α-Aminophosphonous Acids: A New Class of Biologically Active Amino Acid Analogs

Baylis, E. K.; Campbell, Charlotte H.; Dingwall, J. G.; Pickles, W.

doi:10.1021/bk-1981-0171.ch037

Cited by 12 publications

(9 citation statements)

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“…The amino acid isoster 1-(aminoethyl)phosphinic acid (9) [K i = 0.4 mM], a phosphinic analogue of Ala(P) (4), was synthesized to analyze the effect of the oxidation state of the phosphorus atom on the inhibition [93,94]. In the phosphinate, the C-P bond found in the phosphonate is present as well, but one of the P-O bonds is replaced by a P-H bond.…”

Section: Analogues Of the Substratementioning

confidence: 99%

DD-Ligases as a Potential Target for Antibiotics: Past, Present and Future

Tytgat¹,

Colacino²,

Tulkens³

et al. 2009

CMC

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DD-ligases catalyze the synthesis of the D-Ala-D-Ala and D-Ala-D-Ser dipeptides or the D Ala-D-Lac depsipeptide in an early step of peptidoglycan synthesis. Their function is essential for bacterial growth and specific to bacteria, making them attractive targets for the development of novel antibiotics. This review examines the biochemical and structural features of these enzymes and presents the main families of inhibitors described so far. Over the last 20 years, 7 structures of DD-ligases have been solved by X-ray crystallography, giving a detailed view of the general topology of the active site and of the residues in the catalytic pocket that play a central role in substrate recognition. This has paved the way to the rational design of inhibitors, which can be classified as (i) analogues of substrates, (ii) analogues of the product of the reaction, (iii) analogues of the transition state, and (iv) original scaffolds discovered by screening or by rational computer-aided design. The three first strategies have led to molecules that are polar by nature and have therefore poor access to their cytosolic target. The fourth one is potentially most promising as it yields more diverse structures. The most active molecules show affinity constants in the microM range, but microbiological evaluation remains scarce (typical MIC 1-8 mg/L for the tested compounds). These data strongly suggest targeting DD-ligases is a promising approach for discovery of new antibiotics. Future research should, however, aim at finding more potent inhibitors endowed with the appropriate pharmacokinetic properties that ensure access to their intracellular target.

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Section: Analogues Of the Substratementioning

confidence: 99%

DD-Ligases as a Potential Target for Antibiotics: Past, Present and Future

Tytgat¹,

Colacino²,

Tulkens³

et al. 2009

CMC

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“…Phosphororganic analogues of amino acids ( I , R = Alk, X = H, OH) are known to display high biological activities [1–7], thus investigation of their interaction with the enzymes involved in amino‐acid transformations is useful for understanding the enzymatic mechanisms and creating new probes for studies in this field.…”

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confidence: 99%

“…It may be concluded that differences in structure and chemical properties between (HO) 2 (O)P and HOOC groups are very important for the factors controlling the substrate specificities of the respective enzymes. For the groups (HO)(O)PH and HOOC, the differences are less pronounced, and aminophosphinic acids ( I , R = Alk, X = H) are considered to be closer analogues of natural amino acids [4,5]. For example, the phosphinic analogue of methionine ( I , R = CH 3 S CH 2 CH 2 , X = H) is a much better competitive inhibitor of enzymic aminoacylation of tRNA and it is a substrate of the ATP–PP i exchange reaction, the first stage of this process [4].…”

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Interaction of tyrosine phenol‐lyase with phosphoroorganic analogues of substrate amino acids

Faleev

Zhukov

Khurs

et al. 2000

European Journal of Biochemistry

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The phosphinic analogues of tyrosine and pyruvate were first demonstrated to be substrates in the reactions of elimination and synthesis catalyzed by tyrosine phenol-lyase. Kinetic parameters of the enzymatic process were determined, and the first enzymic synthesis of an aminophosphinic acid was carried out. Replacement of the planar HOOC-group by the tetrahedral (HO)(O)PH-group in the substrate slightly affected its affinity for the enzyme but substantially diminished the conversion rate. For phosphonic analogues, containing (HO)2(O)P group, the affinity to the enzyme was decreased considerably while the conversion was completely prevented. Thus, the structural parameters of the acid group are important not only for the affinity for the enzyme, but also for the formation of the catalytically competent conformation of the active site.

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“…This ten‐year ‘Manchester Era’ was, however, dominated by biological applications of phosphorus. John's group pioneered the synthesis of α‐aminoalkylphosphinic acids as close analogues of the protein amino acids 10,11. Original syntheses using hypophosphorous acid (H 3 PO 2 ) led to poor yields.…”

mentioning

confidence: 99%

John Grey Dingwall 1943-2000

Hall

2001

Pest. Manag. Sci.

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α-Aminophosphonous Acids: A New Class of Biologically Active Amino Acid Analogs

Cited by 12 publications

References 0 publications

DD-Ligases as a Potential Target for Antibiotics: Past, Present and Future

DD-Ligases as a Potential Target for Antibiotics: Past, Present and Future

Interaction of tyrosine phenol‐lyase with phosphoroorganic analogues of substrate amino acids

John Grey Dingwall 1943-2000

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