Structure and function of S-adenosylhomocysteine hydrolase |
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Authors: | Mary A Turner Xiaoda Yang Dan Yin Krzysztof Kuczera Ronald T Borchardt P Lynne Howell |
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Institution: | (1) Present address: Structural Biology and Biochemistry, Hospital for Sick Children, 5555 University Avenue, M5G 1X8 Toronto, ON, Canada;(2) Department of Molecular Biosciences, University of Kansas, 66045 Lawrence, KS;(3) Department of Pharmaceutical Chemistry, University of Kansas, 66045 Lawrence, KS;(4) Department of Chemistry, University of Kansas, 66045 Lawrence, KS;(5) Department of Biochemistry, Faculty of Medicine, University of Toronto, Medical Sciences Building, M5S 1A8 Toronto, ON, Canada |
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Abstract: | In mammals, S-adenosylhomocysteine hydrolase (AdoHcyase) is the only known enzyme to catalyze the breakdown of S-adenosylhomocysteine
(AdoHcy) to homocysteine and adenosine. AdoHcy is the product of all adenosylmethionine (AdoMet)-dependent biological transmethylations.
These reactions have a wide range of products, and are common in all facets of biometabolism. As a product inhibitor, elevated
levels of AdoHcy suppress AdoMet-dependent transmethylations. Thus, AdoHcyase is a regulator of biological transmethylation
in general. The three-dimensional structure of AdoHcyase complexed with reduced nicotinamide adenine dinucleotide phosphate
(NADH) and the inhibitor (1′R, 2′S, 3′R)-9-(2′,3′-dihyroxycyclopenten-1-yl)adenine (DHCeA) was solved by a combination of
the crystallographic direct methods program, SnB, to determine the selenium atom substructure and by treating the multiwavelength anomalous diffraction data as a special
case of multiple isomorphous replacement. The enzyme architecture resembles that observed for NAD-dependent dehydrogenases,
with the catalytic domain and the cofactor binding domain each containing a modified Rossmann fold. The two domains form a
deep active site cleft containing the cofactor and bound inhibitor molecule. A comparison of the inhibitor complex of the
human enzyme and the structure of the rat enzyme, solved without inhibitor, suggests that a 17° rigid body movement of the
catalytic domain occurs upon inhibitor/substrate binding. |
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Keywords: | Adenosine (Ado) Ado kinase(AK) Homocysteine (Hcy) Neplanocin A (Nep A) S-adenosylhomocysteine (AdoHcy) S-adenosylhomocysteine hydrolase (AdoHcyase) Transmethylations |
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