1,2-dehydroreticulinium

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). 

The later steps of morphine biosynthesis have been investigated in P. somniferum cells and tissue. Notably, in morphine biosynthesis, (S)-reticuline is converted to (R)-reticuline, thereby epimerizing the stereocenter generated by norcoclaurine synthase at the start of the pathway (Fig. Id). (S)-reticuline is converted to (R)-reticuline through a 1,2-dehydroreticuline intermediate. Dehydroreticuline synthase catalyzes the oxidation of (S)-reticuline to 1,2-dehydroreticulinium ion (44). This enzyme has not been cloned but has been purified partially and shown to be membrane-associated. This intermediate then is reduced by dehydroreticuline reductase, an NADPH-dependent enzyme that stereoselectively transfers a hydride to dehydroreti-culinium ion to yield (R)-reticuline. This enzyme has not been cloned yet but has been purified to homogeneity (45). 

Following the formation of S-norcoclaurine, hydroxylation at C3 with subsequent methylation yields S-reticuline.24 Although the R form corresponds to the correct stereochemistry of morphine at C9, both R and S isomers of reticuline have been found to act as precursors for thebaine, codeine and morphine and it is therefore apparent that S-reticuline is con-verted to its R form.25 Inversion is best explained by formation of an intermediate 1,2-dehydroreticulinium ion 22, followed by stereospecific reduction to yield R-reticuline, Figure 3. An NADPH-dependent enzyme, 1,2-dehydroreticuline... 

Now, it is known (Scheme 13.42) that 1,2-dehydroreticuline is reduced by 1,2-dehydroreticulinium reductase (EC 1.5.1.27) with the reduced form of NADPH being oxidized to NADP. However, the enzyme required for the oxidation of (5)-reticuline to 1,2-dehydroreticuline has not yet been characterized. 

Reticuline is a chemical compound that can be found in Lindera aggregata. It is also one of the alkaloids found in opium. Metabolism showed that 3 -hydroxy-A -methyl-(S)-coclaurine 4 -0-methyltransferase uses 5-adenosyl methionine and 3 -hydroxy-A -methyl-(S)-coclaurine to produce S-adenosylhomocysteine and (S)-reticuline. Reticuline oxidase uses (S)-reticuline and O2 to produce (S)-scoulerine and H2O2. Salutaridine synthase uses (R)-reticuline, NADPH, H", and O2 to produce salutaridine, NADP", and H2O. 1,2-dehydroreticulinium reductase (NADPH) uses (R)-reticuline and NADP + to produce 1,2-dehydroreticulinium, NADPH, and H". ... 

Battersby AR, Evans GW, Martin RO, Warren ME Jr, Rapoport H (1965b) Configuration of re-ticuline in the opium poppy. Tetrahedron Lett 1275-1278 Battersby AR, Martin JA, Brochmann-Hanssen E (1967) Alkaloid biosynthesis, part X. Terminal steps in the biosynthesis of the morphine alkaloids. J Chem Soc (C) 1785-1788 Blaschke G, Parker HI, Rapoport H (1967) Codeinone as the intermediate in the biosynthetic conversion of thebaine to codeine. J Am Chem Soc 89 1540-1541 Borkowski PR, Horn JS, Rapoport H (1978) Role of 1,2-dehydroreticulinium ion in the biosynthetic conversion of reticuline to thebaine. J Am Chem Soc 100 276-281 Brochmann-Hanssen E (1984) A second pathway for the terminal steps in the biosynthesis of morphine. Planta Med 51 343-345... 

S)-reticuline to ( )-reticuline in Papver somniferum is achieved by enantiospecific oxidation of the (5 )-enantiomer (273), and it is followed by an NADPH-dependent enzymatic reduction of the dehydroreticulinium ion, which also is highly substrate specific since no reduction of 1,2-dehydronorreticuline was observed (275). 

Although dehydroreticulinium chloride has been identified as a natural alkaloid (276a), its chemical stability at pH 8.5, the optimum for enzymatic reduction (275), requires some comment. The amorphous base obtained on extraction of an aqueous solution of dehydroreticulinium iodide rendered alkaline with ammonium hydroxide suggests that it is an enamine with an exocyclic double bond (276b), which is readily converted to a quaternary iminium salt on addition of acid. Therefore, it cannot be excluded that the species reduced at pH 8.5 is the enamine. 

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