The Mechanism of Orotidine 5‘-Monophosphate Decarboxylase:  Catalysis by Destabilization of the Substrate

Feng, Wan Yong; Austin, Travis J.; Chew, Frank; Gronert, Scott; Wu, Weiming

doi:10.1021/bi992553w

Cited by 56 publications

(82 citation statements)

References 28 publications

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…[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%

Section: Introductionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

“…On the other hand, the two-step mechanism shown in Scheme 2 was able to account for the large difference in the reaction rates. 1,7 We are currently investigating each individual step in the proposed mechanism.…”

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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%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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Crystal Structures of Orotidine Monophosphate Decarboxylase: Does the Structure Reveal the Mechanism of Nature's Most Proficient Enzyme?

Houk¹,

Lee²,

Tantillo³

et al. 2001

ChemBioChem

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The mystery of proficiency remains: The recently solved crystal structures of free orotidine monophosphate decarboxylase (ODCase) and of the enzyme in complex with inhibitors reveal unusual structural features. However, despite the similarities among the structures, several startling new mechanisms of action have been proposed to explain how ODCase achieves its spectacular catalytic proficiency in catalyzing the decarboxylation of OMP (1) to UMP (2). R = ribose 5′‐monophosphate.

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The most proficient enzyme as the central theme in an integrated, research‐based biochemistry laboratory course

Smiley

2002

Biochem Molecular Bio Educ

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The enzyme orotidine-5-monophosphate decarboxylase is an attractive choice for the central theme of an integrated, research-based biochemistry laboratory course. A series of laboratory exercises common to most instructional laboratories, including enzyme assays, protein purification, enzymatic characterization, elementary kinetics, and recombinant DNA methods, has been devised. The series of exercises requires biochemical instrumentation common to most laboratories and some specialized materials available from the author's institution to laboratory instructors.

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The Mechanism of Orotidine 5‘-Monophosphate Decarboxylase: Catalysis by Destabilization of the Substrate

Cited by 56 publications

References 28 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

Crystal Structures of Orotidine Monophosphate Decarboxylase: Does the Structure Reveal the Mechanism of Nature's Most Proficient Enzyme?

The most proficient enzyme as the central theme in an integrated, research‐based biochemistry laboratory course

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