Branched-chain amino acid biosynthetic platforms in prokaryotic cell factories: metabolic engineering and value-added chemical biomanufacturing

Abstract

Branched-chain amino acids (BCAAs) are recognized not only as industrially important fermentation products but also as versatile biosynthetic platforms for the production of branched-chain value-added chemicals. The characteristic branched carbon skeletons of BCAAs, together with their metabolically versatile intermediates, enable the biosynthesis of a broad spectrum of value-added chemicals, including branched-chain α-keto acids (BCKAs), alcohols, and carboxylic acids. This review systematically examines the metabolic basis of BCAA biosynthesis and the features underpinning its platform functionality, followed by a comprehensive overview of metabolic engineering strategies for constructing efficient BCAA-producing prokaryotic cell factories. Particular emphasis is placed on bacterial production platforms, especially Escherichia coli and Corynebacterium glutamicum, in which engineering carbon flux through enhanced glucose uptake, expanded pyruvate availability, reinforced biosynthetic flux, regulated cofactor supply, and improved product export. Advances in enzyme engineering are also discussed, with four complementary strategies highlighted for expanding the branched-chain chemical repertoire: enhancement of catalytic activity, improvement of substrate selectivity, engineering of cofactor utilization through NADH regulation, and optimization of enzyme expression. Finally, current challenges and future directions are discussed, and an engineering framework is proposed for the rational development of BCAA platform-based biomanufacturing toward an expanded repertoire of branched-chain chemicals.