Benzylisoquinoline alkaloids sanguinarine

Benzylisoquinoline is the structural backbone of many alkaloids that possess potent therapeutic properties. Benzylisoquinoline alkaloids (BIAs) include the narcotic analgesics codeine and morphine, the antimicrobials sanguinarine and berberine, the anti-tussive and anticancer agent noscapine, and the muscle relaxants papaverine and tubocurarine. 

Figure 6.21 Biosynthesis of benzylisoquinoline alkaloids berberine, noscapine, pabnatine, and sanguinarine.

Morphine and codeine are members of the large and diverse group of benzylisoquinoline alkaloids, of which morphine and sanguinarine share a common biosynthetic pathway, beginning with the condensation of two L-Tyr derivatives to produce the central precursor (S)-norcoclaurine yields (S)-reticuline, the last common intermediate in the biosynthesis of both sanguinarine and morphine. Berberine bridge enzyme (BBE) catalyzes the conversion of (S)-reticuline to (S)-scoulerine, the first committed step in the sanguinarine pathway. Alternatively, (S)-reticuline can be isomerized to its (R)-epimer as the first step in the formation of morphine. Since the pathway from tyrosine to (S)-reticuline is also known at the enzyme level, the conversion of L-tyrosine to macarpine involves a total of 19 enzymes which are now at least partially characterized. 

At the subcellular level, the morphine biosynthetic pathway combines several cytochrome P-450 enzymes, bound to ER membranes (Chou and Kutchan, 1998) with soluble enzymes that reside in ER derived vesicles, e.g. norcoclaurine synthase, or in the cytosol, e.g. codeinone reductase (Zenk, 1994 Facchini and St-Pierre, 2005). The diverse localization of the biosynthetic enzymes requires several transport steps of the intermediates between cytosol, vesicles and vacuoles. Only one of them has been characterized by pioneering experiments (Deus-Neumann and Zenk, 1986) vacuolar vesicles prepared from Fumaria capreolata accumulate (S)-reticulin or (S)-scoulerin via highly specific transporters, that discriminate between (S)- and (R) stereoisomer and exclude other benzylisoquinolines (sanguinarine, protopine, morphine) and alkaloids of unrelated families (e.g. indoles or tropanes). Uptake is energized by the pH gradient across the tonoplast. Accumulated... 

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