Abstract:
:The reactions of a ribonuclease model substrate, the compound uridine-3'-p-nitrophenyl phosphate, have been examined using heavy-atom isotope effects and stereochemical analysis. The cyclization of this compound is subject to catalysis by general base (by imidazole buffer), specific base (by carbonate buffer), and by acid. All three reactions proceed by the same mechanistic sequence, via cyclization to cUMP, which is stable under basic conditions but which is rapidly hydrolyzed to a mixture of 2'- and 3'-UMP under acid conditions. The isotope effects indicate that the specific base-catalyzed reaction exhibits an earlier transition state with respect to bond cleavage to the leaving group compared to the general base-catalyzed reaction. Stereochemical analysis indicates that both of the base-catalyzed reactions proceed with the same stereochemical outcome. It is concluded that the difference in the nucleophile in the two base-catalyzed reactions results in a difference in the transition state structure but both reactions are most likely concerted, with no phosphorane intermediate. The (15)N isotope effects were also measured for the reaction of the substrate with ribonuclease A. The results indicate that considerably less negative charge develops on the leaving group in the transition state than for the general base-catalyzed reaction in solution. Copyright 2000 Academic Press.
journal_name
Bioorg Chemjournal_title
Bioorganic chemistryauthors
Hengge AC,Bruzik KS,Tobin AE,Cleland WW,Tsai MDdoi
10.1006/bioo.2000.1170subject
Has Abstractpub_date
2000-06-01 00:00:00pages
119-133issue
3eissn
0045-2068issn
1090-2120pii
S0045-2068(00)91170-2journal_volume
28pub_type
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