Formation of DNA Adducts with Cholyl Adenylate, a Putative Intermediate for Biosynthesis of Cholyl-CoA

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• 作者：Takeji Takamura-Enya ; Nariyasu Mano ; Nobuo Kawahara ; Junichi Goto ; and Keiji Wakabayashi
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：November 2005
• 年：2005
• 卷：18
• 期：11
• 页码：1715 - 1720
• 全文大小：122K
• 年卷期：v.18,no.11(November 2005)
• ISSN：1520-5010

文摘

Cholyl adenylate is a putative intermediate for biosynthesis of cholic acid-coenzyme A (CoA)thioester conjugates by acyl-CoA synthetase. Early studies showed the conjugated acidanhydride moiety of cholyl adenylate to be reactive, attacking proteins to form protein-cholicacid adducts. In the present study, to clarify reactions of cholyl adenylate with DNA underphysiological conditions, products with nucleosides were analyzed. HPLC-MS analyses indicatedcholyl adenylate to primarily attack hydroxy groups of ribose moieties of nucleosides. Moreover,as speculated from UV and MS studies, exocyclic amino groups of 2'-deoxycytidine and 2'-deoxyadenosine were found to serve as targets of cholyl adenylate; the corresponding cholicamides, N⁴-cholyl-2'-deoxycytidine and N⁶-cholyl-2'-deoxyadenosine, were formed at yields of0.32 and 0.06%, respectively. Structures of these base modified adducts were confirmed bydirect comparison with synthetic compounds obtained from coupling reactions of cholic acidwith each nucleoside in the presence of dicyclohexylcarbodiimide in pyridine at 70 C. N⁴-Cholyl-2'-deoxycytidine was also obtained at a level of 1.6 adducts per 10⁵ nucleosides fromenzymatic hydrolysates of calf thymus DNA reacted with cholyl adenylate. These results suggestthat cholyl adenylate, released from CoA synthetase, may have some possibility as a DNAmodifier in vivo.