2onm
From Proteopedia
(New page: 200px<br /> <applet load="2onm" size="450" color="white" frame="true" align="right" spinBox="true" caption="2onm, resolution 2.500Å" /> '''Human Mitochondria...) |
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caption="2onm, resolution 2.500Å" /> | caption="2onm, resolution 2.500Å" /> | ||
'''Human Mitochondrial Aldehyde Dehydrogenase Asian Variant, ALDH2*2, complexed with NAD+'''<br /> | '''Human Mitochondrial Aldehyde Dehydrogenase Asian Variant, ALDH2*2, complexed with NAD+'''<br /> | ||
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==Overview== | ==Overview== | ||
The common mitochondrial aldehyde dehydrogenase (ALDH2) ALDH2(*)2, polymorphism is associated with impaired ethanol metabolism and decreased, efficacy of nitroglycerin treatment. These physiological effects are due, to the substitution of Lys for Glu-487 that reduces the k(cat) for these, processes and increases the K(m) for NAD(+), as compared with ALDH2. In, this study, we sought to understand the nature of the interactions that, give rise to the loss of structural integrity and low activity in, ALDH2(*)2 even when complexed with coenzyme. Consequently, we have solved, the crystal structure of ALDH2(*)2 complexed with coenzyme to 2.5A(.) We, have also solved the structures of a mutated form of ALDH2 where Arg-475, is replaced by Gln (R475Q). The structural and functional properties of, the R475Q enzyme are intermediate between those of wild-type and the, ALDH2(*)2 enzymes. In both cases, the binding of coenzyme restores most of, the structural deficits observed in the apoenzyme structures. The binding, of coenzyme to the R475Q enzyme restores its structure and catalytic, properties to near wild-type levels. In contrast, the disordered helix, within the coenzyme binding pocket of ALDH2(*)2 is reordered, but the, active site is only partially reordered. Consistent with the structural, data, ALDH2(*)2 showed a concentration-dependent increase in esterase, activity and nitroglycerin reductase activity upon addition of coenzyme, but the levels of activity do not approach those of the wild-type enzyme, or that of the R475Q enzyme. The data presented shows that Glu-487, maintains a critical function in linking the structure of the, coenzyme-binding site to that of the active site through its interactions, with Arg-264 and Arg-475, and in doing so, creates the stable structural, scaffold conducive to catalysis. | The common mitochondrial aldehyde dehydrogenase (ALDH2) ALDH2(*)2, polymorphism is associated with impaired ethanol metabolism and decreased, efficacy of nitroglycerin treatment. These physiological effects are due, to the substitution of Lys for Glu-487 that reduces the k(cat) for these, processes and increases the K(m) for NAD(+), as compared with ALDH2. In, this study, we sought to understand the nature of the interactions that, give rise to the loss of structural integrity and low activity in, ALDH2(*)2 even when complexed with coenzyme. Consequently, we have solved, the crystal structure of ALDH2(*)2 complexed with coenzyme to 2.5A(.) We, have also solved the structures of a mutated form of ALDH2 where Arg-475, is replaced by Gln (R475Q). The structural and functional properties of, the R475Q enzyme are intermediate between those of wild-type and the, ALDH2(*)2 enzymes. In both cases, the binding of coenzyme restores most of, the structural deficits observed in the apoenzyme structures. The binding, of coenzyme to the R475Q enzyme restores its structure and catalytic, properties to near wild-type levels. In contrast, the disordered helix, within the coenzyme binding pocket of ALDH2(*)2 is reordered, but the, active site is only partially reordered. Consistent with the structural, data, ALDH2(*)2 showed a concentration-dependent increase in esterase, activity and nitroglycerin reductase activity upon addition of coenzyme, but the levels of activity do not approach those of the wild-type enzyme, or that of the R475Q enzyme. The data presented shows that Glu-487, maintains a critical function in linking the structure of the, coenzyme-binding site to that of the active site through its interactions, with Arg-264 and Arg-475, and in doing so, creates the stable structural, scaffold conducive to catalysis. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Alcohol intolerance, acute OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=100650 100650]], Fetal alcohol syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=100650 100650]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2ONM is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NA, ADP, NAD, EDO and GAI as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Aldehyde_dehydrogenase_(NAD(+)) Aldehyde dehydrogenase (NAD(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.1.3 1.2.1.3] Full crystallographic information is available from [http:// | + | 2ONM is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NA:'>NA</scene>, <scene name='pdbligand=ADP:'>ADP</scene>, <scene name='pdbligand=NAD:'>NAD</scene>, <scene name='pdbligand=EDO:'>EDO</scene> and <scene name='pdbligand=GAI:'>GAI</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Aldehyde_dehydrogenase_(NAD(+)) Aldehyde dehydrogenase (NAD(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.1.3 1.2.1.3] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ONM OCA]. |
==Reference== | ==Reference== | ||
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[[Category: rossman fold]] | [[Category: rossman fold]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:04:15 2008'' |
Revision as of 13:04, 23 January 2008
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Human Mitochondrial Aldehyde Dehydrogenase Asian Variant, ALDH2*2, complexed with NAD+
Overview
The common mitochondrial aldehyde dehydrogenase (ALDH2) ALDH2(*)2, polymorphism is associated with impaired ethanol metabolism and decreased, efficacy of nitroglycerin treatment. These physiological effects are due, to the substitution of Lys for Glu-487 that reduces the k(cat) for these, processes and increases the K(m) for NAD(+), as compared with ALDH2. In, this study, we sought to understand the nature of the interactions that, give rise to the loss of structural integrity and low activity in, ALDH2(*)2 even when complexed with coenzyme. Consequently, we have solved, the crystal structure of ALDH2(*)2 complexed with coenzyme to 2.5A(.) We, have also solved the structures of a mutated form of ALDH2 where Arg-475, is replaced by Gln (R475Q). The structural and functional properties of, the R475Q enzyme are intermediate between those of wild-type and the, ALDH2(*)2 enzymes. In both cases, the binding of coenzyme restores most of, the structural deficits observed in the apoenzyme structures. The binding, of coenzyme to the R475Q enzyme restores its structure and catalytic, properties to near wild-type levels. In contrast, the disordered helix, within the coenzyme binding pocket of ALDH2(*)2 is reordered, but the, active site is only partially reordered. Consistent with the structural, data, ALDH2(*)2 showed a concentration-dependent increase in esterase, activity and nitroglycerin reductase activity upon addition of coenzyme, but the levels of activity do not approach those of the wild-type enzyme, or that of the R475Q enzyme. The data presented shows that Glu-487, maintains a critical function in linking the structure of the, coenzyme-binding site to that of the active site through its interactions, with Arg-264 and Arg-475, and in doing so, creates the stable structural, scaffold conducive to catalysis.
About this Structure
2ONM is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Active as Aldehyde dehydrogenase (NAD(+)), with EC number 1.2.1.3 Full crystallographic information is available from OCA.
Reference
Structural and functional consequences of coenzyme binding to the inactive asian variant of mitochondrial aldehyde dehydrogenase: roles of residues 475 and 487., Larson HN, Zhou J, Chen Z, Stamler JS, Weiner H, Hurley TD, J Biol Chem. 2007 Apr 27;282(17):12940-50. Epub 2007 Feb 27. PMID:17327228
Page seeded by OCA on Wed Jan 23 15:04:15 2008
Categories: Aldehyde dehydrogenase (NAD(+)) | Homo sapiens | Single protein | Hurley, T.D. | Larson, H.N. | ADP | EDO | GAI | NA | NAD | Aldh | Nad | Oxidoreductase | Rossman fold
