Benzylisoquinoline alkaloids morphin biosynthesis

The stereospecific condensation of dopamine with 4-hydroxyphenylacetaldehyde is catalyzed by NCS to yield S-norcocIaurene, the central precursor of thousands of benzylisoquinoline alkaloids, including morphine. This poorly characterized, but key enzyme in benzylisoquinoline alkaloid biosynthesis has recently been purified to homogeneity, and its kinetic properties have been elucidated.35 NCS occurs as a 28 kDa dimer composed of 15 kDa... 

New investigation of bisbenzylisoquinoline biosynthesis is welcome (see ref. 32 also this Report, p. 16). Although aporphine alkaloids are the simplest developments of the benzylisoquinoline skeleton, their biosynthesis need not, as several examples show, be simple. It has, however, been found that the biosynthesis of boldine and isocorydine is straightforward. Further detail has been repor-ted on the biosynthesis of Erythrina alkaloids, which were established to be modified benzylisoquinolines some time ago. Further detail on the biosynthesis of morphine (23) and related alkaloids continues to be published. Of particular R. B. Herbert, in ref. 9, p. 11. 

Scheme 1. Biosynthesis of the benzylisoquinoline alkaloids berberine, morphine, and sang-uinarine. Enzymes for which corresponding molecular clones have been isolated are shown in bold. Abbreviations 4 OMT, 3 -hydroxy-A-methylcoclaurine 4 -0-methyltransferase 60MT, norcoclaurine 6-0-methyltransferase 70MT, reticuline 7-0-methyltransferase BBE, berberine bridge enzyme CFS, cheilanthifoline synthase CNMT, coclaurine A-methyltransf-erase COR, codeinone reductase CYP719A1, canadine synthase CYP80A1, berbamunine synthase CYP80B1, A-methylcoclaurine 3 -hydroxylase DBOX, dihydrobenzophenanthri-dine oxidase DRR, 1,2-dehydroreticuline reductase DRS, 1,2-dehydro reticuline synthase MSH, A-methylstylopine 14-hydroxylase NCS, norcoclaurine synthase P6H,...

Figure 6.19 Biosynthesis of benzylisoquinoline alkaloids codeine and morphine.

Thus, from the Solanaceae, hyoscyamine, a tropane alkaloid, which we now know to be derived from ornithine and/or arginine (Arg, R, Scheme 12.7), and nicotine, derived from a combination of nicotinic acid (see Scheme 12.103, et seq.) and ornithine, serve as examples of alkaloids based on nonaromatic amino adds. In the benzylisoquinoline alkaloids, only morphine, arguably the first alkaloid isolated in purified form and known to be derived from tyrosine (Tyr, T), itself a prephenic acid derivative, is discussed. For the indole alkaloids, the single example of this rich family to be illustrated is vinblastine, a (relatively) recently isolated base of some medicinal value and which is shown to be composed of two different expressions of tryptophan (Trp, W) and mevalonate (Scheme 11.40). Finally, caffeine is chosen as the member of the purine alkaloids, a relatively small family of compounds but one of major commercial import and one whose biosynthesis is closely tied to the library of life. 

Morphine and codeine are members of the large and diverse group of benzylisoquinoline alkaloids, of which morphine and sanguinarine share a common biosynthetic pathway, beginning with the condensation of two L-Tyr derivatives to produce the central precursor (S)-norcoclaurine yields (S)-reticuline, the last common intermediate in the biosynthesis of both sanguinarine and morphine. Berberine bridge enzyme (BBE) catalyzes the conversion of (S)-reticuline to (S)-scoulerine, the first committed step in the sanguinarine pathway. Alternatively, (S)-reticuline can be isomerized to its (R)-epimer as the first step in the formation of morphine. Since the pathway from tyrosine to (S)-reticuline is also known at the enzyme level, the conversion of L-tyrosine to macarpine involves a total of 19 enzymes which are now at least partially characterized. 

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 idea that the opium alkaloid morphine is a modified benzyliso-quinoline provided the key to the structure 6.152) for the alkaloid twisting of the benzylisoquinoline skeleton into that shown for reticuline (6.127) in (6.148) illustrates this relationship and suggests a possible biogenesis. This was later proved correct in the course of a study which is one of the classics of alkaloid biosynthesis. In the first experiments ever to be carried out with complex plant-alkaloid precursors, [1- C]- and [S- Cj-norlaudanosoline [as (6.123) were fed to opium poppies [99, 100]. They were found to label morphine (6.152), codeine (6.153) and thebaine (6.151) specifically, thus establishing that these alkaloids are indeed benzylisoquinoline derivatives. The key intermediate [101] proved to be reticuline (6.148). Both (R) and (5)-isomers were utilized, the latter by way of (6.155) [101, 102] which allowed its conversion into (i )-reticuline (6.148), the correct intermediate, with the same configuration as the three opium alkaloids [as (6.151). ... 

Fig. 129. A few benzylisoquinoline alkaloids (including papervine and morphine alkaloids) and their biosynthesis.

The benzylisoquinolines represent one of the largest group of plant alkaloids (146,147), and catecholic representatives occur in mammalian tissues and fluids. The best known is tetrahydropapaveroline, shown in Fig. 22 as the (5) enantiomer TIQ 75a. Racemic material is often referred to as THP (160,161). The synthesis of TIQ 75a as well as that of the plant alkaloid (5)-N -bisnorreticuline (77a) is shown in Fig. 22. (5)-Tetrahydropapaverine (74a), on treatment with concentrated hydroiodic acid at 125 C, afforded TIQ 75a, which was fully characterized as its hydrochloride (156). TIQ 77a, possibly an intermediate in the plant biosynthesis of (5)-norreticuline (78a) and derived TIQs, and possibly mammalian morphine as well, was prepared from the benzyl-protected TIQ 76a. Deblocking was achieved over Pd catalyst and hydrogen in the presence of hydrochloric acid, leading directly to the hydrochloride salt of TIQ 77a... 

Battersby AR, Binks R, Francis RJ, McCaldin DJ, Ramuz H. Alkaloid biosynthesis. IV. 1-Benzylisoquinolines as precursors of thebaine, codeine, and morphine. J. Chem. Soc. 1964 3600-3610. 

An early key intermediate in benzylisoquinoline biosynthesis is (57), which by decarboxylation affords (59) this in turn leads to (61) and on to alkaloids (Scheme 2). Confirmation of this pathway has come from a study using cell-free preparations of P. somniferum stems and seed capsules. It was found that this preparation catalysed the formation of (57), (59), and (61) from dopamine (54) plus 3,4-dihydroxyphenylpyruvic acid (55) without the addition of 5-adenosyl-methionine, NADPH, and pyridoxal phosphate, the reaction stopped at (57). The formation of the alkaloids reticuline, thebaine, codeine, and morphine, produced by whole plants, could not be detected with this cell-free system. The results confirm not only the intermediacy of (57) and (59) in benzylisoquinoline biosynthesis, but also the involvement of (54) and (55). 

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. 

Barton DHR, Cohen T (1957) In Festschrift Dr A Stoll, Birkhauser, Basel, p 117 Barton DHR, Kirby GW, Taylor JB, Thomas GM (1963) Phenol oxidation and biosynthesis, part VI. The biogenesis of amaryllidaceae alkaloids. J Chem Soc 4545—4558 Barton DHR, Hesse RH, Kirby GW (1965) Phenol oxidation and biosynthesis, part VIII. Investigations on the biosynthesis of berberine and protopine. J Chem Soc 6379-6389 Barton DHR, Bracho RD, Potter CJ, Widdowson DA (1974) Phenol oxidation and biosynthesis, part XXIV. Origin of chirality in the erythrinan system and derivation of the lactone rings of a- and ]3-erythroidine. J Chem Soc Perkin Trans 1 2278-2283 Basmadjian GP, Paul AG (1971) The isolation of an O-methyltransferase from peyote and its role in the biosynthesis of mescaline. Uoydia 34 91-93 Basmadjian GP, Hussain SF, Paul AG (1978) Biosynthetic relationships between phenethylamine and tetrahydroisoquinoline alkaloids in peyote. Lloydia 41 375-380 Battersby AR, Binks R, Francis RJ, McCaldin DJ, Ramuz H (1964) Alkaloid biosynthesis, part IV. 1-Benzylisoquinolines as precursors of thebaine, codeine and morphine. J Chem Soc 3600-3610... 

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