3s5o: Difference between revisions
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The entry | ==Crystal Structure of Human 4-hydroxy-2-oxoglutarate Aldolase Bound to Pyruvate== | ||
<StructureSection load='3s5o' size='340' side='right'caption='[[3s5o]], [[Resolution|resolution]] 1.97Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3s5o]] 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=3S5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S5O FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=KPI:(2S)-2-AMINO-6-[(1-HYDROXY-1-OXO-PROPAN-2-YLIDENE)AMINO]HEXANOIC+ACID'>KPI</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3s5n|3s5n]]</div></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">C10orf65, DHDPSL, HOGA1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/4-hydroxy-2-oxoglutarate_aldolase 4-hydroxy-2-oxoglutarate aldolase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.3.16 4.1.3.16] </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=3s5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s5o OCA], [https://pdbe.org/3s5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s5o RCSB], [https://www.ebi.ac.uk/pdbsum/3s5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s5o ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[https://www.uniprot.org/uniprot/HOGA1_HUMAN HOGA1_HUMAN]] Primary hyperoxaluria type 3. The disease is caused by mutations affecting the gene represented in this entry. | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/HOGA1_HUMAN HOGA1_HUMAN]] Catalyzes the final step in the metabolic pathway of hydroxyproline.<ref>PMID:20797690</ref> <ref>PMID:21998747</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
BACKGROUND: 4-hydroxy-2-oxoglutarate (HOG) aldolase is a unique enzyme in the hydroxyproline degradation pathway catalyzing the cleavage of HOG to pyruvate and glyoxylate. Mutations in this enzyme are believed to be associated with the excessive production of oxalate in primary hyperoxaluria type 3 (PH3), although no experimental data is available to support this hypothesis. Moreover, the identity, oligomeric state, enzymatic activity, and crystal structure of human HOGA have not been experimentally determined. METHODOLOGY/PRINCIPAL FINDINGS: In this study human HOGA (hHOGA) was identified by mass spectrometry of the mitochondrial enzyme purified from bovine kidney. hHOGA performs a retro-aldol cleavage reaction reminiscent of the trimeric 2-keto-3-deoxy-6-phosphogluconate aldolases. Sequence comparisons, however, show that HOGA is related to the tetrameric, bacterial dihydrodipicolinate synthases, but the reaction direction is reversed. The 1.97 A resolution crystal structure of hHOGA bound to pyruvate was determined and enabled the modeling of the HOG-Schiff base intermediate and the identification of active site residues. Kinetic analyses of site-directed mutants support the importance of Lys196 as the nucleophile, Tyr168 and Ser77 as components of a proton relay, and Asn78 and Ser198 as unique residues that facilitate substrate binding. CONCLUSIONS/SIGNIFICANCE: The biochemical and structural data presented support that hHOGA utilizes a type I aldolase reaction mechanism, but employs novel residue interactions for substrate binding. A mapping of the PH3 mutations identifies potential rearrangements in either the active site or the tetrameric assembly that would likely cause a loss in activity. Altogether, these data establish a foundation to assess mutant forms of hHOGA and how their activity could be pharmacologically restored. | |||
Structural and Biochemical Studies of Human 4-hydroxy-2-oxoglutarate Aldolase: Implications for Hydroxyproline Metabolism in Primary Hyperoxaluria.,Riedel TJ, Johnson LC, Knight J, Hantgan RR, Holmes RP, Lowther WT PLoS One. 2011;6(10):e26021. Epub 2011 Oct 6. PMID:21998747<ref>PMID:21998747</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3s5o" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aldolase 3D structures|Aldolase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: 4-hydroxy-2-oxoglutarate aldolase]] | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Lowther, W T]] | |||
[[Category: Riedel, T J]] | |||
[[Category: Aldolase]] | |||
[[Category: Beta barrel]] | |||
[[Category: Hydroxyproline metabolism]] | |||
[[Category: Lyase]] | |||
[[Category: Schiff base]] | |||
Latest revision as of 13:39, 22 June 2022
Crystal Structure of Human 4-hydroxy-2-oxoglutarate Aldolase Bound to PyruvateCrystal Structure of Human 4-hydroxy-2-oxoglutarate Aldolase Bound to Pyruvate
Structural highlights
Disease[HOGA1_HUMAN] Primary hyperoxaluria type 3. The disease is caused by mutations affecting the gene represented in this entry. Function[HOGA1_HUMAN] Catalyzes the final step in the metabolic pathway of hydroxyproline.[1] [2] Publication Abstract from PubMedBACKGROUND: 4-hydroxy-2-oxoglutarate (HOG) aldolase is a unique enzyme in the hydroxyproline degradation pathway catalyzing the cleavage of HOG to pyruvate and glyoxylate. Mutations in this enzyme are believed to be associated with the excessive production of oxalate in primary hyperoxaluria type 3 (PH3), although no experimental data is available to support this hypothesis. Moreover, the identity, oligomeric state, enzymatic activity, and crystal structure of human HOGA have not been experimentally determined. METHODOLOGY/PRINCIPAL FINDINGS: In this study human HOGA (hHOGA) was identified by mass spectrometry of the mitochondrial enzyme purified from bovine kidney. hHOGA performs a retro-aldol cleavage reaction reminiscent of the trimeric 2-keto-3-deoxy-6-phosphogluconate aldolases. Sequence comparisons, however, show that HOGA is related to the tetrameric, bacterial dihydrodipicolinate synthases, but the reaction direction is reversed. The 1.97 A resolution crystal structure of hHOGA bound to pyruvate was determined and enabled the modeling of the HOG-Schiff base intermediate and the identification of active site residues. Kinetic analyses of site-directed mutants support the importance of Lys196 as the nucleophile, Tyr168 and Ser77 as components of a proton relay, and Asn78 and Ser198 as unique residues that facilitate substrate binding. CONCLUSIONS/SIGNIFICANCE: The biochemical and structural data presented support that hHOGA utilizes a type I aldolase reaction mechanism, but employs novel residue interactions for substrate binding. A mapping of the PH3 mutations identifies potential rearrangements in either the active site or the tetrameric assembly that would likely cause a loss in activity. Altogether, these data establish a foundation to assess mutant forms of hHOGA and how their activity could be pharmacologically restored. Structural and Biochemical Studies of Human 4-hydroxy-2-oxoglutarate Aldolase: Implications for Hydroxyproline Metabolism in Primary Hyperoxaluria.,Riedel TJ, Johnson LC, Knight J, Hantgan RR, Holmes RP, Lowther WT PLoS One. 2011;6(10):e26021. Epub 2011 Oct 6. PMID:21998747[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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