Inactivation of bacterial D-amino acid transaminases by the olefinic amino acid D-vinylglycine.

Soper, Thomas S.; Manning, James M.; Marcotte, Patrick A.; Walsh, Christopher T.

doi:10.1016/s0021-9258(17)40588-6

Cited by 59 publications

(19 citation statements)

References 13 publications

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“…Thirdly, the partition ratio of 830/1 for catalytic events per inactivation event might be considered high for efficient in vivo specificity (Walsh, 1977). We have previously noted high partition ratios with hydroxybutynoate as flavin hydroxy acid oxidase suicide substrates (Cromartie & Walsh, 1975;Ghisla et al" 1976), with D-vinylglycine as D-amino acid transaminase suicide substrate (Soper et al, 1977a), and with L-vinylglycine as L-amino acid oxidase inactivator (Marcotte & Walsh, 1976). However, unlike the latter three instances where the products released are reactive electrophiles capable of reaction with cellular nucleophiles, the 830 product molecules released by alanine racemase are unreactive and not even xenobiotic, partitioning ratios in Tables I and II are powerful indices that covalent alkylation arises from Michael attack on bound amino acrylate rather than Sn2 displacement of a leaving group from the ß carbon of the stabilized a carbanion, a distinction which could not be made with the other pyridoxal phosphate enzymes previously inactivated with /3-chloroalanine.…”

Section: Discussionmentioning

confidence: 98%

“…nases are inactivated by D-/3-chloroalanine (Soper et al, 1977b) and D-vinylglycine (Soper et al, 1977a), but we restrict our attention to alanine racemase in this paper. In studies on active transport of solutes in E. coli B membrane vesicles, we have noted that both D-and L-chloroalanine could cause time-dependent, irreversible inactivation of alanine racemase associated with the isolated cytoplasmic membrane vesicles (Kaczorowski et al, 1975a,b).…”

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confidence: 99%

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Suicide substrates for the alanine racemase of Escherichia coli B

Wang¹,

Walsh²

1978

Biochemistry

177

120

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Suicide substrates for the alanine racemase of Escherichia coli B

Wang¹,

Walsh²

1978

Biochemistry

177

120

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“…The β,γ-unsaturated trigger design is bioinspired and derives from the parent compound, α-vinylglycine, a fungal natural product, and an inactivator of both PLP-dependent transaminases and of ACC synthase, a key enzyme in the biosynthesis of the plant-ripening hormone, ethylene. The design of the α-(1′-fluoro)vinyl trigger is due to Abeles, who envisioned that such a motif could lead to the formation of a reactive allene-type intermediate in a PLP-enzyme active site (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1′-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators

et al. 2017

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Developing specific chemical functionalities to deploy in biological environments for targeted enzyme inactivation lies at the heart of mechanism-based inhibitor (MBI) development, but also is central to other protein-tagging methods in modern chemical biology including activity-based protein profiling (ABPP) and proteolysis-targeting chimeras (PROTACS). We describe here a previously unknown class of potential PLP enzyme inactivators; namely, a family of quaternary, α-(1′fluoro)vinyl amino acids, bearing the side chains of the cognate amino acids. These are obtained by the capture of suitably protected amino acid enolates with β,β-difluorovinyl phenyl sulfone, a new 1′-fluorovinyl cation equivalent, and an electrophile that previously eluded synthesis, capture and characterization. A significant variety of biologically relevant AA-side chains are tolerated including those for alanine, valine, leucine, methionine, lysine, phenylalanine, tyrosine and tryptophan. Following addition/elimination, the resulting transoid α-(1′-fluoro)-β-(phenylsulfonyl)vinyl AA esters undergo smooth sulfone-stannane interchange to stereoselectively give the corresponding transoid α-(1′fluoro)-β-(tributylstannyl)vinyl AA esters. Protodestannylation and global deprotection then yields these sterically encumbered and densely functionalized, quaternary amino acids. The α-(1′fluoro)vinyl trigger, a potential allene-generating functionality originally proposed by Abeles, is now available in a quaternary AA context for the first time. In an initial test of this new inhibitor class, α-(1′-fluoro)vinyllysine is seen to act as a time dependent, irreversible inactivator of lysine decarboxylase from Hafnia alvei. The enantiomers of the inhibitor could be resolved and each is seen to give time dependent inactivation with this enzyme. Kitz-Wilson analysis reveals similar inactivation parameters for the two antipodes, L-α-(1′-fluoro)vinyllysine (Ki = 630 ± 20 μM; t1/2 = 2.8 min) and D-α-(1′-fluoro)vinyllysine (Ki = 470 ± 30 μM; t1/2 = 3.6 min). The stage is now set for exploration of the efficacy of this trigger in other PLP-enzyme active sites.

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“…(A) a unimolecular 0-elimination reaction characteristic of 0-bromo-and 0-chloroalanine; (B) a bimolecular "ping-pong" 0-elimination reaction with 0-bromopyruvate which requires a D-amino acid cosubstrate; and (C) a bimolecular "pingpong" transamination between D-vinylglycine and an a-keto acid cosubstrate that also leads to inactivation of the enzyme (Soper et al, 1977a). Figure 7 portrays a composite scheme of the catalytic inactivation of D-amino acid transaminase by the class A and class B inhibitors; some of the intermediates are common to those for normal transamination and also for the class C inhibitor.…”

Section: Discussionmentioning

confidence: 99%

β-Elimination of β-halo substrates by D-amino acid transaminase associated with inactivation of the enzyme. Trapping of a key intermediate in the reaction

Soper¹,

Manning²

1978

Biochemistry

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D-Amino acid transaminase from Bacillus sphaericus catalyzes a @-elimination reaction with either 6bromo-D-alanine or P-bromopyruvate; a D-amino acid cosubstrate is required only with the latter compound. During the course of the reaction, the enzyme is gradually inactivated in proportion to the amount of each substrate processed. The turnover/inactivation ratio is about 350 for P-bromo-D-alanine at pH 7.0 and about 600 for P-bromopyruvate at pH 8.5. When small thiols such as @-mercaptoethylamine are present the enzyme is protected from inactivation, substrate is still consumed, but pyruvate is not produced. The major product of this 1 nitial studies on the antibacterial properties of @-chloro-D-alanine suggested that it acts by inactivating the enzymes that catalyze the formation of D-amino acids that are essential for bacterial growth (Manning et al., 1974). The finding that the inhibition of bacterial growth by the D isomer of 6-chloroalanine could be completely reversed by D-alanine supported this idea and further suggested that the D isomer of 0-chloroalanine had a limited number of target enzymes. Conversely, we found that the antibacterial effect of the L isomer of 0chloroalanine could be only partially reversed by high concentrations of 1.-alanine, and Arfin & Koziell (1971) found that inhibition was reversed completely by t-isoleucine and t-valine. These results indicated that some of the enzyme systems for L-amino acids had been inactivated by P-chloro-

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Inactivation of bacterial D-amino acid transaminases by the olefinic amino acid D-vinylglycine.

Cited by 59 publications

References 13 publications

Suicide substrates for the alanine racemase of Escherichia coli B

Suicide substrates for the alanine racemase of Escherichia coli B

Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1′-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators

β-Elimination of β-halo substrates by D-amino acid transaminase associated with inactivation of the enzyme. Trapping of a key intermediate in the reaction

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