|
|
| Line 3: |
Line 3: |
| | <StructureSection load='1pkx' size='340' side='right'caption='[[1pkx]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='1pkx' size='340' side='right'caption='[[1pkx]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1pkx]] is a 4 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=1PKX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1PKX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1pkx]] 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=1PKX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PKX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=XMP:XANTHOSINE-5-MONOPHOSPHATE'>XMP</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]] 1.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1p4r|1p4r]], [[1pl0|1pl0]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=XMP:XANTHOSINE-5-MONOPHOSPHATE'>XMP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ATIC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=1pkx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pkx OCA], [https://pdbe.org/1pkx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1pkx RCSB], [https://www.ebi.ac.uk/pdbsum/1pkx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1pkx ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1pkx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pkx OCA], [http://pdbe.org/1pkx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1pkx RCSB], [http://www.ebi.ac.uk/pdbsum/1pkx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1pkx ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN]] Defects in ATIC are the cause of AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:[http://omim.org/entry/608688 608688]]. A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA-riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness.<ref>PMID:14966129</ref> <ref>PMID:15114530</ref> | + | [https://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN] Defects in ATIC are the cause of AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:[https://omim.org/entry/608688 608688]. A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA-riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness.<ref>PMID:14966129</ref> <ref>PMID:15114530</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN]] Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.<ref>PMID:14966129</ref> | + | [https://www.uniprot.org/uniprot/PUR9_HUMAN PUR9_HUMAN] Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.<ref>PMID:14966129</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 39: |
Line 38: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Cheong, C G]] | + | [[Category: Cheong CG]] |
| - | [[Category: Greasley, S E]] | + | [[Category: Greasley SE]] |
| - | [[Category: Wilson, I A]] | + | [[Category: Wilson IA]] |
| - | [[Category: Wolan, D W]] | + | [[Category: Wolan DW]] |
| - | [[Category: Aicar transformylase]]
| + | |
| - | [[Category: Atic]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Imp cyclohydrolase]]
| + | |
| - | [[Category: Purine biosynthesis]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Xanthosine monophosphate]]
| + | |
| Structural highlights
Disease
PUR9_HUMAN Defects in ATIC are the cause of AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:608688. A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA-riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness.[1] [2]
Function
PUR9_HUMAN Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.[3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Within de novo purine biosynthesis, the AICAR transformylase and IMP cyclohydrolase activities of the bifunctional enzyme ATIC convert the intermediate AICAR to the final product of the pathway, IMP. Identification of the AICAR transformylase active site and a proposed formyl transfer mechanism have already resulted from analysis of crystal structures of avian ATIC in complex with substrate and/or inhibitors. Herein, we focus on the IMPCH active site and the cyclohydrolase mechanism through comparison of crystal structures of XMP inhibitor complexes of human ATIC at 1.9 A resolution with the previously determined avian enzyme. This first human ATIC structure was also determined to ascertain whether any subtle structural differences, compared to the homologous avian enzyme, should be taken into account for structure-based inhibitor design. These structural comparisons, as well as comparative analyses with other IMP and XMP binding proteins, have enabled a catalytic mechanism to be formulated. The primary role of the IMPCH active site appears to be to induce a reconfiguration of the substrate FAICAR to a less energetically favorable, but more reactive, conformer. Backbone (Arg64 and Lys66) and side chain interactions (Thr67) in the IMPCH active site reorient the 4-carboxamide from the preferred conformer that binds to the AICAR Tfase active site to one that promotes intramolecular cyclization. Other backbone amides (Ile126 and Gly127) create an oxyanion hole that helps orient the formyl group for nucleophilic attack by the 4-carboxamide amine and then stabilize the anionic intermediate. Several other residues, including Lys66, Tyr104, Asp125, and Lys137', provide substrate specificity and likely enhance the catalytic rate through contributions to acid-base catalysis.
Structural insights into the human and avian IMP cyclohydrolase mechanism via crystal structures with the bound XMP inhibitor.,Wolan DW, Cheong CG, Greasley SE, Wilson IA Biochemistry. 2004 Feb 10;43(5):1171-83. PMID:14756553[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cheong CG, Wolan DW, Greasley SE, Horton PA, Beardsley GP, Wilson IA. Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates. J Biol Chem. 2004 Apr 23;279(17):18034-45. Epub 2004 Feb 13. PMID:14966129 doi:10.1074/jbc.M313691200
- ↑ Marie S, Heron B, Bitoun P, Timmerman T, Van Den Berghe G, Vincent MF. AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am J Hum Genet. 2004 Jun;74(6):1276-81. Epub 2004 Apr 26. PMID:15114530 doi:10.1086/421475
- ↑ Cheong CG, Wolan DW, Greasley SE, Horton PA, Beardsley GP, Wilson IA. Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates. J Biol Chem. 2004 Apr 23;279(17):18034-45. Epub 2004 Feb 13. PMID:14966129 doi:10.1074/jbc.M313691200
- ↑ Wolan DW, Cheong CG, Greasley SE, Wilson IA. Structural insights into the human and avian IMP cyclohydrolase mechanism via crystal structures with the bound XMP inhibitor. Biochemistry. 2004 Feb 10;43(5):1171-83. PMID:14756553 doi:10.1021/bi030162i
|
