# Microbial Biosynthesis of Lactones: Gaps and Opportunities towards Sustainable Production
## 3 Pathways and Enzymes Involved in the Biosynthesis of Lactones
### Sporidiobolus salmonicolor  
It was in 1972 that [PERSON] and colleagues reported the de novo biosynthesis of \(\gamma\)-decalactone [4] and in 1973 of cis-6-\(\gamma\)-dodecenolactone [38] by \(S\). _salmonicolor_ (former _Sporobolomyces odorus_). Two years later, \(\delta\)-decalactone and \(\delta\)-jasmin lactone were also identified in cultures of this yeast [39]. Later on, \(\gamma\)-octalactone and \(\gamma\)-nonalactone were also detected in cultures of this yeast when the effect of media composition on the de novo biosynthesis of lactones by \(S\). _salmonicolor_ was investigated [40]. From the five \(\gamma\)-lactones detected in this study, the major lactones produced were cis-6-\(\gamma\)-dodecenolactone and \(\gamma\)-decalactone, while \(\gamma\)-octalactone and \(\gamma\)-nonalactone were reported for the first time [40] (Table 1). In the 1990s, to resolve the intricate pathways of lactone biosynthesis, chirospecific analyses and enantiomer separations of the lactones produced by microorganisms were the preferred tools utilized. These works were mainly based on the study of the biotransformation of labeled fatty acids and derivatives to elucidate the precursors of particular lactones [41]. The yeast \(S\). _salmonicolor_, beyond its ability to produce a wide range of lactones, either through de novo biosynthesis and biotransformation, was the most important study model to this end due to its diverse fatty acid metabolism. The studies with \(S\). _salmonicolor_ gave important insights concerning the de novo biosynthesis process of  
Figure 2: Schematic representation of microbial biosynthesis of \(\gamma\)- and \(\delta\)-lactones. Overview of the different stages: biosynthesis of fatty acids (blue); formation of hydroxy fatty acids (purple); \(\beta\)-oxidation (green); and lactonization (orange). Traditional biotransformation processes are indicated by a grey box. Dashed boxes represent the most relevant enzymatic activities for improvement of lactones biosynthesis. lactones in this yeast, mainly regarding the origin of the oxygenated derivatives of fatty acids that are the reagents of \(\beta\)-oxidation [40]. Many studies demonstrated the biotransformation of fatty acids and hydroxy acids into lactones in this yeast. One of the first demonstrated the conversion of labeled linoleic acid (C18:2) into \(\delta\)-decalactone. This work highlighted the need for linoleic acid to undergo chemical transformations (such as hydroperoxidation) before the action of the \(\beta\)-oxidation pathway in the biosynthesis of \(\delta\)-decalactone [42]. This biotransformation was also studied by [PERSON] and colleagues [43]. In the same study, the biosynthesis of \(\delta\)-jasmin lactone was demonstrated from linoleic acid (C18:3). However, the introduction of the OH group in both precursors was unclear, with the authors suggesting that it may come from the following enzymatic activities: lipoxygenases, epoxygenase/epoxyhydrolase or hydratasees [43]. Subsequent work demonstrated the biotransformation of oleic acid into \(\gamma\)-decalactone, \(\gamma\)-dodecalactone and cis-6-\(\gamma\)-dodecenolactone in \(S\). _salmonicolor_[44]. For \(\gamma\)-decalactone  
\begin{table}
\begin{tabular}{c c c c c c} \hline
**Compound** & **PubChem CID** & **Molecular Formula** & **Odor Descriptor** & **Microorganisms** & **Reference** \\ \hline \multicolumn{6}{c}{\(\gamma\)-lactones} \\ \hline \(\gamma\)-valerolactone (1) & 7921 & C\({}_{5}\)H\({}_{8}\)O\({}_{2}\) & Peach & _F. poae_ & [34] \\  & 7921 & C\({}_{5}\)H\({}_{8}\)O\({}_{2}\) & Peach & _A. gossypii_ & [23] \\ \hline \(\gamma\)-caprolactone (2) & 12756 & C\({}_{6}\)H\({}_{10}\)O\({}_{2}\) & Creamy & _F. poae_ & [34] \\  & 12756 & C\({}_{6}\)H\({}_{10}\)O\({}_{2}\) & Creamy; & _A. gossypii_ & [23] \\ \hline \(\gamma\)-heptalactone (3) & 7742 & C\({}_{7}\)H\({}_{12}\)O\({}_{2}\) & Creamy; & _F. poae_ & [34] \\  & 12756 & C\({}_{7}\)H\({}_{12}\)O\({}_{2}\) & vanilla; & _F. poae_ & [34] \\  & 12756 & C\({}_{7}\)COcount & & _F.