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Structure and function of S-adenosylhomocysteine hydrolase

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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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  1. Mary A. Turner

    Present address: Structural Biology and Biochemistry, Hospital for Sick Children, 5555 University Avenue, M5G 1X8, Toronto, ON, Canada

Authors and Affiliations

  1. Structural Biology and Biochemistry, Hospital for Sick Children, 5555 University Avenue, M5G 1X8, Toronto, ON, Canada

    P. Lynne Howell

  2. Department of Molecular Biosciences, University of Kansas, 66045, Lawrence, KS

    Xiaoda Yang, Dan Yin & Ronald T. Borchardt

  3. Department of Pharmaceutical Chemistry, University of Kansas, 66045, Lawrence, KS

    Xiaoda Yang, Dan Yin, Krzysztof Kuczera & Ronald T. Borchardt

  4. Department of Chemistry, University of Kansas, 66045, Lawrence, KS

    Krzysztof Kuczera

  5. Department of Biochemistry, Faculty of Medicine, University of Toronto, Medical Sciences Building, M5S 1A8, Toronto, ON, Canada

    P. Lynne Howell

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Turner, M.A., Yang, X., Yin, D. et al. Structure and function of S-adenosylhomocysteine hydrolase. Cell Biochem Biophys 33, 101–125 (2000). https://doi.org/10.1385/CBB:33:2:101

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