Mutant form<scp>C</scp>115<scp>H</scp>of<scp><i>C</i></scp><i>lostridium sporogenes</i>methionine γ‐lyase efficiently cleaves<scp>S</scp>‐Alk(en)yl‐<scp>l</scp>‐cysteine sulfoxides to antibacterial thiosulfinates

Kulikova, Vitalia V.; Anufrieva, Natalya V.; Revtovich, Svetlana V.; Chernov, A. S.; Telegin, G. B.; Morozova, Elena A.; Demidkina, Tatyana V.

doi:10.1002/iub.1562

Cited by 14 publications

(5 citation statements)

References 25 publications

(33 reference statements)

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“…Allicin was shown to have a relatively low in vitro antibacterial activity against P. aeruginosa. 23,28,29 Consistent with these data, our in vivo results demonstrate low antibacterial activity of C115H-loaded PIC spheres/alliin against the strain as well. So, the substituents, attached to the thiosulfinate moiety, influence the antibacterial activity of thiosulfinates.…”

Section: ■ Results and Discussionsupporting

confidence: 88%

Encapsulated Methionine γ-Lyase: Application in Enzyme Prodrug Therapy of Pseudomonas aeruginosa Infection

et al. 2020

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Lung disease caused by Pseudomonas aeruginosa is the leading reason for death in cystic fibrosis patients. Therapeutic efficacy of the pharmacological pairs, the naked/encapsulated mutant form of Citrobacter freundii methionine γ-lyase and the substrates, sulfoxides of S-substituted L-cysteine, generating thiosulfinates, was evaluated on the murine model of experimental sepsis caused by the multidrug-resistant P. aeruginosa 203-2 strain. The pairs containing the naked enzyme and substrates did not have antibacterial activity. The treatment of mice with the pair encapsulated enzyme and S-methyl-L-cysteine sulfoxide, generating dimethyl thiosulfinate, led to a complete recovery of the animals of the model, with the infecting dose equal to LD 50 . The pair generating diallyl thiosulfinate (allicin) proved to be less effective. So, the substituents, attached to the thiosulfinate moiety, affect the antibacterial activity of thiosulfinates against P. aeruginosa.

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Section: ■ Results and Discussionsupporting

confidence: 88%

Encapsulated Methionine γ-Lyase: Application in Enzyme Prodrug Therapy of Pseudomonas aeruginosa Infection

et al. 2020

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“…Interestingly, it was only dimethyl thiosulfinate that, among all thiosulfinates, suppressed the growth of P. aeruginosa at a concentration of 0.4 mg/ml ( Table 2 ). The results obtained for allicin and dimethyl thiosul finate are consistent with the data for P. aeruginosa from murine intestinal [7]. …”

Section: Resultssupporting

confidence: 88%

“…We have shown that thiosulfinates can be obtained using methionine γ-lyase (MGL, [EC 4.4.1.11]) ( Scheme ). Thiosulfinates formed by the cleavage of S-allyl- L -cysteine, S-methyl- L -cysteine, and S-ethyl- L -cysteine sulfoxides catalyzed by both wild-type MGL and its more efficient mutant form, C115H, inhibit the growth of Gram-positive and Gram-negative bacteria [6], including P. aeruginosa isolated from murine intestine [7]. …”

Section: Introductionmentioning

confidence: 99%

Antibacterial Effect of Thiosulfinates on Multiresistant Strains of Bacteria Isolated from Patients with Cystic Fibrosis

Kulikova¹,

Chernukha²,

Morozova³

et al. 2018

Acta Naturae

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The multiresistance of A. ruhlandii 155B, B. cenocepacia 122, and P. aeruginosa 48B strains isolated from patients with cystic fibrosis was established. The antibacterial effect of allicin, dimethyl thiosulfinate, and dipropyl thiosulfinate on multidrug-resistant strains was shown. Thiosulfinates can have both bacteriostatic and bactericidal effects depending on the microorganism and the concentration. The studied thiosulfinates may be candidates for the development of alternative antibiotic drugs to treat infections caused by multidrug-resistant pathogens.

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“…Недавно нами было показано, что МГЛ катализирует реакцию β-элиминирования сульфоксидов S-замещенных аналогов цистеина с образованием тиосульфинатов [17,18]. Антибактериальная активность тиосульфинатов, получаемых «фармакологической парой» МГЛ/сульфоксид S-замещенного L-цистеина, показана in vitro против ряда бактерий [18][19][20] и in vivo против Pseudomonas aueroginosa [21]. Перспективность применения фермента в качестве противоопухолевого агента показана in vitro и in vivo [22][23][24][25].…”

Section: Introductionunclassified

“…Recently, we showed that MGL catalyzes the β-elimination reaction of S-substituted cysteine sulfoxide derivatives to form thiosulfinates [ 17 , 18 ]. Thiosulfinates produced by a “pharmacological pair” MGL/S-substituted L-cysteine sulfoxide exhibited antibacterial activity against a number of bacteria in vitro [ 18 , 19 , 20 ] and Pseudomonas aeruginosa in vivo [ 21 ]. The applicability of the enzyme as an antitumor agent has been demonstrated in vitro and in vivo [ 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Serine 339 in the Catalysis of γ- and β-Elimination Reactions

et al. 2022

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Serine 339 of the active site of Citrobacter freundii methionine -lyase (MGL) is a conserved amino acid in most pyridoxal 5-phosphate-dependent enzymes of the cystathionine -lyase subclass, to which MGL belongs. The reaction mechanism of the MGL-catalyzed -elimination reaction is poorly explored. We replaced serine 339 with alanine using site-directed mutagenesis. The replacement of serine 339 with alanine led to a significant (by two orders of magnitude) decrease in efficiency in the catalysis of the - and -elimination reactions by the mutant form of the enzyme. The exchange rates of the C-- and C--protons in the amino acids in complexes consisting of the enzyme and competitive inhibitors decreased by one-two orders of magnitude. The spectral characteristics of the mutant form indicated that the replacement did not lead to significant changes in the conformation and tautomerism of MGL internal aldimine. We crystallized the holoenzyme and determined its spatial structure at 1.7 resolution. The replacement of serine 339 with alanine did not affect the overall course of the polypeptide chain of the MGL subunit and the tetrameric enzyme structure. An analysis of the obtained kinetic and spectral data, as well as the known spatial structures of C. freundii MGL, indicates that serine 339 is necessary for efficient catalysis of - and -elimination reactions at the stage of C--proton abstraction from the external aldimine, the -elimination reaction at the stages of coenzyme C4-atom protonation, and C--proton abstraction from a ketimine intermediate.

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Mutant formC115HofClostridium sporogenesmethionine γ‐lyase efficiently cleavesS‐Alk(en)yl‐l‐cysteine sulfoxides to antibacterial thiosulfinates

Cited by 14 publications

References 25 publications

Encapsulated Methionine γ-Lyase: Application in Enzyme Prodrug Therapy of Pseudomonas aeruginosa Infection

Encapsulated Methionine γ-Lyase: Application in Enzyme Prodrug Therapy of Pseudomonas aeruginosa Infection

Antibacterial Effect of Thiosulfinates on Multiresistant Strains of Bacteria Isolated from Patients with Cystic Fibrosis

Serine 339 in the Catalysis of γ- and β-Elimination Reactions

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