Equilibrium of Formation of the 6-Carbanion of UMP, a Potential Intermediate in the Action of OMP Decarboxylase

Sievers, Annette; Wolfenden, Richard

doi:10.1021/ja021073g

Cited by 55 publications

(66 citation statements)

References 19 publications

(36 reference statements)

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“…[1][2][3][4][5][6][7][8][9][10][11][12] Most of the studies involve the investigation of the nature and stability of the intermediate. As shown in Scheme 1, acid 1 decarboxylates at elevated temperatures to give 1,3-dimethyluracil (2) as the sole product.…”

Section: Introductionmentioning

confidence: 99%

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Stability of the 6-Carbanion of Uracil Analogues: Mechanistic Implications for Model Reactions of Orotidine-5‘-monophosphate Decarboxylase

Wong

Capule

2006

Org. Lett.

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The pK a 's of the 6-CH groups of N-methyl-2-pyridone and N-methyl-4-pyridone in aqueous solution were determined. No correlation between the stability of the carbanions and the rate of decarboxylation of corresponding carboxylic acids was found.The decarboxylation of 1,3-dimethylorotic acid (1) and its analogues has been proven to be a useful model for the enzymatic decarboxylation catalyzed by orotidine-5'-monophosphate decarboxylase (ODCase). [1][2][3][4][5][6][7][8][9][10][11][12] Most of the studies involve the investigation of the nature and stability of the intermediate. As shown in Scheme 1, acid 1 decarboxylates at elevated temperatures to give 1,3-dimethyluracil (2) as the sole product.The decarboxylation of acids 1, 4 and 5 to uracil 2 and pyridones 6 and 7 (Figure 1), respectively, provides a unique opportunity to systematically investigate the mechanism of the reactions due to the large difference in their reaction rates despite their structural similarity. 1,6,7 Acids 1 and 4 decarboxylate at the same rate, while acid 5 decarboxylates almost 3000 times faster. 1,7 Studies on the gas-phase stability of the corresponding carbanions 3, 8, and 9 have established a lack of correlation between the rate of decarboxylation and the gas-phase stability of resulted carbanions. 7 It was found that carbanion 3 is much more stable while carbanions 8 and 9 share the same stability. 6,7 As a result, a two-step mechanism has been proposed to account for the large difference in rate constants measured for acids 1, 4, and 5 (Scheme 2). 1,7 In this mechanism, the large differences in the equilibrium constants explain the differences in rate constants.The pK a of uracil 2 in water has been determined to be 34 ± 2, which is suggested to be the evidence for the high reaction barrier for catalysis by ODCase. 8 However, our gas-phase study has demonstrated that the stability of the carbanionic intermediates does not correlate with the rate of decarboxylation. 7 One concern about gas-phase studies is that the results may not represent those in condensed phase. In condensed phase, solvation plays a major rule in the wuw@sfsu.edu. relative stability of species, especially ions. In this report, we have extended the study on the stability of carbanions 3, 8, and 9 to the aqueous solution. NIH Public AccessAuthor Manuscript Org Lett. Author manuscript; available in PMC 2009 September 14.Richard and coworkers have determined pK a of weak carbon acids in aqueous solution by measuring the rate of proton-deuterium exchange on interested carbons using NMR spectroscopy. 13,14 This method was employed by Sievers and Wolfenden in determining the pK a of 6-CH of uracil 2. 8 However, when pyridones 6 and 7 were heated in acetate buffer in D 2 O as reported for 2, no proton-deuterium exchange was observed after 5 hrs. This observation indicates that pyridones 6 and 7 are less acidic than uracil 2 at carbon-6 and a much stronger base is required. Proton-deuterium exchange on carbon-6 of pyridones 6 and 7 has been reported in NaOD/D ...

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Section: Introductionmentioning

confidence: 99%

“…A rate constant of 10 11 s −1 was employed for the reaction between the carbanion and water, k HOH , as in the case of uracil 2. 8 The pK a values of the 6-CH groups of both pyridones 6 and 7 are thus estimated to be 32 ± 2, using equation 1.(1) …”

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confidence: 99%

Stability of the 6-Carbanion of Uracil Analogues: Mechanistic Implications for Model Reactions of Orotidine-5‘-monophosphate Decarboxylase

Wong

Capule

2006

Org. Lett.

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“…This result has further demonstrated that there is a lack of correlation between the stability of the carbanion and the rate of the decarboxylation (see Table 1). However, the values from two separate studies on uracil 4 do not agree with each other very well [12,13]. The two studies were carried out using the same kinetic method but under somewhat different conditions due to the chemical reactivity of 4 [13].…”

Section: Resultsmentioning

confidence: 93%

“…The pK a values of the 6-CH groups of compounds 4-6 in water were determined in order to estimate the stability of carbanions 7-9 in aqueous medium [12,13]. Unfortunately, the pK a values determined for uracil 4 in two separate studies were not consistent as shown in Table 1 [12,13]. In this study, we report the estimated pK a values determined in DMSO, a solvent with similar properties to that employed in kinetic measurement of the decarboxylation reactions, sulfolane.…”

Section: Introductionmentioning

confidence: 99%

Carbanions from decarboxylation of orotate analogs: Stability and mechanistic implications

Yeoh

Cuasito

Capule

et al. 2007

Bioorganic Chemistry

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“…9 However, when pyridones 5 and 6 were treated under the same conditions, no proton-deuterium exchange was observed, indicating that carbanions 8 and 9 are less stable than carbanion 7 . The rates of proton-deuterium exchange were eventually determined over the temperature range of 80–110 °C in 1 N NaOD/D 2 O and the results are summarized in Table 2.…”

Section: Resultsmentioning

confidence: 97%

Stabilities of uracil and pyridone-based carbanions: a systematic study in the gas phase and solution and implications for the mechanism of orotidine-5′-monophosphate decarboxylase

et al. 2013

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The stabilities of the C6-centered carbanions derived from 1,3-dimethyluracil, N-methyl-2-pyridone, and N-methyl-4-pyridone were systematically investigated in the gas phase and in DMSO and water solutions. The stabilities of the carbanions in the gas phase and DMSO were directly measured through their reactions with carbon acids with known proton affinity or pKa values. The stabilities of the carbanions in DMSO were also probed through their kinetic isotope effects of protonation over deuteriation using acids with different acidity. The stabilities of the carbanions in water were determined through the rates of hydrogen-deuterium exchange reactions of the corresponding conjugate acids. The carbanions derived from the two pyridones were found to have the same stability, whereas the carbanion derived from 1,3-dimethyluracil was more stable. The order of the stability of the carbanions showed no correlation with the decarboxylation rates of their corresponding carboxylic acids. The implications of the results for the mechanism of orotidine-5′-monophosphate decarboxylase (ODCase) are discussed.

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Equilibrium of Formation of the 6-Carbanion of UMP, a Potential Intermediate in the Action of OMP Decarboxylase

Cited by 55 publications

References 19 publications

Stability of the 6-Carbanion of Uracil Analogues: Mechanistic Implications for Model Reactions of Orotidine-5‘-monophosphate Decarboxylase

Stability of the 6-Carbanion of Uracil Analogues: Mechanistic Implications for Model Reactions of Orotidine-5‘-monophosphate Decarboxylase

Carbanions from decarboxylation of orotate analogs: Stability and mechanistic implications

Stabilities of uracil and pyridone-based carbanions: a systematic study in the gas phase and solution and implications for the mechanism of orotidine-5′-monophosphate decarboxylase

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