Chalcone Synthase: From Discovery to Biotechnological Applications

Flavonoids, a class of phenolic compounds widely distributed throughout the plant kingdom, exhibit extensive physiological and pharmacological properties. Chalcone synthase (CHS), the key and rate-limiting gateway enzyme in flavonoid biosynthesis, catalyzes the condensation reaction between malonyl-CoA and p-coumaroyl-CoA to produce chalcone, the core C6-C3-C6 skeleton of flavonoids and related secondary metabolites. This review systematically summarizes the current knowledge of CHS, focusing on its protein structure, catalytic mechanism, evolutionary origin, and divergence patterns. It further elaborates on the precisely orchestrated multilayered regulation of CHS, including tissue-specific and developmental transcription mediated by MYB, bHLH, and WD40 transcription factors, responses to key environmental cues (light and biotic/abiotic stress stimuli), and post-translational modifications (ubiquitination and phosphorylation) that modulate its stability and catalytic activity. Additionally, targeted rational design and metabolic engineering strategies (gene-directed evolution, heterologous expression, pathway optimization) to efficiently enhance CHS performance in microbial and plant cell factories for boosted flavonoid production are summarized. This comprehensive analysis provides a solid theoretical and practical basis for optimizing CHS function and flavonoid biosynthesis, facilitating the sustainable development and practical implementation of industrial and agricultural applications of these bioactive compounds.