Reconstructing the scent of nature: advanced biosynthesis and engineering strategies for high-value natural fragrance...

Natural fragrance compounds determine the sensory quality of food, cosmetics, and consumer goods. Driven by the limitations of traditional botanical extraction and petrochemical synthesis, sustainable biomanufacturing empowered by systems metabolic engineering and enzyme biocatalysis has emerged as a compelling alternative. This review systematically summarizes recent advances in the biosynthesis of high-value natural fragrances. First, we delineate the biosynthesis-driven classification of these volatile molecules and elucidate the structure-odor relationship, establishing a rational basis for target selection. Subsequently, we outline the core biosynthetic networks responsible for generating the four major lineages: terpenoids, phenylpropanoids and benzenoids, fatty acid derivatives, and amino acid derivatives. To provide systematic guidance for the biosynthesis of natural fragrance compounds, we comprehensively detail advanced engineering strategies across three progressive hierarchical tiers: the enzyme, metabolic, and cellular levels. Finally, we evaluate current challenges and future directions, with a specific emphasis on biosynthetic bottlenecks, bioprocess scale-up, and the rational design of complex multi-component aromas, thereby providing new insights into the sustainable bioproduction of these high-value natural fragrance compounds.