## 1 Introduction  
Terpenoids are a large family of natural products with diverse biological functions and an incredible array of industrial applications, including being used as vitamins, pigments, medicine, and fragrances [1, 2]. Notable examples of terpenoids currently used for human consumption include the anticancer agent taxol, the antimalarial drug artemisinin, the powerful antioxidant astaxanthin, and the essential oils from sandalwood and agarwood. Production of these compounds by extraction from natural sources largely fails to scale up to meet industrial scale and is dependent on seasonal conditions. These factors, coupled with the increasing demands for terpenoids, have led to an interest in finding an alternative production platform [3, 4, 5]. Notably, the production of terpenoids in the yeast _Saccharomyces cerevisiae_ has emerged as an attractive alternative, with several terpenoids (such as farresene [6] and artemisinin [7]) already making their way into the market [8]. Despite their vast structural and functional diversity, all terpenoids are synthesized from the isomeric five-carbon (C5) precursors isopenetyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which, in yeast and mammals, are produced by the mevalonate (MEV) pathway (Figure 1) [2]. The MEV pathway involves the condensation of three molecules of acetyl-CoA to 3-hydroxy-3- methylglutaryl CoA (HMG-CoA) and subsequent reduction to MEV by HMG-CoA reductase. From MEV, three phosphorylations and one decarboxylation produce IPP, and isomerization to DMAPP completes the pathway. The IPP and DMAPP precursors are then condensed to lengthen the carbon chain in C5 increments to form geranyl pyrophosphate (GPP, C10) and farnesyl pyrophosphate (FPP, C15). In _S. cerevisiae_, this condensation step is catalyzed by the enzyme FPP synthase (FPPS) [9]. Finally, dedicated terpene synthases convert these prenyl pyrophosphate intermediates to monoterpenes (C10) and sesquiterpenes (C15), and, in the process, generate structural diversity as well as biological activities of the resulting terpenoids (Figure 1). In sandalwood (_Santalum album_ Linn), sandalene synthase converts FPP to \(\alpha\)-santalene as a major product and small amounts of \(\beta\)-santalene and \(\alpha\)-exo-bergamotene [10; 11]. In Agarwood (_Aquilaria_ spp. ), several dedicated terpene synthases exist to convert FPP into a variety of fragrant terpenoids including \(\alpha\)-humulene, \(\delta\)-guaiene and \(\beta\)-eudesmol [12; 13; 14]. In this work, we engineered the budding yeast _S. cerevisiae_ to produce fragrant terpenids found naturally in sandalwood and agarwood. We chose _S. cerevisiae_ as the production host for several reasons. First, _S. cerevisiae_ is genetically tractable; thus, genetic tools for metabolic pathway manipulation are abundant. Second, the construction, isolation, and analysis of _S. cerevisiae_ mutant strains can be performed with relative ease. Third, _S. cerevisiae_ has a long and proven track record in various industrial applications, and the fermentation of _S. cerevisiae_ has previously been manipulated to produce numerous heterologous metabolites including other terpenoids. Finally, _S. cerevisiae_ can be cultivated  
Figure 1: Metabolic engineering of _S. cerevisiae_ for production of fragrant terpenids from agarwood and sandalwood. Mevalonate pathway enzymes (yellow box, highlighted in red) were overexpressed to increase the pool of the key intermediate farnesyl pyrophosphate (FPP). Terpene synthase enzymes (highlighted in blue) were heterologously expressed in the engineered yeast to produce the fragrant terpenids. Expression of the squalene synthase enzyme ERG9 was repressed to minimize the diversion of FPP towards sterol biosynthesis.