH_HUMAN SAHH_HUMAN] Defects in AHCY are the cause of hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:[https://omim.org/entry/613752 613752]. A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy.<ref>PMID:15024124</ref> <ref>PMID:16736098</ref> <ref>PMID:19177456</ref> <ref>PMID:20852937</ref> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/SAHH_HUMAN SAHH_HUMAN]] Adenosylhomocysteine is a competitive inhibitor of S-adenosyl-L-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration of adenosylhomocysteine.<ref>PMID:12590576</ref>
| + | [https://www.uniprot.org/uniprot/SAHH_HUMAN SAHH_HUMAN] Adenosylhomocysteine is a competitive inhibitor of S-adenosyl-L-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration of adenosylhomocysteine.<ref>PMID:12590576</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3'-oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4'-CH(2)OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4'-CH(2)OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.
| + | |
| - | | + | |
| - | X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues.,Lee KM, Choi WJ, Lee Y, Lee HJ, Zhao LX, Lee HW, Park JG, Kim HO, Hwang KY, Heo YS, Choi S, Jeong LS J Med Chem. 2011 Feb 24;54(4):930-8. Epub 2011 Jan 12. PMID:21226494<ref>PMID:21226494</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 3nj4" style="background-color:#fffaf0;"></div>
| + | |
| | | | |
| | ==See Also== | | ==See Also== |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Adenosylhomocysteinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Choi, S]] | + | [[Category: Choi S]] |
| - | [[Category: Heo, Y S]] | + | [[Category: Heo YS]] |
| - | [[Category: Hwang, K Y]] | + | [[Category: Hwang KY]] |
| - | [[Category: Jeong, L S]] | + | [[Category: Jeong LS]] |
| - | [[Category: Lee, K M]] | + | [[Category: Lee KM]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Nad]]
| + | |
| - | [[Category: S-adenosylhomocystein]]
| + | |
| Structural highlights
Disease
SAHH_HUMAN Defects in AHCY are the cause of hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:613752. A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy.[1] [2] [3] [4]
Function
SAHH_HUMAN Adenosylhomocysteine is a competitive inhibitor of S-adenosyl-L-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration of adenosylhomocysteine.[5]
See Also
References
- ↑ Baric I, Fumic K, Glenn B, Cuk M, Schulze A, Finkelstein JD, James SJ, Mejaski-Bosnjak V, Pazanin L, Pogribny IP, Rados M, Sarnavka V, Scukanec-Spoljar M, Allen RH, Stabler S, Uzelac L, Vugrek O, Wagner C, Zeisel S, Mudd SH. S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4234-9. Epub 2004 Mar 15. PMID:15024124 doi:10.1073/pnas.0400658101
- ↑ Buist NR, Glenn B, Vugrek O, Wagner C, Stabler S, Allen RH, Pogribny I, Schulze A, Zeisel SH, Baric I, Mudd SH. S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man. J Inherit Metab Dis. 2006 Aug;29(4):538-45. Epub 2006 May 30. PMID:16736098 doi:10.1007/s10545-006-0240-0
- ↑ Vugrek O, Beluzic R, Nakic N, Mudd SH. S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome. Hum Mutat. 2009 Apr;30(4):E555-65. doi: 10.1002/humu.20985. PMID:19177456 doi:10.1002/humu.20985
- ↑ Grubbs R, Vugrek O, Deisch J, Wagner C, Stabler S, Allen R, Baric I, Rados M, Mudd SH. S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes. J Inherit Metab Dis. 2010 Dec;33(6):705-13. doi: 10.1007/s10545-010-9171-x. Epub , 2010 Sep 18. PMID:20852937 doi:10.1007/s10545-010-9171-x
- ↑ Yang X, Hu Y, Yin DH, Turner MA, Wang M, Borchardt RT, Howell PL, Kuczera K, Schowen RL. Catalytic strategy of S-adenosyl-L-homocysteine hydrolase: transition-state stabilization and the avoidance of abortive reactions. Biochemistry. 2003 Feb 25;42(7):1900-9. PMID:12590576 doi:http://dx.doi.org/10.1021/bi0262350
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