Kinetics and mechanism of decarboxylation of some pyridinecarboxylic acids in aqueous solution. II

Dunn, G. E.; Thimm, H.F.

doi:10.1139/v77-185

Cited by 13 publications

(11 citation statements)

References 6 publications

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“…QAPRTase is unique among PRTases in catalyzing a decarboxylation linked to phosphoribosyl transfer. From both model studies (21) and enzyme experiments (22), the decarboxylation appears likely to occur via a hypothetical "quinolinate mononucleotide" intermediate, which is pro- † Supported by NIH Grant GM48623. * To whom correspondence should be addressed.…”

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confidence: 99%

Quinolinate Phosphoribosyltransferase: Kinetic Mechanism for a Type II PRTase

2002

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Quinolinate phosphoribosyltransferase (QAPRTase, EC 2.4.2.19) catalyzes the formation of nicotinate mononucleotide, carbon dioxide, and pyrophosphate from 5-phosphoribosyl 1-pyrophosphate (PRPP) and quinolinic acid (QA, pyridine 2,3-dicarboxylic acid). The enzyme is the only type II PRTase whose X-ray structure is known. Here we determined the kinetic mechanism of the enzyme from Salmonella typhimurium. Equilibrium binding studies show that PRPP and QA each form binary complexes with the enzyme, with K D values (53 and 21 µM, respectively) similar to their K M values (30 and 25 µM, respectively). Although neither PP i nor NAMN products bound well to the enzyme, 130-fold tighter binding of PP i (K D ) 75 µM) and NAMN (K D ) 6 µM) in a ternary complex was observed. Phthalic acid (K D ) 21 µM) and PRPP each caused a 2.5-fold tightening of the other's binding. Isotope trapping experiments indicated that the E‚QA complex is catalytically competent, whereas the E‚PRPP complex could not be trapped. Pre-steady-state kinetics gave a linear rate of NAMN formation, indicating that on-enzyme phosphoribosyl transfer chemistry is rate-determining. Isotope trapping from the steady state revealed that nearly all QA and about one-third of PRPP in ternary enzyme‚QA‚PRPP complexes could be trapped as the product. Substrate inhibition by PRPP was observed. These data demonstrate a predominantly ordered kinetic mechanism in which productive binding of quinolinic acid precedes that of PRPP. An E‚PRPP complex exists as a nonproductive side branch.

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confidence: 99%

Quinolinate Phosphoribosyltransferase: Kinetic Mechanism for a Type II PRTase

2002

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“…Displacement of the 3-position fluorine with the morpholine at rt afforded carboxylic acid 5 , which upon heating underwent decarboxylation to afford 6 . Thermal decarboxylation of 2-picolinic acids is known, but proceeds at a considerably higher temperature without the amine substituent . It is noteworthy and useful (see below) that the selectivity of room temperature displacement with morpholine is 30:1 for the 3- over the 5-position fluorine atom due to the carboxylate directing the morpholine nucleophile similar to reported amine displacements of 2,4-difluorobenzoic acids …”

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confidence: 53%

“…Thermal decarboxylation of 2-picolinic acids is known, but proceeds at a considerably higher temperature without the amine substituent. 10 It is noteworthy and useful (see below) that the selectivity of room temperature displacement with morpholine is 30:1 for the 3-over the 5-position fluorine atom due to the carboxylate directing the morpholine nucleophile similar to reported amine displacements of 2,4-difluorobenzoic acids. 11 Continuing the synthetic sequence from 6 (Scheme 2), a series of directed lithiations were carried out.…”

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confidence: 82%

Synthesis of a Tetrahydronaphthyridine Spiropyrimidinetrione DNA Gyrase Inhibiting Antibacterial Agent - Differential Substitution at all Five Carbon Atoms of Pyridine.

et al. 2014

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The synthesis of (-)-1, a potent antibacterial agent, was achieved stereoselectively in nine steps from readily available starting materials. Directed metalations were developed to assemble a pentasubstituted pyridine with appropriately positioned aldehyde and dimethylmorpholine substituents for a key tertiary amino effect reaction (T-reaction) that led to the spirocylic architecture. Ultimately, (-)-1 was isolated as the thermodynamically most favored stereoisomer.

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“…The synthesis of 3-aminopicolinic acid has been described previously (2), as have the methods of measuring rates (2) and 13C kinetic isotope effects (12 …”

Section: Methodsmentioning

confidence: 99%

“…The preceding papers in this series reported that the pH dependence of the first-order rate constants isotope effect at all pH's, both of which criteria were satisfied (1,2). However, the pH-rate profiles for 3-hydroxy-and 3-aminopicolinic acids do not have maxima at their isoelectric pH's, so they were assumed to proceed by some mechanism other than [I].…”

Section: Introductionmentioning

confidence: 99%

Kinetics and mechanism of decarboxylation of some pyridinecarboxylic acids in aqueous solution. III. 3-Hydroxy- and 3-aminopyridine-2-carboxylic acids

Dunn¹,

Thimm²,

Mohanty³

1979

Can. J. Chem.

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. Can. J. Chem. 57, 1098 (1 979).Pseudo-first-order rate constants for the decarboxylation of 3-hydroxy-and 3-aminopicolinic acids in aqueous solution at 150°C were determined and plotted as a function of acidity. Each rate profile has a maximum at an acidity well above the isoelectric point and this is attr~buted to decarboxylation of an intermediate protonated at the 2-position, analogous to the intermediates involved in the decarboxylation of salicylic and anthranilic acids. There is also a shoulder on each rate profile at a lower acidity corresponding to the isoelectric point where the Hammick ylide mechanism has a rate maximum in most picolinic acid decarboxylations. It is concluded that 3-hydroxy-and 3-aminopicolinic acids decarboxylate by the ylide mechanism at low acidity and by the protonation mechanism at higher acidities. In agreement with this interpretation, the 13C kinetic isotope effect in 3-hydroxypicolinic acid decarboxylation is 2.0% on the ylide part of the curve, 1.3% where decarboxylation of the protonated intermediate is rate determining, and drops to 0.4% in the intermediate region.Comparison of the rate constants for ylide decarboxylation with those for other 3-substituted picolinic acids shows that 3-hydroxy and 3-amino substituents facilitate decarboxylation, probably by their inductive and field effects on the developing negative charge at the 2-position of the transition state. GERALD E. DUNN, HARALD F. THIMM et RAJANI K. MOHANTY. Can. J. Chem. 57, 1098 (1979.On a determine les constantes de vitesse de pseudo-premier ordre pour la decarboxylation des acides hydroxy-3 et amino-3 picoliniques en solution aqueuse a 150°C et on a trace la courbe qui les relie a l'aciditk. Pour chaque profil de vitesse, il existe un maximum a une acidit6 bien au dessus du point isoelectrique et on I'attribue a la decarboxylation d'un intermediaire protone en position 2, analogue aux intermediaires impliques dans la decarboxylation des acides salicyclique et anthranilique. On note aussi un epaulement sur chaque profil de vitesse, a une acidlte plus basse que celle du point isoelectrique, ou la vitesse pour le mecanisme ylide de Hammick est maximale pour les decarboxylations de la plupart des acides picoliniques. On en conclut que les acides hydroxy-3 et amino-3 picoliniques se decarboxylent par un mecanisme ylide a faible acidite et par un mkcanisme de protonation a des acidites plus 6levCes. En accord avec cette interpretation, l'effet isotopique cinetique 13C observe lors de la decarboxylat~on de l'acide hydroxy-3 picolinique est &gal a 2% dans la portion ylide de la courbe, a 1.3% lorsque la decarboxylation implique un intermediaire dans 1'Ctape qui determine la vitesse et tombe a 0.4% dans la region intermediaire. Une comparaison des constantes de vitesse pour la dtcarboxylation par I'intermediaire d'ylides avec celles d'autres acides picoliniques substitues en position 3 montre que les substituants hydroxy-3 et amino-3 facilitent la decarboxylation, probablement grdce a leurs effets inductifs et de c...

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Kinetics and mechanism of decarboxylation of some pyridinecarboxylic acids in aqueous solution. II

Cited by 13 publications

References 6 publications

Quinolinate Phosphoribosyltransferase: Kinetic Mechanism for a Type II PRTase

Quinolinate Phosphoribosyltransferase: Kinetic Mechanism for a Type II PRTase

Synthesis of a Tetrahydronaphthyridine Spiropyrimidinetrione DNA Gyrase Inhibiting Antibacterial Agent - Differential Substitution at all Five Carbon Atoms of Pyridine.

Kinetics and mechanism of decarboxylation of some pyridinecarboxylic acids in aqueous solution. III. 3-Hydroxy- and 3-aminopyridine-2-carboxylic acids

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