Stereoelectronic control in the reactions of ketones and their enol(ate)s

Pollack, Ralph M.

doi:10.1016/s0040-4020(01)81073-5

Cited by 53 publications

(14 citation statements)

References 119 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6A. Based on stereo-electronic considerations [61][62][63][64], decarboxylation of the 4-keto intermediate would be optimal with the carboxylate grouporiented axially, for the dihedral angle between the C = O bond of the ketone and the C5-C6 bond could thus approach the ideal~90°. It follows that, by maintaining the dihedral angle at close to~0°due to the equatorial carboxylate, the epimerase might constrain its catalytic reaction so as to minimize decarboxylation.…”

Section: Kinetic Properties Of Ugaepimentioning

confidence: 99%

Mechanistic characterization of UDP‐glucuronic acid 4‐epimerase

et al. 2020

View full text Add to dashboard Cite

UDP-glucuronic acid (UDP-GlcA) is a central precursor in sugar nucleotide biosynthesis and common substrate for C4-epimerases and decarboxylases releasing UDP-galacturonic acid (UDP-GalA) and UDP-pentose products, respectively. Despite the different reactions catalyzed, the enzymes are believed to share mechanistic analogy rooted in their joint membership to the short-chain dehydrogenase/reductase (SDR) protein superfamily: Oxidation at the substrate C4 by enzyme-bound NAD + initiates the catalytic pathway. Here, we present mechanistic characterization of the C4-epimerization of UDP-GlcA, which in comparison with the corresponding decarboxylation has been largely unexplored. The UDP-GlcA 4-epimerase from Bacillus cereus functions as a homodimer and contains one NAD + /subunit (k cat = 0.25 AE 0.01 s −1). The epimerization of UDP-GlcA proceeds via hydride transfer from and to the substrate's C4 while retaining the enzyme-bound cofactor in its oxidized form (≥ 97%) at steady state and without trace of decarboxylation. The k cat for UDP-GlcA conversion shows a kinetic isotope effect of 2.0 (AE0.1) derived from substrate deuteration at C4. The proposed enzymatic mechanism involves a transient UDP-4-keto-hexose-uronic acid intermediate whose formation is rate-limiting overall, and is governed by a conformational step before hydride abstraction from UDP-GlcA. Precise positioning of the substrate in a kinetically slow binding step may be important for the epimerase to establish stereo-electronic constraints in which decarboxylation of the labile β-keto acid species is prevented effectively. Mutagenesis and pH studies implicate the conserved Tyr149 as the catalytic base for substrate oxidation and show its involvement in the substrate positioning step. Collectively, this study suggests that based on overall mechanistic analogy, stereo-electronic control may be a distinguishing feature of catalysis by SDR-type epimerases and decarboxylases active on UDP-GlcA.

show abstract

Section: Kinetic Properties Of Ugaepimentioning

confidence: 99%

Mechanistic characterization of UDP‐glucuronic acid 4‐epimerase

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In general, the PM3 method predicts a larger stabilization than the ab initio molecular orbital method. According to PM3 calculations, the internal hydrogen bonding stabilizes the enolate intermediate by 15.1 kcal͞mol, which is about 5.9 kcal͞mol larger than the MP2 value. In 4a, the PM3 calculated differential stabilization is about 27.9 kcal͞mol, which is about 11.4 kcal͞mol higher than the ab initio value at MP2 level.…”

Section: Biochemistry: Zheng and Bruicementioning

confidence: 82%

“…The interconversion of a carbonyl-containing molecule with its enol is a fundamental process in organic and biological chemistry, which has been much studied (14,15). Normally, reactions of this kind can take place by one of the three possible reaction pathways, the choice between them depending on the reaction conditions, in particular the pH of the solution.…”

Section: Resultsmentioning

confidence: 99%

Role of a critical water in scytalone dehydratase-catalyzed reaction

Zheng

Bruice

1998

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

View full text Add to dashboard Cite

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...

show abstract

“…However, the corresponding intramolecular alkylation reactions are often controlled by stereoelectronic effects and strongly favor O -alkylation regardless of the reaction conditions. 38 …”

Section: Resultsmentioning

confidence: 99%

Toward a Synthesis of Hirsutellone B by the Concept of Double Cyclization

et al. 2013

View full text Add to dashboard Cite

This account describes a strategy for directly forming three of the six rings found in the polyketide natural product hirsutellone B via a novel cyclization cascade. The key step in our approach comprises two transformations: a large-ring forming, nucleophilic capture of a transient acyl ketene and an intramolecular Diels–Alder reaction, both of which occur in tandem through thermolyses of appropriately functionalized, polyunsaturated dioxinones. These thermally induced “double cyclization” cascades generate three new bonds, four contiguous stereocenters, and a significant fraction of the polycyclic architecture of hirsutellone B. The advanced macrolactam and macrolactone intermediates that were synthesized by this process possess key features of the hirsutellone framework, including the stereochemically dense decahydrofluorene core and the strained para-cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon-carbon bond formation were undermined by competitive O-alkylation reactions. This account also documents how we adapted to this undesired outcome through an evaluation of several distinct strategies for synthesis, as well as our eventual achievement of a formal total synthesis of hirsutellone B.

show abstract

Stereoelectronic control in the reactions of ketones and their enol(ate)s

Cited by 53 publications

References 119 publications

Mechanistic characterization of UDP‐glucuronic acid 4‐epimerase

Mechanistic characterization of UDP‐glucuronic acid 4‐epimerase

Role of a critical water in scytalone dehydratase-catalyzed reaction

Toward a Synthesis of Hirsutellone B by the Concept of Double Cyclization

Contact Info

Product

Resources

About