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| | ==Crystal structure of Canton G6PD in complex with structural NADP== | | ==Crystal structure of Canton G6PD in complex with structural NADP== |
| - | <StructureSection load='6e07' size='340' side='right' caption='[[6e07]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='6e07' size='340' side='right'caption='[[6e07]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6e07]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5vg5 5vg5]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E07 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E07 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6e07]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5vg5 5vg5]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E07 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E07 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 2.6Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">G6PD ([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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucose-6-phosphate_dehydrogenase Glucose-6-phosphate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.49 1.1.1.49] </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=6e07 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e07 OCA], [https://pdbe.org/6e07 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e07 RCSB], [https://www.ebi.ac.uk/pdbsum/6e07 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e07 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=6e07 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e07 OCA], [http://pdbe.org/6e07 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e07 RCSB], [http://www.ebi.ac.uk/pdbsum/6e07 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e07 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN]] Defects in G6PD are the cause of chronic non-spherocytic hemolytic anemia (CNSHA) [MIM:[http://omim.org/entry/305900 305900]]. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of CNSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity.<ref>PMID:1611091</ref> | + | [https://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN] Defects in G6PD are the cause of chronic non-spherocytic hemolytic anemia (CNSHA) [MIM:[https://omim.org/entry/305900 305900]. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of CNSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity.<ref>PMID:1611091</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN]] Produces pentose sugars for nucleic acid synthesis and main producer of NADPH reducing power. | + | [https://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN] Produces pentose sugars for nucleic acid synthesis and main producer of NADPH reducing power. |
| | <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: Glucose-6-phosphate dehydrogenase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Mochly-Rosen, D]] | + | [[Category: Mochly-Rosen D]] |
| - | [[Category: Rahighi, S]] | + | [[Category: Rahighi S]] |
| - | [[Category: Wakatsuki, S]] | + | [[Category: Wakatsuki S]] |
| - | [[Category: G6pd]]
| + | |
| - | [[Category: Nadp]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Disease
G6PD_HUMAN Defects in G6PD are the cause of chronic non-spherocytic hemolytic anemia (CNSHA) [MIM:305900. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of CNSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity.[1]
Function
G6PD_HUMAN Produces pentose sugars for nucleic acid synthesis and main producer of NADPH reducing power.
Publication Abstract from PubMed
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the Canton mutant and several other common G6PD mutants. AG1 reduces oxidative stress in cells and zebrafish. Furthermore, AG1 decreases chloroquine- or diamide-induced oxidative stress in human erythrocytes. Our study suggests that a pharmacological agent, of which AG1 may be a lead, will likely alleviate the challenges associated with G6PD deficiency.
Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator.,Hwang S, Mruk K, Rahighi S, Raub AG, Chen CH, Dorn LE, Horikoshi N, Wakatsuki S, Chen JK, Mochly-Rosen D Nat Commun. 2018 Oct 2;9(1):4045. doi: 10.1038/s41467-018-06447-z. PMID:30279493[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Beutler E, Westwood B, Prchal JT, Vaca G, Bartsocas CS, Baronciani L. New glucose-6-phosphate dehydrogenase mutations from various ethnic groups. Blood. 1992 Jul 1;80(1):255-6. PMID:1611091
- ↑ Hwang S, Mruk K, Rahighi S, Raub AG, Chen CH, Dorn LE, Horikoshi N, Wakatsuki S, Chen JK, Mochly-Rosen D. Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator. Nat Commun. 2018 Oct 2;9(1):4045. doi: 10.1038/s41467-018-06447-z. PMID:30279493 doi:http://dx.doi.org/10.1038/s41467-018-06447-z
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