Morphine, biosynthesis from opium

There are two possible biosynthetic pathways for the conversion of thebaine to morphine, Fig. (67) [148]. One is orthodoxically known in the litreatures [4, 130, 131], that is morphine biosynthesis from thebaine via codeinone and codeine. Another one i.e. the first ever demonstrated by Brochmann-Hanssen in 1984 [149], is the biosynthesis via oripavine and morphinone. The transformed clone could synthesize codeine but lacked morphine though the non-transformed clone obtained from the same plant material accumulated morphine at the latter developmental stage (Table 21). This suppressed morphine content was also observed in the opium derived from the transformed P. somniferum plants that had been... 

Conversion of (S)-reticuline to its ( )-epimer is the first committed step in morphinan alkaloid biosynthesis in certain species. 1,2-Dehydroreticuline reductase catalyzes the stereospecific reduction of 1,2-dehydroreticuline to (7 )-reticuline.39 Intramolecular carbon-carbon phenol coupling of (if)-reticuline by the P450-dependent enzyme salutaridine synthase (STS) results in the formation of salutaridine.40 The cytosolic enzyme, salutaridine NADPH 7-oxidoreductase (SOR), found in Papaver bracteatum and P. somniferum, reduces salutaridine to (7S)-salutaridinol.41 Conversion of (7S)-salutaridinol into thebaine requires closure of an oxide bridge between C-4 and C-5 by acetyl coenzyme A salutaridinol-7-0-acetyltransferase (SAT). The enzyme was purified from opium poppy cultures and the corresponding gene recently isolated (Fig.7.2).42,43 In the last steps of morphine... 

The role of reticuline as an intermediate in the biosynthesis of the mor-phinan alkaloids (Fig. 2.8) was demonstrated by the isolation both of (S)-and (f )-reticuline from the opium poppy. An excess of the (S)-reticuline over the (f )-isomer was found in opium (poppy latex) obtained from the mature plant, in contrast to the roughly equal amounts of these two isomers that occur in poppy seedlings. Both isomers were found to be incorporated into morphine, the major alkaloid isolated from opium, although incorporation of the (f )-isomer was slightly more efficient. (f )-Reticuline is firmly established in P. somniferum as the precursor of the morphinan-type alkaloids (Loefer and Zenk, 1990). (S)-Reticuline, however, is the central intermediate in isoquinoline alkaloid biosynthesis. It has been postulated that (R)-reticuline is formed from (S)-reticuline by isomerization. This inversion of configuration can be explained by the intermediate formation of the 1,2-dehydroreticulinium ion originating from (S)-reticuline, followed by stereospecific reduction to yield the (R) counterpart. The 1,2-dehydroreticulinium ion is efficiently incorporated into opium alkaloids and its role as a precursor of the morphinan-t)q)e alkaloids has been unequivocally established (De-Eknamkul and Zenk, 1990, 1992). 

Figure 2 Semisynthetic bulk drugs Ampicillin (antibacterial) from penicillin G. Modifications of biosynthetic structures are often created to improve the in vivo attributes of the original compound, utilizing the biosynthesis product as the starting material containing most, if not all, of the structural complexity that provides the basic biological activity. Similarly, codeine (analgesic), although found in opium from Papaver plants, is most economically made by methylation of morphine, which is more efficiently isolated from opium.

Having looked at the biosynthesis of pyridoxal 5 -phosphate in the previous section, let s now go up a level in complexity by looking at morphine biosynthesis. Morphine, perhaps the oldest and best known of all alkaloids, is obtained from the opium poppy, Papaver somniferum, which has been cultivated for more than 6000 years. Medical uses of the poppy have been known since the early 1500s, when crude extracts, called opium, were used for the relief of pain. Morphine was the first pure compound to be isolated from opium, but its close relative codeine also occurs naturally. Codeine, which is simply the methyl ether of morphine and is converted to morphine in the... 

The opium poppy (Papaver somniferum L. [Papaveraceae]) latex contains benzylisoquinoline alkaloids and is a widely known source of the analgesic drugs morphine and codeine. The biosynthesis of benzylisoquinoline alkaloids begins with a condensation reaction catalyzed by norcoclaurine synthase of DA [161]. The structural features of benzylisoquinoline alkaloids derived from DA might provide some explanation for the documented affinity of some natural alkaloids of this class, and some synthetic derivatives, for DA receptors [162]. Indeed, the chemical structure of morphine has been used as a template for the development of the PD drug, apomorphine (47). Apomorphine includes a catecholaminergic moiety in its... 

The existence of a metabolic channel wonld be in line with the regnlatory independence of the enzymes of the morphinane branch from the general benzylisoqninohne biosynthesis. A well known expression of this phenomenon is the intimate link between lacticifer development and biosynthesis of morphine dedifferentiated, cultured cells of opium poppy do not prodnce... 

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