title: S-adenosyl-homocysteine is a weakly bound inhibitor for a flaviviral methyltransferase.
abstract: The methyltransferase enzyme (MTase), which catalyzes the transfer of a methyl group from S-adenosyl-methionine (AdoMet) to viral RNA, and generates S-adenosyl-homocysteine (AdoHcy) as a by-product, is essential for the life cycle of many significant human pathogen flaviviruses. Here we investigated inhibition of the flavivirus MTase by several AdoHcy-derivatives. Unexpectedly we found that AdoHcy itself barely inhibits the flavivirus MTase activities, even at high concentrations. AdoHcy was also shown to not inhibit virus growth in cell-culture. Binding studies confirmed that AdoHcy has a much lower binding affinity for the MTase than either the AdoMet co-factor, or the natural AdoMet analog inhibitor sinefungin (SIN). While AdoMet is a positively charged molecule, SIN is similar to AdoHcy in being uncharged, and only has an additional amine group that can make extra electrostatic contacts with the MTase. Molecular Mechanics Poisson-Boltzmann Sovation Area analysis on AdoHcy and SIN binding to the MTase suggests that the stronger binding of SIN may not be directly due to interactions of this amine group, but due to distributed differences in SIN binding resulting from its presence. The results suggest that better MTase inhibitors could be designed by using SIN as a scaffold rather than AdoHcy.
authors.affiliation: Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Bing
authors.initials: B
authors.lastname: Zhou
authors.forename: Matthew
authors.initials: M
authors.lastname: Brecher
authors.forename: Nilesh
authors.initials: N
authors.lastname: Banavali
authors.forename: Susan A
authors.initials: SA
authors.lastname: Jones
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Dilip
authors.initials: D
authors.lastname: Nag
authors.forename: Laura D
authors.initials: LD
authors.lastname: Kramer
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Hongmin
authors.initials: H
authors.lastname: Li
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology*; D005416:Flavivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D012435:S-Adenosylhomocysteine / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology*; D014902:West Nile virus / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D012435:S-Adenosylhomocysteine; D008780:Methyltransferases; D000241:Adenosine; C006235:sinefungin