Structural insights into the reaction mechanism of S-adenosyl-L-homocysteine hydrolase.

Yoshio Kusakabe, Masaaki Ishihara, Tomonobu Umeda, Daisuke Kuroda, Masayuki Nakanishi, Yukio Kitade, Hiroaki Gouda, Kazuo T Nakamura, Nobutada Tanaka

Scientific reports 2015

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S-adenosyl-L-homocysteine hydrolase (SAH hydrolase or SAHH) is a highly conserved enzyme that catalyses the reversible hydrolysis of SAH to L-homocysteine (HCY) and adenosine (ADO). High-resolution crystal structures have been reported for bacterial and plant SAHHs, but not mammalian SAHHs. Here, we report the first high-resolution crystal structure of mammalian SAHH (mouse SAHH) in complex with a reaction product (ADO) and with two reaction intermediate analogues-3'-keto-aristeromycin (3KA) and noraristeromycin (NRN)-at resolutions of 1.55, 1.55, and 1.65 Å. Each of the three structures constitutes a structural snapshot of one of the last three steps of the five-step process of SAH hydrolysis by SAHH. In the NRN complex, a water molecule, which is an essential substrate for ADO formation, is structurally identified for the first time as the candidate donor in a Michael addition by SAHH to the 3'-keto-4',5'-didehydroadenosine reaction intermediate. The presence of the water molecule is consistent with the reaction mechanism proposed by Palmer &Abeles in 1979. These results provide insights into the reaction mechanism of the SAHH enzyme.

Citation

Yoshio Kusakabe, Masaaki Ishihara, Tomonobu Umeda, Daisuke Kuroda, Masayuki Nakanishi, Yukio Kitade, Hiroaki Gouda, Kazuo T Nakamura, Nobutada Tanaka. Structural insights into the reaction mechanism of S-adenosyl-L-homocysteine hydrolase. Scientific reports. 2015;5:16641