Inactivation of γ-aminobutyric acid aminotransferase by (Z)-4-amino-6-fluoro-5-hexenoic acid: Identification of an active site residue

Leon, Andrew J.; Silverman, Richard B.

doi:10.1016/0960-894x(96)00226-0

Cited by 2 publications

(3 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After inactivation by both 74 and 75, an absorption peak in the UV−visible spectrum at 430 nm appears. To rationalize these results, multiple mechanisms are necessary; the principal inactivation mechanisms for 74 and 75 appear to be 125 To account for the identification of only one metabolite produced from 75 (77 not 78), an S N 2 mechanism, leading to 82, was invoked instead of elimination (Scheme 17 instead of Scheme 15; Scheme 16 can still occur for 75). The difference in these two inactivator mechanisms could be rationalized by a difference in hydrogen bonding of the two isomers (Scheme 18).…”

Section: Chemical Reviewsmentioning

confidence: 99%

See 1 more Smart Citation

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

Silverman

2018

Chem. Rev.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Chemical Reviewsmentioning

confidence: 99%

“…PMP (and 91 ) also could come from hydrolysis of 88 (pathway g). The X group in Scheme was identified as Cys294 (actually Cys293; there must have been a numbering error in the peptide map) by [2- 3 H]- 74 inactivation of GABA-AT, tryptic digestion, HPLC, and mass spectrometry …”

Section: Diverse Gaba-at Inactivator Mechanismsmentioning

confidence: 99%

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

Silverman

2018

Chem. Rev.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In light of earlier success with the simple α-vinyl trigger and Hafnia alvei L-lysine decarboxylase (LDC) [115], we set to examine the α-(2′Z-fluoro)vinyl trigger [116,117] for AADC inactivation in this active site. Figure 13 illustrates the proposed mechanism(s) of AADC inactivation with this new AADC suicide substrate trigger.…”

Section: Use Of Fluorinated Functionality For “Suicide Substrate” mentioning

confidence: 99%

Use of fluorinated functionality in enzyme inhibitor development: Mechanistic and analytical advantages

Berkowitz

Karukurichi

Salud-Bea

et al. 2008

Journal of Fluorine Chemistry

View full text Add to dashboard Cite

On the one hand, owing to its electronegativity, relatively small size, and notable leaving group ability from anionic intermediates, fluorine offers unique opportunities for mechanism-based enzyme inhibitor design. On the other, the “bio-orthogonal” and NMR-active 19-fluorine nucleus allows the bioorganic chemist to follow the mechanistic fate of fluorinated substrate analogues or inhibitors as they are enzymatically processed. This article takes an overview of the field, highlighting key developments along these lines. It begins by highlighting new screening methodologies for drug discovery that involve appropriate tagging of either substrate or the target protein itself with 19F-markers, that then report back on turnover and binding, respectively, via an the NMR screen. Taking this one step further, substrate-tagging with fluorine can be done is such a manner as to provide stereochemical information on enzyme mechanism. For example, substitution of one of the terminal hydrogens in phosphoenolpyruvate, provides insight into the, otherwise latent, facial selectivity of C-C bond formation in KDO synthase. Perhaps, most importantly, from the point of view of this discussion, appropriately tailored fluorinated functionality can be used to form to stabilized “transition state analogue” complexes with a target enzymes. Thus, 5-fluorinated pyrimidines, α-fluorinated ketones, and 2-fluoro-2-deoxysugars each lead to covalent adduction of catalytic active site residues in thymidylate synthase, serine protease and glycosidase enzymes, respectively. In all such cases, 19F NMR allows the bioorganic chemist to spectrally follow “transition state analogue” formation. Finally, the use of specific fluorinated functionality to engineer “suicide substrates” is highlighted in a discussion of the development of the α-(2′Z-fluoro)vinyl trigger for amino acid decarboxylase inactivation. Here 19F NMR allows the bioorganic chemist to glean useful partition ratio data directly out of the NMR tube.

show abstract

Inactivation of γ-aminobutyric acid aminotransferase by (Z)-4-amino-6-fluoro-5-hexenoic acid: Identification of an active site residue

Cited by 2 publications

References 7 publications

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

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

Use of fluorinated functionality in enzyme inhibitor development: Mechanistic and analytical advantages

Contact Info

Product

Resources

About