Copper Ions Inhibit S-Adenosylhomocysteine Hydrolase by Causing Dissociation of NAD+ Cofactor

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• 作者：Mengyao Li ; Yanjie Li ; Jiejin Chen ; Wei Wei ; Xiaowei Pan ; Jing Liu ; Qingyu Liu ; Wei Leu ; Liangren Zhang ; Xiaoda Yang ; Jingfen Lu ; Kui Wang
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：October 16, 2007
• 年：2007
• 卷：46
• 期：41
• 页码：11451 - 11458
• 全文大小：366K
• 年卷期：v.46,no.41(October 16, 2007)
• ISSN：1520-4995

文摘

S-Adenosylhomocysteine hydrolase (SAHH) regulates biomethylation and homocysteinemetabolism and thus is an attractive target in drug design studies. SAHH has been shown to be a copperbinding protein in vivo; however, the structure and catalytic mechanism of SAHH exclude a role forCu²⁺. In the present work, we studied the mechanism of inhibition of SAHH activity by Cu²⁺. Theexperimental results showed that Cu²⁺ inhibited SAHH activity in a noncompetitive manner. Binding ofCu²⁺ to SAHH resulted in the release of NAD⁺ cofactors, explaining the loss of the enzymatic activityof SAHH. Further investigation by an ESR probe and computational simulation suggested that Cu²⁺ couldbind at the central channel and interrupt the subunit interactions of SAHH, resulting in a large decreasein affinity to the NAD⁺ cofactor. This effect of Cu²⁺ resembled that of enzyme mutations at the C-terminaldomain or Asp244 [Komoto, J., Huang, Y., Gomi, T., Ogawa, H., Takata, Y., Fujioka, M., and Takusagawa,F. (2000) Effects of site-directed mutagenesis on structure and function of recombinant rat liverS-adenosylhomocysteine hydrolase. Crystal structure of D244E mutant enzyme, J. Biol. Chem. 275, 32147-32156]. The mechanism of action of Cu²⁺ on SAHH suggested a possible regulative role for Cu²⁺ on theintracellular activity of SAHH. This could be helpful in understanding the biological effects of coppercompounds and suggest a potential coupling mechanism between biomethylation and the redox states ofcells.