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6o4c

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Structure of ALDH7A1 mutant W175A complexed with NAD

Structural highlights

6o4c is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.7Å
Ligands:	, , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AL7A1_HUMAN Pyridoxine-dependent epilepsy. The disease is caused by mutations affecting the gene represented in this entry.

Function

AL7A1_HUMAN Multifunctional enzyme mediating important protective effects. Metabolizes betaine aldehyde to betaine, an important cellular osmolyte and methyl donor. Protects cells from oxidative stress by metabolizing a number of lipid peroxidation-derived aldehydes. Involved in lysine catabolism.^[1] ^[2]

Publication Abstract from PubMed

In humans, certain mutations in the gene encoding aldehyde dehydrogenase 7A1 are associated with pyridoxine-dependent epilepsy (PDE). Understanding the impact of PDE-causing mutations on the structure and activity of ALDH7A1 could allow for the prediction of symptom-severity and aid the development of patient-specific medical treatments. Herein, we investigate the biochemical and structural consequences of PDE missense mutations targeting residues in the aldehyde substrate binding site: N167S, P169S, A171V, G174V, and W175G. All but G174V could be purified for biochemical and X-ray crystallographic analysis. W175G has a relatively mild kinetic defect, exhibiting a 5-fold decrease in kcat with no change in Km . P169S and N167S have moderate defects, characterized by catalytic efficiencies of 20- and 100-times lower than wild-type, respectively. A171V has a profound functional defect, with catalytic efficiency 2000-times lower than wild-type. The crystal structures of the variants are the first for any PDE-associated mutant of ALDH7A1. The structures show that missense mutations that decrease the steric bulk of the side chain tend to create a cavity in the active site. The protein responds by relaxing into the vacant space, and this structural perturbation appears to cause misalignment of the aldehyde substrate in W175G and N167S. The P169S structure is nearly identical to that of the wild-type enzyme; however, analysis of B-factors suggests the catalytic defect may result from altered protein dynamics. The A171V structure suggests that the potential for steric clash with Val171 prevents Glu121 from ion pairing with the amino group of the aldehyde substrate. This article is protected by copyright. All rights reserved.

Structural and Biochemical Consequences of Pyridoxine-Dependent Epilepsy Mutations That Target the Aldehyde Binding Site of Aldehyde Dehydrogenase ALDH7A1.,Laciak AR, Korasick DA, Wyatt JW, Gates KS, Tanner JJ FEBS J. 2019 Jul 14. doi: 10.1111/febs.14997. PMID:31302938^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006 Mar;12(3):307-9. Epub 2006 Feb 19. PMID:16491085 doi:http://dx.doi.org/nm1366
↑ Brocker C, Lassen N, Estey T, Pappa A, Cantore M, Orlova VV, Chavakis T, Kavanagh KL, Oppermann U, Vasiliou V. Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme involved in cellular defense against hyperosmotic stress. J Biol Chem. 2010 Jun 11;285(24):18452-63. Epub 2010 Mar 5. PMID:20207735 doi:10.1074/jbc.M109.077925
↑ Laciak AR, Korasick DA, Wyatt JW, Gates KS, Tanner JJ. Structural and Biochemical Consequences of Pyridoxine-Dependent Epilepsy Mutations That Target the Aldehyde Binding Site of Aldehyde Dehydrogenase ALDH7A1. FEBS J. 2019 Jul 14. doi: 10.1111/febs.14997. PMID:31302938 doi:http://dx.doi.org/10.1111/febs.14997

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6o4c"

Categories: Homo sapiens | Large Structures | Korasick DA | Laciak AR | Tanner JJ

@@ Line 3: / Line 3: @@
 <StructureSection load='6o4c' size='340' side='right'caption='[[6o4c]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6o4c]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O4C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O4C FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6o4c]] is a 8 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=6O4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O4C FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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]] 1.7&#8491;</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=6o4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o4c OCA], [http://pdbe.org/6o4c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o4c RCSB], [http://www.ebi.ac.uk/pdbsum/6o4c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o4c ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></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=6o4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o4c OCA], [https://pdbe.org/6o4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o4c RCSB], [https://www.ebi.ac.uk/pdbsum/6o4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o4c ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/AL7A1_HUMAN AL7A1_HUMAN]] Pyridoxine-dependent epilepsy. The disease is caused by mutations affecting the gene represented in this entry.
+[https://www.uniprot.org/uniprot/AL7A1_HUMAN AL7A1_HUMAN] Pyridoxine-dependent epilepsy. The disease is caused by mutations affecting the gene represented in this entry.
 == Function ==
-[[http://www.uniprot.org/uniprot/AL7A1_HUMAN AL7A1_HUMAN]] Multifunctional enzyme mediating important protective effects. Metabolizes betaine aldehyde to betaine, an important cellular osmolyte and methyl donor. Protects cells from oxidative stress by metabolizing a number of lipid peroxidation-derived aldehydes. Involved in lysine catabolism.<ref>PMID:16491085</ref> <ref>PMID:20207735</ref>
+[https://www.uniprot.org/uniprot/AL7A1_HUMAN AL7A1_HUMAN] Multifunctional enzyme mediating important protective effects. Metabolizes betaine aldehyde to betaine, an important cellular osmolyte and methyl donor. Protects cells from oxidative stress by metabolizing a number of lipid peroxidation-derived aldehydes. Involved in lysine catabolism.<ref>PMID:16491085</ref> <ref>PMID:20207735</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 6o4c" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Aldehyde dehydrogenase 3D structures|Aldehyde dehydrogenase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Korasick, D A]]
+[[Category: Korasick DA]]
-[[Category: Laciak, A R]]
+[[Category: Laciak AR]]
-[[Category: Tanner, J J]]
+[[Category: Tanner JJ]]
-[[Category: Aldehyde dehydrogenase]]
-[[Category: Lysine catabolism]]
-[[Category: Nad]]
-[[Category: Oxidoreductase]]

6o4c

From Proteopedia

Current revision

Structure of ALDH7A1 mutant W175A complexed with NAD

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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