Electrostatic stabilization can explain the unexpected acidity of carbon acids in enzyme-catalyzed reactions

Guthrie, J. Peter; Kluger, Ronald

doi:10.1021/ja00077a063

Cited by 154 publications

(154 citation statements)

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“…In particular, if the ratio ln(H/T)/ln(D/T) is significantly larger than 3.3 this would indicate that transfer of the lighter proton has a substantial contribution from tunneling. Another useful probe of tunneling effects is the temperature dependence of KIEs (25,26,28). As far as the ratio ln(H/ T)/ln(D/T) is concerned, we obtain here values of 4.8 Ϯ 1.0, 3.2 Ϯ 0.3, and 3.4 for the enzyme, solution, and ab initio gas phase reactions, respectively.…”

Section: Resultsmentioning

confidence: 75%

Computer Simulation of Primary Kinetic Isotope Effects in the Proposed Rate-limiting Step of the Glyoxalase I Catalyzed Reaction

Feierberg

Luzhkov²,

Åqvist

2000

Journal of Biological Chemistry

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The proposed rate-limiting step of the glyoxalase I catalyzed reaction is the proton abstraction from the C1 carbon of the substrate by Glu 172 . Here we examine primary kinetic isotope effects and the influence of quantum dynamics on this process by computer simulations. The calculations utilize the empirical valence bond method in combination with the molecular dynamics free energy perturbation technique and path integral simulations. For the enzyme-catalyzed reaction a H/D kinetic isotope effect of 5.0 ؎ 1.3 is predicted in reasonable agreement with the experimental result of about 3. Furthermore, the magnitude of quantum mechanical effects is found to be very similar for the enzyme reaction and the corresponding uncatalyzed process in solution, in agreement with other studies. The problems associated with attaining the required accuracy in order for the present approach to be useful as a diagnostic tool for the study of enzyme reactions are also discussed.

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Section: Resultsmentioning

confidence: 75%

Computer Simulation of Primary Kinetic Isotope Effects in the Proposed Rate-limiting Step of the Glyoxalase I Catalyzed Reaction

Feierberg

Luzhkov²,

Åqvist

2000

Journal of Biological Chemistry

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“…This fact has been gaining increasingly wider recognition, due, in part, to mutation experiments (6, 7) that confirmed earlier theoretical estimates of the catalytic HBs and the prediction that ''preorganized local dipoles'' (e.g., HBs and carbonyls) are very important in TS stabilization (8-10). However, the physical reasons for the importance of catalytic HBs are apparently still subject to debate (3)(4)(5)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Energy considerations show that low-barrier hydrogen bonds do not offer a catalytic advantage over ordinary hydrogen bonds

Warshel

Papazyan

1996

Proc. Natl. Acad. Sci. U.S.A.

191

199

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Low-barrier hydrogen bonds have recently been proposed as a major factor in enzyme catalysis. Here we evaluate the feasibility of transition state (TS) stabilization by low-barrier hydrogen bonds in enzymes. Our analysis focuses on the facts that (i) a low-barrier hydrogen bond is less stable than a regular hydrogen bond in water, (ii) TSs are more stable in the enzyme active sites than in water, and (iii) a nonpolar active site would destabilize the TS relative to its energy in water. Combining these points and other experimental and theoretical facts in a physically consistent framework shows that a low-barrier hydrogen bond cannot stabilize the TS more than an ordinary hydrogen bond. The reason for the large catalytic effect of active site hydrogen bonds is that their formation entails a lower reorganization energy than their solution counterparts, due to the preorganized enzyme environment.The origin of the enormous catalytic power of enzymes is a problem of great fundamental and practical importance. It is becoming increasingly clear that this catalytic power is mainly due to transition state (TS) stabilization, but there is yet to be a consensus on how the stabilization is provided. The uncatalyzed versions of reactions that are catalyzed by enzymes often proceed extremely slowly in aqueous solution. Associating the polarity of water with this slowness, a nonpolar environment has often been thought to be necessary for accelerating those reactions (1, 2). This has lead to proposals of enzymatic reaction mechanisms that are viable only in nonpolar media, whereas enzyme active sites are usually polar. One such proposal suggests that the enzyme forms a partial covalent bond with the ionic TS through a low-barrier hydrogen bond (LBHB) that is stabilized by quantum resonance interactions (3-5). Hydrogen bonds (HBs) do contribute substantially to enzyme catalysis. This fact has been gaining increasingly wider recognition, due, in part, to mutation experiments (6, 7) that confirmed earlier theoretical estimates of the catalytic HBs and the prediction that ''preorganized local dipoles'' (e.g., HBs and carbonyls) are very important in TS stabilization (8-10). However, the physical reasons for the importance of catalytic HBs are apparently still subject to debate (3)(4)(5)(11)(12)(13)(14)(15).Using a valence bond (VB) description of hydrogen bonding and analyzing energetic requirements, we conclude that LBHBs do not offer extra TS stabilization over regular HBs. This conclusion is independent of specific computational or experimental methodologies, although they are used to provide examples, hopefully making the arguments clearer. Hydrogen BondingBelow we define ordinary HB (OHB) and LBHB in a way that will hopefully make the analysis amenable to a clear discussion. Note that terms such as ''short'' or ''low-barrier'' by themselves do not add any new physics to the regular HB description-i.e., they cannot define a new kind of HB. As we describe below, the only relevant and novel concept introduced by LBHBs is...

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“…This might be achieved with a positively charged amino acid residue at the active site binding to the carboxylate group or through binding of a metal cation. 10,12,13 Although, in chemical terms, abstraction of an acidic proton at the aposition of the methyl ester is expected, the esterification of the carboxylate group in C-OMe might alter the interaction of anion-stabilizing elements in an enzymatic reaction, adversely impacting catalysis. Kinetic studies show that the K m on C-OMe is comparable to that for CS-A and lower than that observed on chondroitin (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Chondroitin O-methyl ester: an unusual substrate for chondroitin AC lyase

Avci

Toida

Linhardt

2003

Carbohydrate Research

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Electrostatic stabilization can explain the unexpected acidity of carbon acids in enzyme-catalyzed reactions

Cited by 154 publications

References 0 publications

Computer Simulation of Primary Kinetic Isotope Effects in the Proposed Rate-limiting Step of the Glyoxalase I Catalyzed Reaction

Computer Simulation of Primary Kinetic Isotope Effects in the Proposed Rate-limiting Step of the Glyoxalase I Catalyzed Reaction

Energy considerations show that low-barrier hydrogen bonds do not offer a catalytic advantage over ordinary hydrogen bonds

Chondroitin O-methyl ester: an unusual substrate for chondroitin AC lyase

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