Morphine pathway

Gerlach WL, Fist AJ, Larkin PJ. Analgesia morphine-pathway block in topi poppies. Nature 2004 431 413-414. 

Other constraints are important for more complex products, for which mass is not central, but value. For example, central nervous system stimulants are a new class of substances addressed by production with engineered baker s yeast. Expressing the biosynthetic pathways for the opioids thebaine and hydrocodone, and parts of the morphine pathway in yeast, a first step is taken for easy production of opiates [21, 22]. This opens the possibility for the development of new painldllers with less addictive potential. However, it clearly is a new technology that could be abused with many negative consequences - so some contemplation about how to control these developments seems advisable [23]. Not only are narcotics in the center of interest but stimulants such as caffeine and theobromine have also recently been produced with genetically engineered 5. cerevisiae strains [24]. 

Figure 1.19. Tyrosine-derived alkaloids in the Rhoeadales, Berberidales, and Ranales. The first compound synthesized is norlaudanosoline, and nine distinct types of alkaloids are encountered either in restricted taxa or widely distributed A—salutaridine B— morphine pathway restricted to Papaver section Mecones C—isothebaine pathway, characteristic of Papaver section Macrantha D—Papaver section Miltantha E—Papaver section Scapiflora F-encountered in Chelidonium (Papaveraceae-Rhoeadales) and Berberis G—characteristic for Papaver section Orthoroedes, the Corydalis dicentra and Chelidonium spp. H—cryptowoline I—Papaver section Scapiflora, genus Escholtzia, and Argemone J—Papaver sections Orthoroedes and Pilosa, Data are compiled from publications by Stermitz (1968, 1974), Santavy (1966), Santavy et al. (1965, 1966) Slavik (1955), Slavik et al. (1963), Pfeifer (1962), and Tetenyi and co-workers (1961, 1965, 1967, 1968), Bandoni, et al. (1972, 1975). The reaction pathways are according to Barton and Widdowson (1972). Only pathways A, B, and C are shown in detail the others are only suggestions. The pathways leading to the dimeric (bis) alkaloids are not shown.

With a morphine biosynthetic gene in hand, we believed we could begin to address the question why only P. somniferum produces morphine, while other Papaver species such as P. rhoeas, P. orientale, and P. bracteatum do not. Unexpectedly, we found that the codeinone reductase transcript was present to some degree in all four species investigated. A review of the literature revealed no alkaloids reported in P. rhoeas for which codeinone reductase should participate in the synthesis. Similarly, P. orientale accumulates the alternate morphine biosynthetic precursor oripavine, but codeinone reductase is not involved in the biosynthesis of oripavine, acting instead after this alkaloid along the biosynthetic pathway to morphine.22 P. bracteatum produces the morphine precursor thebaine as a major alkaloid. As for oripavine in P. orientale, codeinone reductase would act in P. bracteatum after thebaine formation on the pathway to morphine. It appears, therefore, that the reason that P. rhoeas, P. orientale, and P. bracteatum do not produce morphine is not related to the absence of the transcript of the morphine biosynthesis-specific gene codeinone reductase. The expression of codeinone reductase may simply be an evolutionary remnant in these species. 

Salutaridinol 7-0-acetyltransferase catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-Oacetate, the immediate precursor of thebaine along the morphine biosynthetic pathway in P. somniferum (Fig. 10.7).26 Acetyl CoA-dependent acetyltransferases have an important role in plant alkaloid metabolism. They are involved in the synthesis of monoterpenoid indole alkaloids in medicinal plant species such as Rauwolfia serpentina. In this plant, the enzyme vinorine synthase transfers an acetyl group from acetyl CoA to 16-epi-vellosimine to form vinorine. This acetyl transfer is accompanied by a concomitant skeletal rearrangement from the sarpagan- to the ajmalan-type (reviewed in2). An acetyl CoA-dependent acetyltransferase also participates in vindoline biosynthesis in Catharanthus roseus, the source of the chemotherapeutic dimeric indole alkaloid vinblastine (reviewed in2). Acetyl CoA deacetylvindoline 4-O-acetyltransferase catalyzes the last step in vindoline biosynthesis. A cDNA encoding acetyl CoA deacetylvindoline 4-0-acetyltransferase was recently successfully isolated.27... 

---