Papaverine biosynthesis

The biosynthesis of camptothecin (102) follows that of terpenoid indole alkaloids through strictosidine (79) The lactam (101) derived from (79), and not the C-3 epimer, is the next intermediate.Several unknown steps follow, included in which is dehydrogenation of ring d [see (101)]. In this process a proton is lost from C-14. Tritium label at this site in (101) is retained by a primary isotope effect, the result of non-stereospecific deprotonation.This indicates that removal of the proton is not enzyme-controlled (c/. papaverine biosynthesis ref. 8, p. 19). 

Pienkny, S., et al., Fimctional characterization of a novel benzylisoquinoline O-methyltransferase suggests its involvement in papaverine biosynthesis in opium poppy (Papaver somniferum L). Plant J., 2009. 60(1) p. 56-67. 

Hagel, J. M., et al.. Characterization of a Flavoprotein Oxidase from Opium Poppy Catalyzing the Final Steps in Sanguinarine and Papaverine Biosynthesis. Journal of Biological Chemistry, 2012. 287(51) p. 42972-42983. 

Papaverine. The BIA papaverine is a minor (about 1%) component in most the opium varieties of P. somniferum and used as a vasodilator, a muscle relaxant, and an antispasmodic. Controversial information exists on the papaverine biosynthesis pathway. Two putative pathways have been proposed (Figure 6.22). The first one involves fV-desmethyl intermediates and utilizes (5)-coclaurine, which is transformed, under the control of 3 -hydroxylase (3 -OHase), into (5)-methylnorlaudanosoline. The latter undergoes three consecutive methylation steps leading to (5)-tetrahydropapaverine through the successive mediations of 3 -OMT 4 -OMT, and norreticuline 7-0-methyltransferase (N70MT). (5)-Tetrahydropapaverine is finally converted fo papaverine by dehydrogenase (deHase) enzymes. 

There would appear, from Scheme 4, to be many opportunities to modify the genetic material that creates the enzymes responsible for the biosynthesis of the morphinans. Blocking the specific methylation of norlaudanosine to (—) retuciline would be one worthwhile target, perhaps coupled with promoting the aromatization and methylation sequences leading from norlaudanosine to papaverine. 

Papaverine.—The biosynthesis of the simple benzylisoquinoline papaverine (89) is known to proceed via nor-reticuline (48) and tetrahydropapaverine (88).71 Dehydrogenation of the latter affords papaverine, and examination of the stereochemistry of the processes involved has led to the conclusion72 that loss of the proton at C-3 [in nor-reticuline (48)] is stereospecific (loss of the pro-S hydrogen atom) but removal of the C-4 proton is essentially non-stereospecific. These observations are perhaps best explained if enzyme-catalysed oxidation of (88) occurs to give (90), subsequent non-stereospecific imine-enamine isomerization occurring without enzyme participation to give (91). A further amine to imine oxidation then occurs to give papaverine (89).72... 

The stereochemical removal of hydrogen from positions 3 and 4 of the isoquinoline ring during aromatization of papaverine during biosynthesis has been studied by incorporation experiments, using stereospecifically labelled [3H]nor-reticulines.24... 

The three steps in the biosynthesis of papaverine set out below involve pyridoxal (or pyridoxamine). Write detailed mechanisms. 

These hypotheses, although not always correct, have been of inestimable value in guiding tracer experiments on living plants. Experiments on the biosynthesis of berberine and related alkaloids have had, in addition to these guidelines, the benefit of the knowledge gained from previous tracer studies on the biosynthesis of the isoquinoline alkaloids of the papaverine and the morphine series, where it was known that two molecules of the aromatic amino acid, tyrosine, are built into these alkaloids via a pathway involving the intermediacy of norlaudanosoline (XCIV). 

These results, summarized in Scheme 2, indicate that the methylation pattern can be important in deciding the metabolic fate of precursors at this particular stage of biosynthesis (c/. ref. 75) as well as during oxidative phenol coupling. In addition in vivo O- and 7V-methylation in P. somniferum was found to be dependent, and variably so, on the configuration of the substrate. Further, dehydrogenation of (59) depends on the stereochemistry at C-1 since only the (-)-isomer affords papaverine (62). Moreover it is (-)-norreticuline [as (55)] rather than the ( + )-isomer which is implicated. Finally it is to be noted that norlaudanidine (66) is as efficient a precursor for papaverine as is (59). ... 

Protein biosynthesis is essential for all cells and thus provides another important target. Indeed, a number of alkaloids have been detected (although not too many have been studied in this context) which inhibit protein biosynthesis in vitro. Emetine from Cephaelis ipecacuanha (Rubiaceae) is the most potent plant constituent other alkaloids with the same ability include harringtonine, homoharringtonine, cryptopleurine, tubulosine, hemanthamine, lycorine, narciclasine, pretazettine, pseudolycorine, tylocrepine, and tylopherine [5] and furthermore, ajmaline, berberine, boldine, cinchonine, cinchonidine, harmalin, harmin, lobeline, norharman, papaverine, quinidine, quinine, salsoline, sanguinarine,... 

The biosynthesis of papaverine (85) and laudanosine (86) in P. somniferum, has received attention. ( )-[3- " C]Nor-reticuline (as 80) was specifically and efficiently incorporated into papaverine, and so was [6-0-Mc- C]nor-reticu-line, this latter result indicating that incorporation was not via norlaudanosoline (87). Reticuline itself was poorly utilized and 1,2-dehydronor-reticuline, perhaps surprisingly, not at all. Therefore, 1,2-dehydronor-reticuline was not reduced to nor-reticuline, and its incorporation into morphine must be by N-methylation... 

Pantoyl lactone, biosynthesis of pantothenic acid from, VI, 183 Papaverine,... 

The biosynthesis of papaverine in P. somniferum L. has been investigated using and H-labeled precursors and follows the sequence shown in Scheme... 

Isoquinoline alkaloid biosynthesis is one of the well-characterized pathways in the secondary metabolism of plant cells which comprises some of the most important drugs for therapy and euphoria (e.g., morphine and its chemical derivatives, papaverine, berberine, dimeric bisbenzylisoquinolines). 

Recent developments in the biogenesis of the benzylisoquinoline alkaloids were briefly referred to in the introduction to this chapter furthermore, when dealing with each particular base, its role as biogenetic precursor of other alkaloids was mentioned. Although the advances have been considerable, little is known of the detailed metabolic pathways which lead to the biosynthesis of these alkaloids. Practically all the results obtained derive from the administration of labeled precursors. Enzymatic w ork is just beginning. We shall consider here only the biogenesis of papaverine (CIII) and reticuline (LI) which have been more thoroughly studied. 

The existence of a different metabolic pathway for each unit became more evident when labeled dopamine (CLIII) was used as precursor of hydrastine. Only one unit was incorporated it formed the isoquinoline moiety of the alkaloid (225), a specific type of incorporation which was also found in the biosynthesis of morphine (226), chelidonine (227), and berberine (228) when the base was fed to the proper plants. Although dopamine has not been experimentally tested in the biogenesis of papaverine it is an acceptable hypothesis that it will be incorporated following the same pattern as with the other alkaloids. 

The biosynthesis starts from the amino acid tyrosine which is first hy-droxylated to DOPA (Fig. 129). Two units of DOPA provide the skeleton of the benzyl-isoquinoline. Norlaudanosoline is a key substance which has also been shown to be present, among others, in the genus Papaver. The rest of the benzylisoquinolines can be derived from it. Only two kinds of derivatives will be mentioned here, papaverine and morphine alkaloids. 

Uprety H, Bhakuni DS, Kapil RS (1975) Biosynthesis of papaverine. Phytochemistry 14 1535-1537... 

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