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Cited by 31Enzyme Catalysis and ImmobilizationEnzyme Production and CharacterizationSynthesis of β-Lactam Compounds

The DOI matches its Crossref record; 95 of the 95 references it cites were found in a registry or an index.

Strategies to Improve the Biosynthesis of β-Lactam Antibiotics by Penicillin G Acylase: Progress and Prospects

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Pan, Xin, Xu, Lei, Li, Yaru, Wu, Sihua, Wu, Yong, Wei, Wenping·2022·Frontiers in Bioengineering and Biotechnology
DOI 10.3389/fbioe.2022.936487PMC PMC9340067
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Abstract

β-Lactam antibiotics are widely used anti-infection drugs that are traditionally synthesized via a chemical process. In recent years, with the growing demand for green alternatives, scientists have turned to enzymatic synthesis. Penicillin G acylase (PGA) is the second most commercially used enzyme worldwide with both hydrolytic and synthetic activities toward antibiotics, which has been used to manufacture the key antibiotic nucleus on an industrial level. However, the large-scale application of PGA-catalyzed antibiotics biosynthesis is still in the experimental stage because of some key limitations, such as low substrate concentration, unsatisfactory yield, and lack of superior biocatalysts. This paper systematically reviews the strategies adopted to improve the biosynthesis of β-lactam antibiotics by adjusting the enzymatic property and manipulating the reaction system in recent 20 years, including mining of enzymes, protein engineering, solvent engineering, in situ product removal, and one-pot reaction cascade. These advances will provide important guidelines for the future use of enzymatic synthesis in the industrial production of β-lactam antibiotics.

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Crossref · 10.3389/fbioe.2022.936487

Cites

95 of 95 references verified0 citation errors · 0 not checkable

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Figures

FIGURE 1 (A) Traditional chemical synthesis of β-lactam antibiotics. (B) Enzymatic synthesis of β-lactam antibiotics by PGA. PGA first deacylates penicillin G to produce key antibiotic nucleus 6-APA. Subsequently, PGA catalyzes the condensation of the nucleus and the acyl donor under thermodynamic or kinetic control, resulting in the generation of a series of semisynthetic penicillins.
FIGURE 1 (A) Traditional chemical synthesis of β-lactam antibiotics. (B) Enzymatic synthesis of β-lactam antibiotics by PGA. PGA first deacylates penicillin G to produce key antibiotic nucleus 6-APA. Subsequently, PGA catalyzes the condensation of the nucleus and the acyl donor under thermodynamic or kinetic control, resulting in the generation of a series of semisynthetic penicillins.CC BY · PubMed Central
FIGURE 2 (A) The structure characteristics of PGA-catalyzed semisynthetic penicillins, first- and second-generation cephalosporins. (B) The structure characteristics of third- and fourth-generation cephalosporins.
FIGURE 2 (A) The structure characteristics of PGA-catalyzed semisynthetic penicillins, first- and second-generation cephalosporins. (B) The structure characteristics of third- and fourth-generation cephalosporins.CC BY · PubMed Central
FIGURE 3 The phylogenetic tree of industrially relevant PGAs reported in the literature and their strain origins.
FIGURE 3 The phylogenetic tree of industrially relevant PGAs reported in the literature and their strain origins.CC BY · PubMed Central
FIGURE 4 Crystal structure of EcPGA with ligand penicillin G sulfoxide (PGSO) (yellow) (PDB ID: 1GM9). The α and β subunits are coloured fuchsia and cyan, respectively. The active sites βS1, βA69, and βN241 are coloured green and good mutation sites αR145, αF146, and βF24 are coloured light grey.
FIGURE 4 Crystal structure of EcPGA with ligand penicillin G sulfoxide (PGSO) (yellow) (PDB ID: 1GM9). The α and β subunits are coloured fuchsia and cyan, respectively. The active sites βS1, βA69, and βN241 are coloured green and good mutation sites αR145, αF146, and βF24 are coloured light grey.CC BY · PubMed Central
FIGURE 5 Application of one-pot reaction cascade in the synthesis of β-lactam antibiotics by PGA.
FIGURE 5 Application of one-pot reaction cascade in the synthesis of β-lactam antibiotics by PGA.CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Moody, 2011, Process for the Synthesis of Cefaclor

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Metadata

Authors
Pan, X., Xu, L., Li, Y., Wu, S., Wu, Y., & Wei, W.
Affiliations
  • Northern Jiangsu People's Hospital (CN)
  • Gunma University (JP)
Corresponding author
  • Pan, Xin
  • Wu, Yong
  • Wei, Wenping
ORCID
Venue
Frontiers in Bioengineering and Biotechnology
Publisher
Frontiers Media SA
Published
2022-07-18
Volume
10
Pages
936487-936487
ISSN
2296-4185 (ISSN-L)
DOI
10.3389/fbioe.2022.936487
PMC
PMC9340067
OpenAlex
W4285801616
Cited by
31
References
95
Citations by year
2026: 10 · 2025: 10 · 2024: 7 · 2023: 4
FWCI
0.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Bioengineering and Biotechnology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Institute of Process Engineering, CAS Institutional Repository (submittedVersion)
Funders
  • National Natural Science Foundation of China
  • Natural Science Research of Jiangsu Higher Education Institutions of China
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Enzyme Production and Characterization
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis of β-Lactam Compounds
Keywords
beta-lactam antibiotics, penicillin G acylase, enzymatic synthesis, biocatalysis, protein engineering, solvent engineering, in situ product removal, antibiotic biosynthesis, green synthesis

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