Galanthamine biosynthesis

From L-tyrosine, or alternatively from L-phenylalanine, there is one further alkaloid biosynthesis pathway. This is the galanthamine pathway (Figure 38). Galanthamine synthesizes with tyramine, norbelladine, lycorine, crinine, N-demethylnarwedine and Al-demethylgalanthamine. Schiff base and reduction reaction, oxidative coupling and enzyme NADPH and SAM activity occur in this pathway. Schiff base is a reaction for the ehmination of water in formation with the C—N bonds process. 

In daffodil plants, galanthamine (147) is biosynthesized from the aminophenols 397, 398, and 399 but not from 343 which is, however, in the same plants a good precursor of haemanthamine (318) and lycorine (1) (Vol. XI, p. 397). These experimental results were interpreted as proving the existence of a definite order of methylation of norbelladine (399) during the biosynthesis of 147. Thus, methylation takes place in the first instance at nitrogen to give 398, later converted into 397. 

Although norbelladine was shown not to be a precursor of galanthamine (101) in King Alfred daffodils, an incorporation of this compound with labels as shown (103), comparable to that for lycorine (104), has been obtained for galanthamine in Leucojum aestivum As expected, the lycorine showed loss of half its tritium. On the other hand, no loss of tritium was apparent in the galanthamine. The latter result suggested that in the biosynthesis of galanthamine conversion of (105) to narwedine (100) was either not reversible or, if so, enzy-mically controlled. 

The work on the biosynthesis of Amaryllidaceae alkaloids reached a peak in the period 1960-1976 with a great number of studies related with this subject. However, since then, little new work has been produced apart from the isolation of compounds predicted as biosynthetic intermediaries of a certain pathway or, more recently, a new biosynthetic proposal to obtain galanthamine (70), which differs from the initial one. 

However, the most recent studies related to the biosynthesis of galanthamine (70) seem to contradict the evidence set forth here. Experiments carried out in cell suspension cultures of Leucojum vemum have shown that the methylation of the nitrogen atom occurs after the phenolic coupling and is brought about through an acetyl intermediate (140) (Fig. 12b). 

It is well established that profiles of alkaloids vary with time, location, and developmental stage. In many instances, the site of biosynthesis is restricted to a single organ, but accumulation of the corresponding products can be detected in several other plant tissues. Long-distance transport must take place in these instances. There are only a few data on the ontogenic variations and distribution of alkaloids in species of the Amaryllidaceae family, and some results have been obtained in Narcissus species, such as N. assoanus (with only lycorine-type alkaloids) or N. confusus (with alkaloids of the homolycorine, hemanthamine, tazettine, and galanthamine types) 84,87). 

Most of the biosynthetic research done on Amaryllidaceae alkaloids was carried out in the 1960s and early 1970s. Since then, the only noteworthy study has been the biosynthesis of galanthamine (75) and related alkaloids (181). As in most alkaloid biosyntheses, that of the Amaryllidaceae follows a sequential pattern. 

Keywords Amaryllidaceae alkaloid plant secondary metabolism alkaloid biosynthesis natural products systems biology galanthamine... 

Figure 5. Biosynthesis of p-o alkaloids such as galanthamine and derivatives. Abbreviations R, reduction NMT, TV-methylation ODM, O-demethylation OMT, (9-methylation.

Biosynthesis of the third type of Amaryllidaceae alkaloids is represented by the formation of galanthamine (18) (Fig. 33.6). 

In daffodil plants, galanthamine is biosynthesized from compounds 19-21, but not from norbelladine (5) [which is a good precursor of haemanthamine (14) and lycorine (8) in the same plants] (Fig. 33.6). These experiments suggest a definite order of methylation of norbelladine (5) during the biosynthesis of galathamine. In feeding experiments with the plant Leucojum aestivum, [2,4- H2 C-0-methyl]0-methylnorbelladine (13) is a precursor of galanthamine (18) that retains the same ratio as in the precursor. There... 

Fuganti C (1969) Biosynthesis of galanthamine feeding experiments in Leucojum aestivum (Amaryllidaceae). La Chimica e I Industria 51 1254... 

Elchhom J, Takada T, Klta Y, Zenk MH (1998) Biosynthesis of the Amaryllidaceae alkaloid galanthamine. Phytochemistry 49 1037... 

Further experimental results established norbelladine 6.180) and some of its methylated derivatives (clearly not others) as key biosynthetic intermediates in the biosynthesis of, e.g., lycorine 6.185), haemanthamine 6.187) and galanthamine 6.190) [125-128, 132, 133]. As elsewhere (see Section 6.3) hydroxy-groups ortho and/or para to sites of new bond formation between aromatic rings are essential for biosynthesis to proceed, a telling set of examples in support of the phenol-oxidative coupling hypothesis. Of further interest is the reported isolation of an enzyme, from a plant of the Amaryl-lidaceae, which, when incubated with norbelladine and 5-adenosylmethionine (source of methyl groups), yielded almost entirely the 0-methylnorbelladine, 6.181), that is involved in alkaloid biosynthesis [134]. 

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