The flavor and fragrance industries are a burgeoning sector with an estimated market value of USD 40 billion in 2018 (S&P Global, 2021). Petrochemical synthesis or extraction from cultivated crops are the incumbent technologies for most flavors and fragrances due to cost or the natural availability of desired products, respectively. However, given advances in biotechnology, a surge in the interest in biomanufacturing flavors and fragrances using microbial or enzymatic platforms is ongoing (J. Zhou et al., 2020a). Unpredictable weather dependencies cause natural extraction processes to suffer from ingredient supply variability and pricing instability. Furthermore, the use of petrochemical precursors in these syntheses places additional demand on already limited fossil fuel reserves and can introduce abiological impurities. In contrast, biomanufacturing approaches can offer greener alternatives (Carroll et al., 2016a) and also have potential to exhibit higher yields and selectivity. Additionally, flavor and fragrance molecules derived from bioprocesses can be more commercially desirable than chemical synthesis routes if they can achieve the ‘natural’ label by starting with substrates identified in plants or other natural sources (Schrader et al., 2004, Schober et al., 2023). It is important to keep in mind that the use of enzymatic or cellular biocatalysts to convert chemically synthesized substrates to naturally occurring products does not qualify as ‘natural’, nor does biosynthesis of a product that does not exist in nature.

The range of relevant products, platforms, and participants in the flavors and fragrances sector is broad. Microbes can be genetically engineered to convert simple carbon sources such as sugars into compounds responsible for flavors such as lemon, peppermint, lavender, patchouli, grape, rose, cinnamon, vanillin, and much more (Mikš-Krajnik et al., 2017). Beyond their roles in aroma, several natural products in this class also appear to exhibit desirable biological properties, either towards humans (anti-inflammatory, anti-oxidant, etc.), insects (repellant or insecticide), or microbes (anti-microbial or anti-viral) (Paulino et al., 2021, Salehi et al., 2019). Given that many of the natural biosynthetic pathways in plants are still to be elucidated, much innovation has occurred in the design of biosynthetic pathways within microbial hosts, often beginning with fast-growing and well-characterized bacteria and yeast such as Escherichia coli and Saccharomyces cerevisiae. Next steps typically include the metabolic rewiring of the resulting organisms to increase carbon flux towards the pathway of interest though the optimization of native and heterologous gene expression, as well as the engineering of rate-limiting enzymes to exhibit greater activity or selectivity. However, a common challenge with developing an engineered fermentation process that is competitive economically is achieving a sufficient titer, rate, and productivity at large scale (Schempp et al., 2018). Finally, a large number of established and start-up specialty chemical companies across the globe are increasingly turning to biotechnology for flavor and fragrance manufacture, such as International Flavors and Fragrances (IFF), Givaudan, Solvay, DSM, Novozymes, BASF, Robertet, Ajinomoto, Conagen, Evolva, Manus Bio, and Ginkgo Bioworks.

Given the anticipated growth of the flavor and fragrance sector and the strong commercial interest in biomanufacturing (Chen, 2020), here we highlight the latest advancements in enzymatic and microbial production. We organize this review by the chemical class of flavors and fragrances, including terpenoids, esters, ketones, lactones, aldehydes, alcohols, and others. We cover both de novo biosynthesis (Fig. 1) and enzymatic biotransformation (Fig. 2). We also provide estimates of the total market size for flavor and fragrance molecules and compile recent patents available for some of these molecules. A concise overview of metabolic engineering approaches, such as overexpression of efflux pumps, transcriptional inactivation of oxidoreductases for aldehyde tolerance or enzymes involved in cofactor regeneration, that can enhance microbial tolerance to inhibitory aroma compounds produced during fermentation is also provided.