General-acid catalysis of imidazolidine ring opening. The hydrolysis of ethyl N,N'-[1-(p-(dimethylamino)phenyl)propenediyl]-p-[((2-tetrahydroquinolinyl)methylene)amino]denzoate

Fife, Thomas H.; Pellino, August M.

doi:10.1021/ja00395a034

Cited by 14 publications

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“…Presumably, an activated form of the cofactor, such as the ¡minium ion 5-CH2=H4folate, is the electrophilic species in this condensation reaction (Kallen & Jencks, 1966;Benkovic & Bullard, 1973). An acidic group on the enzyme was proposed to catalyze opening of the imidazolidine ring of CH2-H4folate by protonation at N-10 (Benkovic, 1980; Fife & Pellino, 1981). A basic group on the enzyme was postulated to abstract a proton from C-5 of dUMP.…”

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confidence: 99%

Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthase

Finer-Moore¹,

Montfort²,

Stroud³

1990

Biochemistry

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The structures of thymidylate synthase (TS) from Escherichia coli, in ternary complexes with substrate and an analogue of the cofactor, are the basis of a stereochemical model for a key reaction intermediate in the catalyzed reaction. This model is used to compare the reaction chemistry and chirality of the transferred methyl group with structures of the components, to identify those residues that participate, and to propose a stereochemical mechanism for catalysis by TS. Effects of chemical modification of specific amino acid residues and site-directed mutations of residues are correlated with structure and effects on enzyme mechanism. The ordered binding sequence of substrate deoxyuridine monophosphate and methylenetetrahydrofolate can be understood from the structure, where each forms a large part of the binding site for the other. The catalytic site serves to orient the reactants, which are sequestered along with many water molecules within a cavernous active center. Conformational changes during the reaction could involve nearby residues in ways that are not obvious in this complex.

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confidence: 99%

Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthase

Finer-Moore¹,

Montfort²,

Stroud³

1990

Biochemistry

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“…Cleavage of unsymmetrical imidazolidines23 and the reduction of methylenetetrahydrofolic acid and its analogues24 also with departure of the less basic amine as a consequence of the dominant role of electron donation and positive-charge development on the remaining amine. However, these reactions are complicated by the presence of general-acid catalysis of imidazoline cleavage, which has been attributed to a concerted reaction mechanism, 23 and the probability that the preferred direction of reduction reflects the equilibrium constants rather than the rate constants for bond cleavage,24 which would certainly favor formation of the iminium ion of the more basic amine. The methoxyaminolysis of formamidines gives expulsion of the more basic amine, but in this reaction the product-determining step is the protonation of the amine, not C-N cleavage, so that the more basic amine is preferentially protonated and expelled.10 The transiminations of p-methoxybenzaldehyde and benzophenone imines with hydroxylamine proceed with rate-determining proton removal from HONH2+ in the addition intermediate.…”

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confidence: 99%