Benzylisoquinoline alkaloid formation

Zenk, M. H., Enzymology of benzylisoquinoline alkaloid formation, in The Chemistry and Biology of Isoquinoline Alkaloids (J. D. Phillipson, M. F. Roberts, and M. H. Zenk, eds.), 241-256, Springer-Verlag, Berlin, 1985. 

RUEFFER, M., ZENK, M.H., Distant precursors of benzylisoquinoline alkaloids and their enzymatic formation. Z. Naturforsch, 1987,42C, 319-332. 

Investigations of a number of enzymes involved in tyrosine conversion have suggested that the first committed step in the biosynthesis of benzylisoquinolines involves a Picfef-Spengler-type condensation of dopamine with 4-hydroxyphenylacetaldehyde (which derived from tyrosine) to give (S)-norcoclaurine, a compound that has proved to be pivotal in the formation of all benzylisoquinoline alkaloids (Fig. 2.5). The condensafion sfep is cafalysed... 

The alkaloids of the narcotine type can also be synthesized from benz[d]indeno(l,2-f ]azepine (133a) (698) (Scheme 45). Moreover, compound 133a forms a key substance for the synthesis of the tetrahydro-protoberberine (58), protopine (101), rhoeadane (154), and spiroben-zylisoquinoline (191) ring skeletons. The compounds 133a and 133b arise also by rearrangement from the spirobenzylisoquinoline, protoberberine, and 1-benzoylisoquinoline skeletons. Therefore, it is assumed that even in the plants it plays a key role in the formation and interconversion of the benzylisoquinoline alkaloids with 17 carbon atoms in the skeleton (Scheme 45). 

Isoquinoline alkaloids are derived from tyrosine through the intermediacy of 3,4-dihydroxyphenylethylamine (dopamine) and a carbonyl unit of various origins. The genesis of tyramine, and dopamine from tyrosine has been described previously (see Chapter 28). In contrast to benzylisoquinoline alkaloids (see below), the formation of isoquinoline alkaloids usually involves the amine and an a-ketoacid instead of an amine and aldehyde. However, several compounds can... 

Fig. 32.9. Formation of the precursors of benzylisoquinoline alkaloids (modified from Zenk et al., 1985 used with permission of the copyright owner, the American Society of Pharmacognosy Downers Grove, Illinois).

Although norlaudanosoline (26) (Fig. 32.7) was previously assumed to be the precursor of (5)-reticuline (20) (based on the condensation of dopamine and 3,4-dihydroxy-phenylacetaldehyde), this route of biosynthesis is no longer considered to account for the formation of benzylisoquinoline alkaloids. In previous reports, it was noted that an en-... 

Various species of Argemone and Eschscholtzia (Papavera-ceae) and Thalictrum (Ranunculaceae) contain pavine alkaloids (about 20) and isopavine alkaloids (about 10) with a tetracyclic nucleus derived from benzylisoquinoline alkaloids (Gozler, 1987 Guinaudeau and Bruneton, 1993 Schiff, 1987). The formation of argemonine (93) and related alkaloids is rationalized as follows (Fig. 32.31) (Geissman and Crout, 1969). An alternate mode of cyclization also has been observed in the formation of (— )-eschscholtzine (94) and (- )-munitagine (95). 

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. 

Besides the selection of high yielding cell lines and specialized methods for increasing alkaloid formation, the right choice of culture media is indispensable for an optimal production of benzylisoquinolines. 

Roberts MF, Antoun MD (1978) The relationship between L-DOPA decarboxylase in the latex of Papaver somniferum and alkaloid formation. Ph3rtochemistry 17 1083-1087 Roberts MF, McCarthy D, Kutchan TM, Coscia CJ (1983) Localization of enzyme and alkaloidal metabolites in Papaver latex. Arch Biochem Biophys 222 599-609 Rueffer M, El-Shagi H, Nagakura N, Zenk MH (1981) (S)-Norlaudanosoline synthetase the first enzyme in the benzylisoquinoline biosynthetic pathway. FEBS Lett 129 5-9 Sasse F, Backs-Hiisemann D, Barz W (1979) Isolation and characterization of vacuoles from cell suspension cultures of Daucus carota. Z Naturforsch 34 848-853 Schuchmann R, Wellmann E (1983) Somatic embryogenesis of tissue cultures of Papaver somniferum and Papaver orientate and its relationship to alkaloid and lipid metabolism. Plant Cell Rep 2 88-91... 

Singly bridged dimers resulting from C—C coupling had been produced by in vitro oxidation of benzylisoquinoline monomers, but this is the first report of their natural occurrence. Pisopowine-type dimers may be biogenetic intermediates in the formation of alkaloids of the funiferine (71) and tiliacorine (65) groups (566). 

Since it is reasonable that the two molecules derived from tyrosine which are involved in the formation of the benzylisoquinoline system should be different, an inequality of labeling at C-1 and C-3 in the derived alkaloids was anticipated. Whereas this was true for hydrastine, the ratio of activity at the two positions in berberine was approximately unity. 

Since both the dopamine and noradrenaline experiments gave berberastine of a much higher specific activity than that found in berberine and tetrahydroberberine, the latter alkaloids cannot be precursors of berberastine. Further, since noradrenaline is efficiently incorporated into berberastine, whereas berberine and tetrahydroberberine from this experiment have negligible activity, the C-5 hydroxyl group must be introduced at an early stage in the biosynthesis, certainly prior to the formation of the benzylisoquinoline intermediate. 

The chelidonine group of alkaloids cannot conveniently be looked upon as derived from benzylisoquinolines. In view, however, of the copresence of chelidonine with those already mentioned, it is to be expected that the ultimate precursors are the same. It can be assumed that the dihydroxy-phenylalanine is converted to a substituted phenylacetaldehyde, and two molecules of this can give rise to the aldol XX, which could conceivably ring-close to XXI, in strict analogy with the mechanism which must be involved in the well-known formation of /3-phenylnaphthalene from phenyl-... 

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