Stereoelectronic Control in Enolization-Ketonization Reactions<sup>1</sup>

Corey, E. J.; Sneen, Richard A.

doi:10.1021/ja01605a013

Cited by 231 publications

(120 citation statements)

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“…Most interpretations have invoked the so-called stereoelectronic effect, originally proposed by Corey and Sneen (16) to account for the fact that deprotonation of 13-acetoxycholestan-7-one by loss of axial hydrogen is faster than deprotonation by loss of equatorial hydrogen. However, recent studies (17,18) have cast doubt on the existence of such an effect, and it is in any case uncertain whether it is large enough to account for the observed stereochemistry of base-catalyzed enolizations.…”

Section: Resultsmentioning

confidence: 99%

Role of a critical water in scytalone dehydratase-catalyzed reaction

Zheng

Bruice

1998

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

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Scytalone dehydratase (EC 4.2.1.94) catalyzes the dehydration of two important intermediates in the biosynthesis of melanin, and it functions without metal ions or any cofactors. Using molecular orbital theory, we have examined the role of a critical water molecule in the mechanism of scytalone dehydratase. The water, together with an internal hydrogen bonding, contributes significantly to the stabilization of the transition state (or the enolate intermediate). The role of two active site tyrosines (Tyr-50 and Tyr-30) is (i) to hold the critical water in place so that it may stabilize the transition state without much structural rearrangement during the catalytic reaction, and (ii) to polarize the water, making it a better general acid. The stereochemistry of the scytalone dehydratase-catalyzed dehydration is also discussed.Rapid enzyme-catalyzed proton abstractions from carbon acids have attracted great interest. In view of the basicities of protein bases, these proton abstraction might be expected to be slow owning to low acidities of carbon acids. The mechanism by which enzymes accomplish such a difficult task has been a matter of continuing debate (1-4). One proposal invokes the formation of short strong hydrogen bonds during the catalytic process (2). This concept has been used to explain many enzymatic reactions. Our interest here is scytalone dehydratase.Scytalone dehydratase (EC 4.2.1.94) catalyzes the dehydration of two intermediates in the biosynthesis of melanin (Scheme 1) (5); it has been an important target for fungicides that control rice blast disease. Scytalone dehydratase is a trimeric enzyme consisting of three identical subunits, each unit having 129 amino acid residues. The x-ray crystal structure of scytalone dehydratase with a bound competitive inhibitor has been solved recently (6). Even at 2.9-Å resolution, two tightly bound water molecules were visible in the active site. On the basis of the crystallographic study, a catalytic mechanism was proposed as shown in Scheme 2 (6). According to this proposal, a water acts as a general acid to activate the carbonyl, making the ␣-C-H sufficiently acidic to be abstracted by a protein base, such as His-85, in the active site. As revealed by the x-ray crystallographic structure, the water is held in place by two tyrosine residues (Tyr-50 and Tyr-30). This dehydratase requires no metal ion or cofactors, so it is an especially interesting system.Recently, quantum mechanical methods have been used to examine enolization reactions pertaining to enzyme-catalyzed proton abstraction from weak carbon acids (7-9). Here we decided to employ quantum mechanical theory to investigate the role of the critical water in stabilizing the enolate intermediate and the role of these two active site tyrosine residues (Tyr-50 and Tyr-30) in scytalone dehydration catalyzed by scytalone dehydratase. THEORETICAL PROCEDUREAll calculations were carried out with the GAUSSIAN 94 program (10). For the ab initio molecular orbital calculations, geometry optimization was don...

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Section: Resultsmentioning

confidence: 99%

Role of a critical water in scytalone dehydratase-catalyzed reaction

Zheng

Bruice

1998

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

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“…The above argument is essentially a reapplication of the principle of stereoelectronic control put forward many years ago by Corey and Sneen (28). Several years ago, Bordwell and Scamehorn (29) pointed out that evidence in support of the principle has been equivocal in that the influences of steric and stereoelectronic effects have been difficult to separate.…”

Section: Origin Of Pronounced Stereoselectivitymentioning

confidence: 91%

Stereoselectivity in the Reactions of Nitrosopiperidine Carbanions. Steric vs. Stereoelectronic Control

Fraser¹,

Grindley²,

Passannanti³

1975

Can. J. Chem.

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The anion of N-nitroso-4-phenylpiperidine reacts with methyl iodide, carbon dioxide, and benzophenone to give solely the axial substitution product. A second methylation of the monomethyl derivative gave the 2,6-diaxial derivative. None of the isomer having trans methyl groups could be detected. This trans isomer dominates over cis by 75:25 at equilibrium. From a consideration of the steric interactions present in these nitrosamines, it can be concluded that they alone cannot explain the observed high stereoselectivity. It is proposed that stereoelectronic control contributes significantly to the exclusive axial attack.

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“…Ideally, the calculation would account for the angular dependence of orbital overlap between the π system and the scissile bond ( Figure 11). If decarboxylation in WT takes place from a position less than perfectly parallel to the π system of the aldimine, the WT rate of decarboxylation ∆G stereoelectronic ) -RT ln ( k activated k nonactivated ) (4) …”

Section: Formation Of the Michaelis Complex And Formation Of The Extementioning

confidence: 99%

“…Stereoelectronic effects have been investigated in simple organic systems both experimentally and computationally (3)(4)(5)(6)(7). However, there has been little direct experimental evidence for stereoelectronic effects in enzymatic systems.…”

mentioning

confidence: 99%

Role of Q52 in Catalysis of Decarboxylation and Transamination in Dialkylglycine Decarboxylase

et al. 2005

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Dialkylglycine decarboxylase (DGD) is a pyridoxal phosphate dependent enzyme that catalyzes both decarboxylation and transamination in its normal catalytic cycle. DGD uses stereoelectronic effects to control its unusual reaction specificity. X-ray crystallographic structures of DGD suggest that Q52 is important in maintaining the substrate carboxylate in a stereoelectronically activated position. Here, the X-ray structures of the Q52A mutant and the wild type (WT) DGD-PMP enzymes are presented, as is the analysis of steady-state and half-reaction kinetics of three Q52 mutants (Q52A, Q52I, and Q52E). As expected if stereoelectronic effects are important to catalysis, the steady-state rate of decarboxylation for all three mutants has decreased significantly compared to that of WT. Q52A exhibits an ∼85-fold decrease in k cat relative to that of WT. The rate of the decarboxylation half-reaction decreases ∼10 5 -fold in Q52I and ∼10 4 -fold in Q52E compared to that of WT. Transamination half-reaction kinetics show that Q52A and Q52I have greatly reduced rates compared to that of WT and are seriously impaired in pyridoxamine phosphate (PMP) binding, with K PMP at least 50-100-fold greater than that of WT. The larger effect on the rate of L-alanine transamination than of pyruvate transamination in these mutants suggests that the rate decrease is the result of selective destabilization of the PMP form of the enzyme in these mutants. Q52E exhibits near-WT rates for transamination of both pyruvate and L-alanine. Substrate binding has been greatly weakened in Q52E with apparent dissociation constants at least 100-fold greater than that of WT. The rate of decarboxylation in Q52E allows the energetic contribution of stereoelectronic effects, ∆G stereoelectronic , to be estimated to be -7.3 kcal/mol for DGD.Pyridoxal phosphate (PLP) 1 dependent enzymes constitute a large and well-characterized group of enzymes, catalyzing many different types of chemistry at the R-, -, and γ-carbons of amine and amino acid substrates. Despite the diversity of chemistry catalyzed by PLP dependent enzymes as a group, individual enzymes exhibit remarkably high reaction specificities. In contrast, model studies show that PLP alone is capable of nonenzymatically catalyzing multiple reaction types with a given substrate. For example, reaction of PLP with serine results in transamination, -elimination, and retroaldol cleavage (1). As an explanation for the high enzymatic versus nonenzymatic specificity, it was proposed by Dunathan (2) that PLP dependent enzymes use stereoelectronic effects to control reaction specificity. He proposed that the scissile bond is aligned parallel to the p orbitals of the extended π system of the aldimine, providing maximal orbital overlap and resonance stabilization in the transition state, therefore accelerating the rate of bond cleavage for the activated bond compared to the other bonds to C R .Stereoelectronic effects have been investigated in simple organic systems both experimentally and computationally (...

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Stereoelectronic Control in Enolization-Ketonization Reactions¹

Cited by 231 publications

References 1 publication

Role of a critical water in scytalone dehydratase-catalyzed reaction

Role of a critical water in scytalone dehydratase-catalyzed reaction

Stereoselectivity in the Reactions of Nitrosopiperidine Carbanions. Steric vs. Stereoelectronic Control

Role of Q52 in Catalysis of Decarboxylation and Transamination in Dialkylglycine Decarboxylase

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Stereoelectronic Control in Enolization-Ketonization Reactions1

Cited by 231 publications

References 1 publication

Role of a critical water in scytalone dehydratase-catalyzed reaction

Role of a critical water in scytalone dehydratase-catalyzed reaction

Stereoselectivity in the Reactions of Nitrosopiperidine Carbanions. Steric vs. Stereoelectronic Control

Role of Q52 in Catalysis of Decarboxylation and Transamination in Dialkylglycine Decarboxylase

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Stereoelectronic Control in Enolization-Ketonization Reactions¹