Structure and function of S-adenosylhomocysteine hydrolase.
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 degrees rigid body movement of the catalytic domain occurs upon inhibitor/substrate binding.
Turner
M A
MA
Structural Biology and Biochemistry, Hospital for Sick Children,Toronto, ON, Canada.
Yang
X
X
Yin
D
D
Kuczera
K
K
Borchardt
R T
RT
Howell
P L
PL
D043383:Adenosylhomocysteinase; D000595:Amino Acid Sequence; D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D008322:Mammals; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000977:Antiparasitic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006867:Hydrolases; D043383:Adenosylhomocysteinase