# Bacterial Semichemicals and Transkingdom Interactions with Insets and Plants
## 3 BVOC Biosynthetic Pathways and Their Intersections with Primary and Secondary Metabolism
### BVOCs and Secondary Metabolism
#### 3.2.2 Terpene and Terpenoid Metabolism in Bacteria
Details of the MEP pathway are illustrated in Figure 5. The MEP pathway begins with the addition of pyruvate to glyceraldehyde-3-phosphate with the decarboxylation of pyruvate to yield 1-deoxy-p-xylulose-5-phosphate (DXP) and CO\({}_{2}\). This reaction is catalyzed by DXP synthase (DXS) [153]. However, the same reaction occurs in E1 subunit of pyruvate kinase or decarboxylate as moonlighting activity [154; 155]. The next steps are wel- characterized and are catalyzed by enzymes encoded by 6 _isp_ genes: _ispC_, _ispD_ (_ygbP_), _ispE_ (_ydbB_) and _isP_ (_ygbB_), _isP_ (_gcpE_), _ispH_ (_lytB_) [153]. DXP is reduced to 2-C-methyl-p-erythitol 4-phosphate (MEP) by DXP reducoisomerase (IspC, DXR) [156; 157]. MEP is converted 4-diphosphocytidyl-2-C-methyl-p-erythtritol (CDP-ME) by CDP-ME synthase (IspD, CMS) using CTP [158]. CDP-ME kinase (IspE, CMK) phosphorylates CDP-ME yielding 4-diphosphocytidyl-2-C-methyl-p-erythtritol 2-phosphate (CDP-MEP); 2-C-methyl-p-erythtritol 2,4-cyclodiphosphate synthase (IspF, MCS), then detaches the CMP and converts the intermediate into phosphocyclic compound 2-C-methyl-p-erythtritol 2,4-cyclodiphosphate (ME-cpp) [159; 160]. Finally, hydroxy-methyl-butenyl 4-diphosphate [HMBPP] synthase (IspG, HDS) catalyzes the synthesis of HMBPP from ME-cpp, while 4-hydroxy-3-methylbut-2-enyl-diphosphate reductase (IspH, HDR) synthesizes a mixture of IPP and DMAPP [161]. In the MEP pathway, as well as in the MVA pathway, an isomerase (IDI) catalyzes the interconversion of IPP and DMAPP [162]. Although all terpen are synthesized from two common precursors, the basic C5 isoprene units IPP and DMAPP, the structural and functional diversity of the final products are surprisingly high. Such a diversity is largely dependent on the biosynthetic enzymes that process the precursors to form the terpene rings [143]. The head-to-tail condensation of IPP to DMAPP results in the formation of geranyl pyrophosphate (GPP), and the further addition of another IPP unit leads to production of farnesyl pyrophosphate (FPP). Geranylgeranyl pyrophosphate is formed by the condensation of one FPP with one IPP unit. GPP, FPP, and GGPP are, respectively, the acyclic precursors for the biosynthesis of monoterpene, sesquiterpene, and diterpene, which are the most common terpen in bacteria (Figure 5). Cyclization reactions are catalyzed, respectively, by monoterpene cyclases, sesquiterpene cyclases, and diterpene cyclases. The first bacterial monoterpene synthase (encoded by _cnsA_) was isolated from _Streptomyces clavuligerus_ ATCC 27064 by [PERSON] and coworkers [163]. This enzyme catalyzes the biosynthesis of 1,8-cineole from GPP involving an \(\alpha\)-terpineol intermediate until the complete conversion. The reference monoterpene synthase, 2-methylisoborneol synthase, instead uses (E)-2-methyl-GPP as a substrate. The product, 2-methylisoborneol, is volatile homoterpene alcohol with an earthy, musty odor. The enzyme mechanism is well-understood and involves ionization of the substrate followed by isomerization and final cyclization [164]. A second monoterpene synthase was identified in another _Streptomyces clavuligerus_, the linalool/nerolidol synthase (_lnsA_). This enzyme catalyzes the synthesis of the acyclic terpenoids (_3R_)-linalool and (_3R_)-(_E_)-nerolidol using, GPP and FPP as substrates, respectively [165]. Finally, as a moonlighting function, several sesquiterpene synthases may also produce monoterpenes using GPP, an unusual substrate for this type of terpene synthase. This hypothesis was demonstrated by heterologous expression in _E. coli_ of the epicubebol synthase from _Streptosporagium roseum_[166]. Sesquiiterpenes synthases are the major class of terpene synthases that are found in bacteria. These enzymes use FPP as substrate, but different enzymes can cyclize the precursors with different mechanisms, resulting in various ring closures: 1,6 (bisabolyl cation), 1,7 (cyclohexptenyl cation), 1,10 ((E,E)-germacrenyl cation), and 1,11 ((E,E)-humulyl cation).