Theoretical studies on the inactivation mechanism of γ-aminobutyric acid aminotransferase

Durak, Agata; Gökcan, Hatice; Konuklar, F. A. S.

doi:10.1039/c1ob05146f

Cited by 6 publications

(26 citation statements)

References 44 publications

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“…The use of solvent molecules in the assistance of the proton transfer steps, as in the case here, has proven to be crucial because the solvent serves as the proton conduit 30. Furthermore, several studies have shown that reactions involving the carbonyl functionality, such as peptidic amides, first interconvert into their more reactive tautomeric counterparts; these tautomerization steps were also shown to be facilitated by polar protic solvents 30d,f,g,i…”

Section: Resultsmentioning

confidence: 99%

Solvent‐Catalyzed Ring–Chain–Ring Tautomerization in Axially Chiral Compounds

Yıldırım

Konuklar

Çatak

et al. 2012

Chemistry A European J

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The mechanism of ring-chain-ring tautomerization and the prominent effect of the solvent environment have been computationally investigated in an effort to explain the enantiomeric interconversion observed in 2-oxazolidinone derivatives, heterocyclic analogues of biphenyl atropisomers, which were isolated as single stable enantiomers and have the potential to be used as axially chiral catalysts. This study has shed light on the identity of the intermediate species involved in the ring-chain-ring tautomerization process as well as the catalytic effect of polar protic solvents. These mechanistic details will prove very useful in predicting and understanding ring-chain tautomeric equilibria in similar heterocyclic systems and will further enable experimentalists to devise appropriate experimental conditions in which axially chiral catalysts remain stable as single enantiomers.

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Section: Resultsmentioning

confidence: 99%

Solvent‐Catalyzed Ring–Chain–Ring Tautomerization in Axially Chiral Compounds

Yıldırım

Konuklar

Çatak

et al. 2012

Chemistry A European J

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“…All of the syntheses were carried out under an atmosphere of argon using flame-dried glassware. 1 H NMR and 13 C NMR spectra were recorded on a Bruker AVANCE III 500 spectrometer at 26 °C using DMSO-d 6 or CDCl 3 as solvents. Chemical shifts are reported in parts per million (ppm, δ) and referenced to DMSO-d 6 (2.50 ppm for 1 H NMR and 39.52 ppm for 13 C NMR) or CDCl 3 (7.26 ppm for 1 H NMR and 77.2 ppm for 13 C NMR).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…1 H NMR and 13 C NMR spectra were recorded on a Bruker AVANCE III 500 spectrometer at 26 °C using DMSO-d 6 or CDCl 3 as solvents. Chemical shifts are reported in parts per million (ppm, δ) and referenced to DMSO-d 6 (2.50 ppm for 1 H NMR and 39.52 ppm for 13 C NMR) or CDCl 3 (7.26 ppm for 1 H NMR and 77.2 ppm for 13 C NMR). Coupling constants (J) are reported in Hz, and spin multiplicities are described as s (singlet), br (broad singlet), d (doublet), t (triplet), q (quartet), and m (multiplet).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Theoretical and Mechanistic Validation of Global Kinetic Parameters of the Inactivation of GABA Aminotransferase by OV329 and CPP-115

2021

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((S)-3-Amino-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (OV329) is a recently discovered inactivator of γ-aminobutyric acid aminotransferase (GABA-AT), which has 10 times better inactivation efficiency than its predecessor, CPP-115, despite the only structural difference being an endocyclic double bond in OV329. Both compounds are mechanism-based enzyme inactivators (MBEIs), which inactivate GABA-AT by a similar mechanism. Here, a combination of a variety of computational chemistry tools and experimental methods, including quantum mechanical (QM) calculations, molecular dynamic simulations, progress curve analysis, and deuterium kinetic isotope effect (KIE) experiments, are utilized to comprehensively study the mechanism of inactivation of GABA-AT by CPP-115 and OV329 and account for their experimentally obtained global kinetic parameters k inact and K I. Our first key finding is that the rate-limiting step of the inactivation mechanism is the deprotonation step, and according to QM calculations and the KIE experiments, k inact accurately represents the enhancement of the rate-limiting step for the given mechanism. Second, the present study shows that the widely used simple QM models do not accurately represent the geometric criteria that are present in the enzyme for the deprotonation step. In contrast, QM cluster models successfully represent both the ground state destabilization and the transition state stabilization, as revealed by natural bond orbital analysis. Furthermore, the globally derived K I values for both of the inactivators represent the inhibitor constants for the initial binding complexes (K d) and indicate the inactivator competition with the substrate according to progress curve analysis and the observed binding isotope effect. The configurational entropy loss accounts for the difference in K I values between the inactivators. The approach we describe in this work can be employed to determine the validity of globally derived parameters in the process of MBEI optimization for given inactivation mechanisms.

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“…Density functional theory at the B3LYP/6-31+G(d,p) level of theory was used to differentiate the energies of the three inactivation mechanisms (Scheme 12, pathway a; Scheme 12, pathway b; and Scheme 14). 99 The conclusion that the mechanism in Scheme 14 is least likely, the enamine mechanism (Scheme 12, pathway b) is next likely, and the Michael addition mechanism (Scheme 12, pathway a) is the most energetically favorable, are consistent with the experimental findings. Their calculations of the geometry of Michael adduct 65 also agree well with the X-ray structure.…”

Section: Chemical Reviewsmentioning

confidence: 99%

Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions

Silverman

2018

Chem. Rev.

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When the brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) diminishes below a threshold level, the excess neuronal excitation can lead to convulsions. This imbalance in neurotransmission can be corrected by inhibition of the enzyme γ-aminobutyric acid aminotransferase (GABA-AT), which catalyzes the conversion of GABA to the excitatory neurotransmitter l-glutamic acid. It also has been found that raising GABA levels can antagonize the rapid elevation and release of dopamine in the nucleus accumbens, which is responsible for the reward response in addiction. Therefore, the design of new inhibitors of GABA-AT, which increases brain GABA levels, is an important approach to new treatments for epilepsy and addiction. This review summarizes findings over the last 40 or so years of mechanism-based inactivators (unreactive compounds that require the target enzyme to catalyze their conversion to the inactivating species, which inactivate the enzyme prior to their release) of GABA-AT with emphasis on their catalytic mechanisms of inactivation, presented according to organic chemical mechanism, with minimal pharmacology, except where important for activity in epilepsy and addiction. Patents, abstracts, and conference proceedings are not covered in this review. The inactivation mechanisms described here can be applied to the inactivations of a wide variety of unrelated enzymes.

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Theoretical studies on the inactivation mechanism of γ-aminobutyric acid aminotransferase

Cited by 6 publications

References 44 publications

Solvent‐Catalyzed Ring–Chain–Ring Tautomerization in Axially Chiral Compounds

Solvent‐Catalyzed Ring–Chain–Ring Tautomerization in Axially Chiral Compounds

Theoretical and Mechanistic Validation of Global Kinetic Parameters of the Inactivation of GABA Aminotransferase by OV329 and CPP-115

Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions

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