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A Comparative Study of Biocatalytic Acylation of 7-Aminocephalosporanic Acid and its C3 Derivatives

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Abstract

The efficiency has been compared of the optimized acylation processes of 7-aminocephalosporanic acid (7-ACA) and its С3 derivatives (7-amino-3-[2-methyl-1,3,4-thiadiazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (TDA), and 1-methyl-5-mercapto-1,2,3,4-tetrazolyl-7-aminocephalosporanic acid (7-TMCA)) by methyl esters of 1(H)-terazolylacetic and D-mandelic acids (METzAA and MEMA). These processes are catalyzed by immobilized cephalosporin-acid synthetase (IECASA) and are the biocatalytic stages of two different chemical-biocatalytic pathways for the synthesis of cefazolin (CEZ) and cefamandole (CFM). Biocatalytic acylation of 7-ACA resulting in the formation of semi-products of the synthesis of antibiotics proceeded more efficiently than acylation of the corresponding C3 derivatives of 7-ACA, leading to the formation of CEZ and CFM, in terms of both the achieved product yield and the possibility of obtaining compounds in high concentration in the reaction mixture. At the same time, the synthetase ability of IECASA is highest in the acylation of 7-ACA using METzAA. It was shown that the chemical-biocatalytic synthesis of CEZ and CFM by direct biocatalytic acylation of 7-ACA followed by chemical modification of the semi-product at the C3 position of the β-lactam nucleus is a promising alternative to the traditional pathway using the biocatalytic acylation of 7-ACA derivatives with a substituted 3-acetoxy group.

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Funding

The work was supported by an internal grant from the Kurchatov Institute National Research Center.

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Authors and Affiliations

  1. Kurchatov Institute National Research Center, 123182, Moscow, Russia

    A. V. Sklyarenko, I. A. Groshkova, N. A. Gorbunov & S. V. Yarotsky

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  1. A. V. Sklyarenko
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  2. I. A. Groshkova
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  3. N. A. Gorbunov
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  4. S. V. Yarotsky
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Correspondence to I. A. Groshkova.

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Translated by I. Gordon

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Abbreviations: AA, acylating agent; 7-ACA, 7-aminocephalosporanic acid; CA, carboxylic acid; CASA, cephalosporin-acid synthetase; CEZ, Сefazolin; CFM, Сefamandole; EG, ethylene glycol; IECASA, immobilized cephalosporin-acid synthetase; KA, key amino acid; MA, D-mandelic acid; MEМА, D-mandelic acid methyl ester; METzAA, 1(H)-tetrazolylacetic acid methyl ester; PA, penicillin acylase; PB, phosphate buffer; TDA, (7-amino-3-[2-methyl-1,3,4-thiadiazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid; 7-TMCA, 1-methyl-5-mercapto-1,2,3,4-tetrazolyl-7-aminocephalosporanic acid; TzAA, 1(H)-terazolylacetic acid.

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Sklyarenko, A.V., Groshkova, I.A., Gorbunov, N.A. et al. A Comparative Study of Biocatalytic Acylation of 7-Aminocephalosporanic Acid and its C3 Derivatives. Appl Biochem Microbiol 59, 1089–1101 (2023). https://doi.org/10.1134/S0003683823080094

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