Reticuline, biosynthesis epimerization

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). 

Ortho-para oxidative coupling of the diphenol, reticuline (6.148), can be conceived of as giving the dienone (6.149) which could afibrd thebaine (6.151) as shown [101]. This hypothesis is strongly supported by the observation that this dienone, (6.149), called salutaridine, is a constituent of opium poppies, is formed from radioactive tyrosine (6.94) and norlaudanosoline (6.123), and is a highly efficient and specific precursor for the opium alkaloids. The transformation of salutaridine (6.149) into thebaine (6.151) requires a further ring-closure, which occurs chemically when the two epimeric alcohols (6.150) are treated with acid. In contrast to the purely chemical reaction, only one of the alcohols was efficiently converted into thebaine in vivo, indicating that the reaction is enzyme mediated (and therefore part of normal biosynthesis). 

Why does morphine biosynthesis proceed through initial formation of (S)-reticuline as an intermediate, followed by epimerization, rather than through (J )-reticuline directly There is no obvious answer other than to say that many metabolic pathways contain such small inefficiencies, probably as a result of the evolutionary development of the responsible enzymes— what some people have called unintelligent design. ... 

FIGURE 25.n Mechanism ofthe epimerization of (S)-reticuline to (R)-reticuline in step4of morphine biosynthesis. 

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