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<p>Flavoprotein oxidases constitute a major class of enzymes involved in oxidation reactions essential to primary metabolism and the biosynthesis of specialized metabolites. Within this group, the vanillyl-alcohol oxidase/<i>p</i>-cresol methylhydroxylase (VAO/PCMH) family comprises flavin-dependent oxidases with variable modes of FAD cofactor binding, ranging from non-covalent to mono- or bicovalent linkages, which influence both redox potential and catalytic versatility. Among them, Berberine Bridge Enzymes (BBEs) represent a specialized subgroup characterized by a conserved bicovalent FAD linkage and a distinctive cap-domain architecture that governs substrate recognition and positioning. Initially identified in plants for their role in benzylisoquinoline alkaloid biosynthesis, BBEs catalyze oxidative cyclization reactions that generate key structural scaffolds. Subsequent studies have revealed a broader family of homologous enzymes, collectively referred to as BBE-like oxidases, which are distributed across plants, fungi, and bacteria. These enzymes exhibit a broader functional repertoire, catalyzing oxidative reactions involved in the biosynthesis of alkaloids, cannabinoids, and antibiotics. In plants, BBE-like enzymes also contribute to physiological processes such as lignification, stress responses, and the modulation of plant immunity. The catalytic versatility of BBE-like oxidases arises from a conserved flavin-dependent redox mechanism combined with structural diversification of substrate-binding regions, enabling adaptation to chemically diverse substrates and reaction pathways. This functional plasticity has positioned these enzymes as attractive targets for metabolic engineering and synthetic biology applications aimed at the sustainable production of high-value compounds. This review focuses on the evolution, structural diversity, and catalytic mechanisms of BBE and BBE-like oxidases within the VAO/PCMH family, with particular emphasis on their roles in specialized metabolism and their emerging applications in biotechnology.</p>

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Berberine bridge enzyme-like oxidases in plant specialized metabolism: evolution, catalytic diversity and opportunities for metabolic engineering

  • 期刊论文

  • 发表日期：

    2026年7月11日

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  • Viviane Merveille Bakam,
  • Natacha Mérindol,
  • Hugo Germain,
  • Isabel Desgagné-Penix

摘要

Flavoprotein oxidases constitute a major class of enzymes involved in oxidation reactions essential to primary metabolism and the biosynthesis of specialized metabolites. Within this group, the vanillyl-alcohol oxidase/p-cresol methylhydroxylase (VAO/PCMH) family comprises flavin-dependent oxidases with variable modes of FAD cofactor binding, ranging from non-covalent to mono- or bicovalent linkages, which influence both redox potential and catalytic versatility. Among them, Berberine Bridge Enzymes (BBEs) represent a specialized subgroup characterized by a conserved bicovalent FAD linkage and a distinctive cap-domain architecture that governs substrate recognition and positioning. Initially identified in plants for their role in benzylisoquinoline alkaloid biosynthesis, BBEs catalyze oxidative cyclization reactions that generate key structural scaffolds. Subsequent studies have revealed a broader family of homologous enzymes, collectively referred to as BBE-like oxidases, which are distributed across plants, fungi, and bacteria. These enzymes exhibit a broader functional repertoire, catalyzing oxidative reactions involved in the biosynthesis of alkaloids, cannabinoids, and antibiotics. In plants, BBE-like enzymes also contribute to physiological processes such as lignification, stress responses, and the modulation of plant immunity. The catalytic versatility of BBE-like oxidases arises from a conserved flavin-dependent redox mechanism combined with structural diversification of substrate-binding regions, enabling adaptation to chemically diverse substrates and reaction pathways. This functional plasticity has positioned these enzymes as attractive targets for metabolic engineering and synthetic biology applications aimed at the sustainable production of high-value compounds. This review focuses on the evolution, structural diversity, and catalytic mechanisms of BBE and BBE-like oxidases within the VAO/PCMH family, with particular emphasis on their roles in specialized metabolism and their emerging applications in biotechnology.