Mechanisms of Nucleophilic Substitution in Phosphate Esters

Cox, James R.; Ramsay, O. Bertrand

doi:10.1021/cr60230a001

Cited by 340 publications

(206 citation statements)

References 117 publications

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“…At 373 K, the energy of activation to hydrolysis, AE, for the methyl phosphate, glycerol-1 -phosphate, and glucose-1 -phosphate monoanions is close to 126 kJ1mol for all compounds with corresponding preexponential factors, A, (for k = A exp AEIRT), of 6.5 x lo1* s-I, 4.3 x 10" s-I, and 5.0 x lo1* s-' (45). For methyl phosphate the rate constant for hydrolysis is 8.2 x lo4 s-I compared to 6.1 x lo4 s-' for ethyl phosphate.…”

Section: Discussionmentioning

confidence: 85%

Influence of vanadium(V) complexes on the catalytic activity of ribonuclease A. The role of vanadate complexes as transition state analogues to reactions at phosphate

Leon-Lai¹,

Gresser²,

Tracey³

1996

Can. J. Chem.

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Abstract:The interactions of vanadate and its complexes of uridine, 5,6-dihydrouridine, and methyl P-D-ribofuranoside with bovine pancreatic ribonuclease A (RNase A) (EC 3.1.27.5) were studied by 5 1~ NMR spectroscopy and enzyme kinetics. From kinetic studies, it was found that neither inorganic vanadate nor the methyl P-D-ribofuranoside-vanadate complex significantly inhibited the RNase A catalyzed hydrolysis of uridine 2',3'-cyclic monophosphate. The NMR binding studies were in full agreement with the kinetics studies and showed that neither inorganic vanadate nor the methyl P-D-ribofuranoside-vanadate complex was bound tightly by the enzyme. Approximate binding constants were (5.0 + 1.0) x M and (3.0 + 0.6) x M for the uridine-and 5.6-dihydrouridine-vanadate complexes, respectively. An induced-fit mechanism is suggested, in which the pyrimidine subsite of the active site of RNase A must be fully occupied for the enzyme to be able to tightly bind the transition state or transition state analog. Calculation of the binding energies of vanadate complexes in ribonuclease, phosphoglycerate mutase, and phosphoglucomutase revealed an excess of binding energy over the analogous phosphate derivative of about 25 kJ/mol for all enzymes, even though the binding constants themselves varied by about six orders of magnitude. This energy represents about 40% of that expected to be available for a trigonal-bipyramidal transition state and requires a reassessment of the role of vanadate as a transition state analogue for phosphate transfer.Key words: vanadate, ribonuclease, transition state, binding constants, phosphate analogues, kinetics.Resum6 : Faisant appel a la spectrscopie RMN du 5 1~ et de la cinCtique des enzymes, on a CtudiC les interactions entre le vanadate et ses complexes de I'uridine, de la 5,6-dihydrouridine et du P-D-ribofuranoside de mCthyle avec la ribunuclease A du pancrCas de boeuf (RNase A) (EC 3.1.27.5). Sur la base des Ctudes cinCtiques, on a trouvC que, vis-a-vis de I'hydrolyse du monophosphate 2',3'-cyclique de I'uridine de la RNase A, ni le vanadate inorganique ni le complexe du P-D-ribofuranoside de mCthyle-vanadate n'inhibent cette rCaction d'une f a~o n significative. Les Ctudes par RMN ont montrt qu'il ne se produit aucune fixation entre ces matCriaux et elles Ctaient en parfait accord avec les ttudes cinCtiques; elles montrent aussi que ni le vanadate inorganique ni le complexe du P-D-ribofuranoside de mCthyle-vanadate ne se complexent fortement avec I'enzyme. Les constantes apparentes de fixation ont respectivement de (5,O + 1.0) x M et (3,O + 0.6) x M pour les complexes de I'uridine et du 5,6-dihydrouridine avec le vanadate. On propose un mCcanisme induit d'ajustement dans lequel il est important que tout le sous site de la pyrimidine du site actif de la RNase A soit occupC pour que I'enzyme soit capable de bien fixer 1'Ctat de transition ou son analogue. Des calculs d'Cnergie de fixation des complexes du vanadate dans la ribonucltase, la phosphoglycCratemutase ou la phosphoglucomutase ont rCvC...

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Section: Discussionmentioning

confidence: 85%

Influence of vanadium(V) complexes on the catalytic activity of ribonuclease A. The role of vanadate complexes as transition state analogues to reactions at phosphate

Leon-Lai¹,

Gresser²,

Tracey³

1996

Can. J. Chem.

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“…reaction with nucleophiles should increase as we descend Table 4 and this has been observed (7). Attempts to correlate the charge on phosphorus with ground state phenomena, such as 31P chemical shifts, P-F coupling constants and the infrared absorption of the P -> 0 bond were not successful.…”

Section: Discussionmentioning

confidence: 92%

Effect of the structure of phosphylating agents on their reaction with ethanolamine, an ambident nucleophile

Greenhalgh¹,

Heggie²,

Weinberger³

1970

Can. J. Chem.

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The reactions of a series of phosphylating agents (RRIP(0)X) with ethanolamine have been examined, and relative yields .of the products from the nucleophilic amino and hydroxyl moieties determined. In general the amount of 0-phosphylation increased as R and R' were changed from dimethylamino t h r o~~g h alkoxy to methyl and as the leaving group (X) was changed from OP(0)RR' to CN. The only exceptions occurred when R was dimethylamino and X was CI. When X was F, only 0-phosphylation was observed. Thus, a wide range of essentially continuously varying selectivities was found.The results are disc~lssed in terms of the amount of charge transfer involved in the forn~ation of the transition state which is assumed to be determined by the electrophile. When the charge transfer is small, the contributions to the activation energy of ~L I C~ factors as solvation and ionization potential of the n~~cleophile are most important, resulting in N-phosphylation. As the alnount of charge transfer increases, the energy of bond formation becomes the dominant factor and 0-phosphylation is preferred.Canadian Journal of Chemistry, 48, 1351Chemistry, 48, (1970 IntroductionResults In an earlier study (1) it was shown that, when reacted with ethanolamine in chloroform solution, phosphofluoridates give exclusively Ophosphylation whereas phosphochloridates give mainly N-phosphylation. This study has now been extended to examine the reactions of ethanolamine with a wider variety of phosphylating agents (RRIP(0)X). The compounds studied included phosphorodiamides (R = R' = Me,N), phosphoramidates (R = Me,N, R ' = EtO), phosphates (R = R ' = Pr'O), phosphonates (R = priO, R' = Me), and phospliinic compounds (R = R' = Me) in which tlie leaving group (X) was changed from F t o CI, CN, and OP(0)RR1.

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“…The investigations described by Cox and Ramsey (1964), coworkers (1996), andWolfenden andcoworkers (1998) imply the rates of hydrolysis of the dialkyl phosphates, DBP and BEHP. and the monoalkyl phosphates, MBP and EHP.…”

Section: Phosphate Ester Hydrolysismentioning

confidence: 97%

Origins of volatile organic compounds emerging from tank 241-C-106 during sluicing

Stauffer¹

1999

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Mechanisms of Nucleophilic Substitution in Phosphate Esters

Cited by 340 publications

References 117 publications

Influence of vanadium(V) complexes on the catalytic activity of ribonuclease A. The role of vanadate complexes as transition state analogues to reactions at phosphate

Influence of vanadium(V) complexes on the catalytic activity of ribonuclease A. The role of vanadate complexes as transition state analogues to reactions at phosphate

Effect of the structure of phosphylating agents on their reaction with ethanolamine, an ambident nucleophile

Origins of volatile organic compounds emerging from tank 241-C-106 during sluicing

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