# Microbial Biosynthesis of Lactones: Gaps and Opportunities towards Sustainable Production
###### Abstract  
Lactones are volatile organic compounds widely present in foods. These chemicals are applied as flavors and fragrances in the food, cosmetics and pharmaceutical industries. Recently, the potential of lactones as green solvents and fuel precursors reinforced their role as platform compounds of future bio-based economies. However, their current mode of production needs to change. Lactones are mainly obtained through chemical synthesis or microbial biotransformation of hydroxy fatty acids. The latter approach is preferred but still needs to use more sustainable substrates. Hydroxy fatty acids are non-abundant and non-sustainable substrates from environmental, health and economic points of view. Therefore, it is urgent to identify and engineer microorganisms with the rare ability to biosynthesis2 lactones from carbohydrates or renewable lipids. Here, we firstly address the variety and importance of lactones. Then, the current understanding of the biosynthetic pathways involved in lactone biosynthesis is presented, making use of the knowledge acquired in microorganisms and fruits. From there, we present and make the distinction between biotransformation processes and de novo biosynthesis of lactones. Finally, the opportunities and challenges towards more sustainable production in addition to the relevance of two well-known industrial microbes, the filamentous fungus _Ashlyya gossypii_ and the yeast _Yarrowia lipolytica_, are discussed. 2021  
of million tons per year and values between -US$ 300-6000/kg, with a decreasing trend along the years due to the technological developments regarding their production [14,15]. Additionally, lactones have also been reported to be green solvents and fuel precursors (e.g., \(\gamma\)-valerolactone) [16], expanding their relevance for the transition to a bio-based sustainable economy. Some lactones are green/non-toxic solvent alternatives and their chemical properties enable their use in the production of C8 alkanes (used in jet fuel), C9 and C18-C27 alkanes (gasoline and biodiesel) and other polymers, e.g., nylon precursors [2,16]. Therefore, lactones are currently considered platform compounds for future sustainable circular bioeconomies. Lactones are still mainly obtained through chemical synthesis, via oxidation of cyclic ketones with hydrogen peroxide and acetic acid in the presence of a strong acid catalyst. However, this raises environmental concerns due to the high use of solvents and acids, the generation of undesired racemic mixtures as a final product and the fact that it is not well accepted by consumers. In turn, microbial production is a more sustainable and efficient way of producing optically pure lactones with similar configurations and properties to those found in fruits [2]. Developed and patented biotechnological processes for lactone production have been exclusively made by biotransformation. Biotransformation refers to the microbial conversion of an immediate precursor into a lactone, and is accomplished by adding that precursor to the production medium of microorganisms with the ability to convert it into a specific lactone. For the microbial production of \(\gamma\)-decalactone, the yeast _Yarrowia lipolytica_ has been the preferred system exploited, using hydroxy fatty acids as precursors [17]. However, this method of production holds some limitations. First, the production of a certain lactone completely depends on the availability of the corresponding precursor. It is therefore not possible to use the same medium to produce different lactones. Figure 1: Chemical structures of different \(\gamma\)-lactones and \(\delta\)-lactones produced by microbial de novo biosynthesis. Numbers refer to Table 1, where these lactones are identified and their main properties described. Second, the industrial and commercial value of the precursors used are high and often competitive with that of lactones [2].