## 6 Intra-Cellular Transport of TIA Intermediates and End Products  
The MEP pathway primarily takes place in the stroma of plastids or stromules in IPAP cells [11; 67]. However, isopentenyl diphosphate isomerase (IDI), which catalyzes the interconversion of isopentenyl diphosphate (IPP) and dimethylly diphosphate (DMAPP) to produce plenty of isoprenoids, was targeted to plastids, mitochondria and peroxisome [68]. Therefore, geraniol needs to be exported from the stroma by uncharacterized plastid inner or outer envelope transporter or some efficient metabolic flux into the cytosol of IPAP cells [69]. Geraniol is the substrate of the vacuolar membrane- or endoplasmic reticulum (ER)-associated G10H in the production of 10-hydroxygeraniol [70], which is further converted into the loganic acid by an ER-associated P450 DL7H. 10-hydroxygeraniol dehydrogenase (10 HGO) and 7-DLGT are found in the cytosol in IPAP cells. Loganic acid and secologanin are synthesized in the cytosol of epidermal cells, since LAMT and ER-anchored P450 SLS have been ensured to locate in the cytosol of the epidermis [71]. TDC involved in the shikimate pathway is localized to the cytosol of the epidermis. Tryptamine and secologanin are transported by unidentified transporters from cytosol into the vacuole, in which STR condenses them into strictoisidine [63]. The vacuole-accumulated strictoisidine or its hydrolyzed product aglycon needs to be transported out of the vacuole into the cytosol. SGD was a highly stable supramolecular complex within the nucleus, indicating that transportation of strictoisidine across the tonoplast by unidentified transporter plays a critical role in controlling TIA biosynthesis [63]. Strictsidine aglycone is converted into TIAs, such as catharanthine and tabersonine in the cytosol of epidermis. The conversion of tabersonine to vinodoline occurs in various compartments. The first two steps catalyzed by T16H and 16 OMT were localized in the cytosol [72]. T16H is an ER-anchored P450 and can release  
Figure 3: Tssue-specific biosynthesis and inter-cellular transport of TIAs through known and unknown transporters in _Catharanthus roseus_. The main TIA-biosynthesis cells in the leaf of C. _roseus_ include palisade and spongy mesophyll cells, internal phloem-associated parenchyma (IPAP), epidermal cells, laticifers and idioblasts. So far, most transporters possibly involved in transport of TIA intermediates or end products between these cells are unknown. The symbol “?” indicates the unknown transportation system of inter-cellular transport. The only identified transporter responsible for releasing of catharanthine out of upper epidermal cells onto cuticle is an ABC transporter TPT2. Whether plasmodesmata, symbolized in blue balls, are also involved in TIA intermediate transport between different types of cells remain to be determined. 16-hydroxytabersonine to the cytosol via its exposing catalytic site toward the cytosol [73; 74]. NME is likely to be localized in the leaf epidermis in association with chloroplast thylakoid membranes [75; 76; 77] (Figure 4). Figure 4: Subcellular compartmentation of TIA biosynthesis and inter- or intra-cellular transport of TLAs in _Catharantthus roseus_. TIA biosynthetic pathway in aerial organs of _C. roseus_ occurs in four cell types: internal phloem-associated parenchyma (IPAP), epidermal cells, laticifers and idioblasts. An ATP-binding cassette transporters TPT2 can transport catharanthine from epidermal cells to deposit on cuticle. The transporters transport TIA intermediates between these cells, such as desacetoxyindoline from epidermal cells to laticifers and idioblasts for vindoline biosynthesis and loganic acid communicates between the epidermal cells and IPAP cells, remain unknown, as indicated by question marks. In each type of cells, primarily, the epidermal cells, the vacuole, the chloroplast and possibly, the nucleus, are involved in the TIA biosynthesis. However, transporters or transport mechanisms for cross-membrane communication of these intermediates are largely unknown.