Mechanism-based inactivation of alanine racemase by 3-halovinylglycines.

Thornberry, Nancy A.; Bull, Herbert G.; Taub, D.; Wilson, Kenneth E.; Giménez‐Gallego, Guillermo; Rosegay, Avery; Soderman, Denis D.; Patchett, Arthur A.

doi:10.1016/s0021-9258(18)54687-1

Cited by 36 publications

(23 citation statements)

References 28 publications

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“…β-Fluorinated amino acids have been designed as MBIs of enzymes where metabolism of the amino acid involves condensation of the primary amine with the aldehyde of PLP to form an imine-based intermediate. , Enzymes that fall into this class include bacterial alanine racemase and mammalian and nonmammalian amino acid decarboxylases. Inhibition of these enzymes occurs by elimination of fluorine during metabolism, generating an electrophilic intermediate that reacts covalently with the protein. − As an example, the bacterial alanine racemase inhibitor fludalanine ( 340 ), the Cα-deuterated analogue of d -fluoroalanine ( 339 ), was advanced into clinical trials as a potential anti-infective agent. − The mechanism of inhibition by 339 entailed deprotonation of the PLP-based intermediate 344 followed by departure of fluoride from 345 , as summarized in Scheme . − The loss of fluoride usurped the normal pathway of deprotonation/reprotonation that occurred with the natural substrate alanine to afford 346 , an intermediate of low electrophilicity. Exchange of 346 with the catalytic lysine regenerated the PLP-imine precursor 347 and released 2-aminoacrylic acid ( 348 ), a nucleophilic enamine that reacted covalently with the cofactor-based imine 347 to produce 349 . − The intermediate 348 could not be intercepted by exogenous thiols, suggesting a rapid reaction with 347 .…”

Section: Fluorinated Aminesmentioning

confidence: 99%

“…The remainder (31%) of 368 reacted with a proximal noncatalytic lysine to afford the adduct 375 , a Michael acceptor that reacted with the phenolic hydroxyl of a nearby tyrosine residue to generate 376 . This unstable aminal intermediate degraded to produce the irreversibly inactivated enzyme 377 that retained an alkylated tyrosine residue. ,,, …”

Section: Fluorinated Aminesmentioning

confidence: 99%

“…PLP-dependent decarboxylases are also susceptible to α-(1′-halo)vinyl-α-amino acid MBIs. , One example is d -(1-chlorovinyl)glycine ( 393 ), which inhibited the alanine racemase from Escherichia coli B. , Similarly, (1-fluorovinyl)glycine ( 394 ), an MBI of Escherichia coli B alanine racemase, also inhibited Salmonella typhimurium tryptophan synthase. Compound 395 is an inhibitor of lysine decarboxylase from the Gram-negative bacterium Hafnai alvei .…”

Section: Fluorinated Aminesmentioning

confidence: 99%

“…283,284 Fluorovinylglycine (365) followed a trifurcated pathway during processing by Escherichia coli B alanine racemase (Scheme 47). 276,277,285,286 Exchange of 365 with the enzyme lysine in the cofactor-bound 343 afforded 366, which collapsed to 367. This molecule followed the normal enzymatic pathway to lose fluoride to produce the reactive allene 368.…”

Section: T H Imentioning

confidence: 99%

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Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

et al. 2020

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The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochemical properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated molecules are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C–F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compounds. In this Perspective, we summarize the literature associated with the metabolism of fluorinated molecules, focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.

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Section: Fluorinated Aminesmentioning

confidence: 99%

Section: Fluorinated Aminesmentioning

confidence: 99%

Section: Fluorinated Aminesmentioning

confidence: 99%

Section: T H Imentioning

confidence: 99%

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Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

et al. 2020

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“…reported 3‐halovinylglycines as a new class of potent irreversible inactivators of Alr from E. coli [58] . In further studies both enantiomers of 3‐fluorovinylglycine and 3‐chlorovinylglycine ( 25 and 26 , Figure 2) proved to be mechanism‐based inhibitors of Alr, although fluoro derivatives turned out to be much less reactive than chlorovinylglycines [59] . At the same time, detailed synthesis of those compounds as racemic mixtures were reported [60] .…”

Section: Antibacterial Amino Acid‐based Agentsmentioning

confidence: 99%

Amino Acid Based Antimicrobial Agents – Synthesis and Properties

2021

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Structures of several dozen of known antibacterial, antifungal or antiprotozoal agents are based on the amino acid scaffold. In most of them, the amino acid skeleton is of a crucial importance for their antimicrobial activity, since very often they are structural analogs of amino acid intermediates of different microbial biosynthetic pathways. Particularly, some aminophosphonate or aminoboronate analogs of protein amino acids are effective enzyme inhibitors, as structural mimics of tetrahedral transition state intermediates. Synthesis of amino acid antimicrobials is a particular challenge, especially in terms of the need for enantioselective methods, including the asymmetric synthesis. All these issues are addressed in this review, summing up the current state‐of‐the‐art and presenting perspectives fur further progress.

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Enzyme Inhibitors

Muscate¹,

Levinson²,

Kenyon³

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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Modern approaches to rational drug discovery have led to a number of different strategies for the design of enzyme active‐site directed inhibitors, which can be divided into classes describing noncovalent and covalent binding. Noncovalently binding inhibitors can be subdivided into rapidly reversible, tight, slow, slow‐tight binding inhibitors, transition‐state, and multisubstrate analogues. Covalently binding inhibitors are grouped into mechanism‐based inhibitors, affinity labels, and pseudoirreversible inhibitors. Inhibitors that fall into one or more of these categories have been designed using mechanistic and structural information. Computer‐aided drug design has been used as a new and powerful approach for the design of inhibitors. Using three‐dimensional enzyme structures or pharmacophores, novel, nonsubstrate analogue lead compounds have been developed by de novo design or screening of small molecule databases and further optimized to obtain potent inhibitors. Alternatively, quantitative structure‐activity relationship methods (QSAR), comparative molecular field analysis (CoMFA), or perturbation free‐energy calculations have used the speed and computational power of computer algorithms to establish structure‐activity relationships for a series of structurally related compounds, allowing for the design of more potent inhibitors.

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Mechanism-based inactivation of alanine racemase by 3-halovinylglycines.

Cited by 36 publications

References 28 publications

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

Amino Acid Based Antimicrobial Agents – Synthesis and Properties

Enzyme Inhibitors

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