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| | <StructureSection load='6w44' size='340' side='right'caption='[[6w44]], [[Resolution|resolution]] 1.64Å' scene=''> | | <StructureSection load='6w44' size='340' side='right'caption='[[6w44]], [[Resolution|resolution]] 1.64Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6w44]] is a 1 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=6W44 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W44 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6w44]] is a 1 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=6W44 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W44 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=SLJ:5-[methyl-[(2-propoxypyridin-3-yl)methyl]amino]-2~{H}-indazole-3-carboxylic+acid'>SLJ</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]] 1.64Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HAO1, GOX1, HAOX1 ([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=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=SLJ:5-[methyl-[(2-propoxypyridin-3-yl)methyl]amino]-2~{H}-indazole-3-carboxylic+acid'>SLJ</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/(S)-2-hydroxy-acid_oxidase (S)-2-hydroxy-acid oxidase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.3.15 1.1.3.15] </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=6w44 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w44 OCA], [https://pdbe.org/6w44 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w44 RCSB], [https://www.ebi.ac.uk/pdbsum/6w44 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w44 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=6w44 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w44 OCA], [https://pdbe.org/6w44 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w44 RCSB], [https://www.ebi.ac.uk/pdbsum/6w44 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w44 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/HAOX1_HUMAN HAOX1_HUMAN]] Has 2-hydroxyacid oxidase activity. Most active on the 2-carbon substrate glycolate, but is also active on 2-hydroxy fatty acids, with high activity towards 2-hydroxy palmitate and 2-hydroxy octanoate.
| + | [https://www.uniprot.org/uniprot/HAOX1_HUMAN HAOX1_HUMAN] Has 2-hydroxyacid oxidase activity. Most active on the 2-carbon substrate glycolate, but is also active on 2-hydroxy fatty acids, with high activity towards 2-hydroxy palmitate and 2-hydroxy octanoate. |
| | <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 6w44" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6w44" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Glycolate oxidase 3D structures|Glycolate oxidase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ferguson, A D]] | + | [[Category: Ferguson AD]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Function
HAOX1_HUMAN Has 2-hydroxyacid oxidase activity. Most active on the 2-carbon substrate glycolate, but is also active on 2-hydroxy fatty acids, with high activity towards 2-hydroxy palmitate and 2-hydroxy octanoate.
Publication Abstract from PubMed
Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.
Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening.,Lee ECY, McRiner AJ, Georgiadis KE, Liu J, Wang Z, Ferguson AD, Levin B, von Rechenberg M, Hupp CD, Monteiro MI, Keefe AD, Olszewski A, Eyermann CJ, Centrella P, Liu Y, Arora S, Cuozzo JW, Zhang Y, Clark MA, Huguet C, Kohlmann A J Med Chem. 2021 May 6. doi: 10.1021/acs.jmedchem.0c02271. PMID:33955740[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lee ECY, McRiner AJ, Georgiadis KE, Liu J, Wang Z, Ferguson AD, Levin B, von Rechenberg M, Hupp CD, Monteiro MI, Keefe AD, Olszewski A, Eyermann CJ, Centrella P, Liu Y, Arora S, Cuozzo JW, Zhang Y, Clark MA, Huguet C, Kohlmann A. Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening. J Med Chem. 2021 May 6. doi: 10.1021/acs.jmedchem.0c02271. PMID:33955740 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c02271
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