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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2001-7-26
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pubmed:databankReference |
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pubmed:abstractText |
Nitric oxide synthase is inhibited by asymmetric NG-methylated derivatives of arginine whose cellular levels are controlled in part by dimethylarginine dimethylaminohydrolase (DDAH, EC 3.5.3.18). Levels of asymmetric NG,NG-dimethylarginine (ADMA) are known to correlate with certain disease states. Here, the first structure of a DDAH shows an unexpected similarity to arginine:glycine amidinotransferase (EC 2.1.4.1) and arginine deiminase (EC 3.5.3.6), thus defining a superfamily of arginine-modifying enzymes. The identification of a Cys-His-Glu catalytic triad and the structures of a Cys to Ser point mutant bound to both substrate and product suggest a reaction mechanism. Comparison of the ADMA-DDAH and arginine-amidinotransferase complexes reveals a dramatic rotation of the substrate that effectively maintains the orientation of the scissile bond of the substrate with respect to the catalytic residues. The DDAH structure will form a basis for the rational design of selective inhibitors, which are of potential use in modulating NO synthase activity in pathological settings.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1072-8368
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
8
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
679-83
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:11473257-Amidohydrolases,
pubmed-meshheading:11473257-Amino Acid Sequence,
pubmed-meshheading:11473257-Amino Acid Substitution,
pubmed-meshheading:11473257-Binding Sites,
pubmed-meshheading:11473257-Catalysis,
pubmed-meshheading:11473257-Citrulline,
pubmed-meshheading:11473257-Crystallography, X-Ray,
pubmed-meshheading:11473257-Dimerization,
pubmed-meshheading:11473257-Enzyme Inhibitors,
pubmed-meshheading:11473257-Humans,
pubmed-meshheading:11473257-Hydrogen Bonding,
pubmed-meshheading:11473257-Hydrolases,
pubmed-meshheading:11473257-Hydrolysis,
pubmed-meshheading:11473257-Ligands,
pubmed-meshheading:11473257-Models, Molecular,
pubmed-meshheading:11473257-Molecular Sequence Data,
pubmed-meshheading:11473257-Nitric Oxide Synthase,
pubmed-meshheading:11473257-Point Mutation,
pubmed-meshheading:11473257-Protein Structure, Quaternary,
pubmed-meshheading:11473257-Protein Structure, Tertiary,
pubmed-meshheading:11473257-Rotation,
pubmed-meshheading:11473257-Sequence Alignment,
pubmed-meshheading:11473257-Substrate Specificity
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pubmed:year |
2001
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pubmed:articleTitle |
Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase.
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pubmed:affiliation |
School of Crystallography, Birkbeck, Malet Street, London WC1E 7HX, UK.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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