Monoterpene indole alkaloids MIA

Indole alkaloids are derived from tr)y)tophan, which is formed in the shiki-mate pathway. In the case of the terpenoid indoles, tryptophan is usually first converted to tiyptamine by the enzyme tryptophan decarboxylase (TDC) (Fig. 2.9). This enz)une occurs in the cytosol and has been detected in all parts of the developing seedling and in cell cultures of C. roseus (De Luca, 1993). If appears to be a pyridoxoquinoprotein, as two molecules of pyridoxal phosphafe and two molecules of covalently bound pyrroloquinoline quinone were found per enz)une molecule (Pennings et al, 1989). A tdc cDNA clone has been isolafed by immunoscreening of a C. roseus cDNA expression library (De 

Its identity was confirmed by expression in . coli and N. tahacum (De Luca, 1993 Songstad et al, 1990). TDC is capable of decarboxylating both L-tryptophan and L-tyrosine in vivo. The tdc occurred as a single copy in C. roseus and the protein, when isolated, was found to be similar to that found in parsley and the fruitfly, except that it was found to lack 13 N-terminal amino acids compared with TDC from these sources. This suggested a processing of TDC protein in C. roseus and Camptotheca acuminata, from which it has also been isolated (Goddijn, 1992). However, this cleaved form acts as a functional enzyme and confirms that TDC is a cytosolic enzyme (De Luca, 1993 Stevens et al., 1993). The 13 N-terminal amino acids present in other TDC probably function as a signal peptide for membrane insertion or translocation. 

In cell cultures, the expression of the reductase mRNA, like the tdc and stric-tosidine synthase sts) genes, was found to be induced by elicitors and down-regulated by auxins. GlOH was found to be localized in provacuolar membranes and not in the endoplasmic reticulum like many other cytochrome P450 enzymes. Interestingly, this enzyme is inhibited by the end product, alkaloid catharanthine, but not by vindoline and vinblastine. Therefore, feedback regulation may also operate in vivo, provided that the catharanthine and GlOH are within the same cellular compartment (Facchini and De Luca, 2008). 

Stereospecific condensation between tiyptamine and seco-loganin in a Mannich-like reaction is carried out by the enz)une (S)-strictosidine s)m-thase and results in the formation of the glucoalkaloid, (S)-strictosidine, from which most monoterpene indole alkaloids are derived (Figs. 2.1 and 2.9). 

Isolation of the stereospecific strictosidine s)mthase (STS) and formation of strictosidine with the 3a-(S) configuration proved conclusively that this was the natural precursor of the terpenoid indole alkaloids. Strictosidine occurs naturally in Rhazya stricta and the synthase has been isolated from a number of other species Amsonia salicifolia, A. tabemaemontam, Catharanthus pusillus, C. roseus, Rauvolfia verticillata, R. vomitoria, R. serpentina, Rhazya orientalis and Voacanga africana. The enzyme has been purified to homogeneity from R. serpentina (Hampp and Zenk, 1988). A comparison of the activity of STS from C. roseus roots, the only portion of the plant to contain ajmalicine, with that present in plant cell cultures producing the same alkaloid demonstrated that the plant cell cultures are far more metabolically active (Ziegler and Facchini, 2008). 

---

Some monoterpene indole alkaloids (MIAs) have been evaluated regarding their inhibitory activity on MAOs. Yohimbine (14) displayed a weak rMAO inhibition obtained with a partially purified liver mitochondrial preparation. These effects were observed with concentrations of 100 pM (10-20% inhibition) and 1000 pM (30-40% inhibition) [39]. In another smdy, isomers of 14, tested at 1000 pM, showed weak inhibition (5-15%) of rMAOs obtained with a hypothalamic tissue homogenate [40]. The antitumour agents vinblastine... 

---