Phenethylamines biosynthesis

Several enzymes involved in the biosynthesis of phenethylamines in plants have been studied. A tyrosine carboxy-lyase (decarboxylase) isolated from barley seedlings and barley roots has been studied in considerable detail (347-349). The enzyme is rather specific for L-tyrosine and meta-tyrosine ort/io-tyrosine and L-dopa are decarboxylated slowly. Tyrosine carboxylase activity was also demonstrated in wheat and maize (348). Cytisus scoparius contains dopa car-boxy-lyase which decarboxylates d- and L-dopa at about the same rate (350). Tyrosine is decarboxylated 15 times slower. A similar enzyme has been found in the alga Monostroma juscum (174). 

Phenethylamine-type N-oxides also undergo carbon-carbon bond fragmentation under modified Polo-novski conditions, as illustrated by the reaction of N,A -dimethyltryptamine N-oxide (66), wherein cleavage of the side chain is facilitated through participation of the electrons on the indole nitrogen (equation 18). The ease with which N-oxide (66) undergoes fragmentation implies that the in vivo equivalent of this reaction is important in the biosynthesis of certain indole alkaloids, such as ellipticine (38) and val-lesamine (67 Scheme 13), whose derivation from tryptophan is not immediately obvious. 

L. williamsii does not, however, use any of the above di- and tri-hydroxylated phenethylamines as efficiently as it uses dopamine in the biosynthesis of anhalonine... 

Isoquinoline Alkaloids.—This year has seen the solution of a longstanding mystery in alkaloid biosynthesis the origin of the extra skeletal carbons of the peyote cactus alkaloids, anhalonidine (43) and anhalamine (47). The major portion of the skeleton is derived in each case from tyrosine, by a well established29,30 pathway leading to the intermediate phenethylamine (41) but, despite much research, the origin of C(l) of (47) and C(l) + C(9) of (43) remained unsolved. 

Ironically, the answer to this problem has rested in the literature since Hahn published in 1935 his theory of isoquinoline biosynthesis.34 In his hypothesis (illustrated for anhalonidine in Scheme 5) the phenethylamine is condensed with the appropriate pyruvic acid to form an amino-acid (44) which is decarboxylated to provide the alkaloid (43). 

In view of the importance of the isoquinoline system in biosynthesis it is surprising that so little effort has been devoted in the past to the biosynthesis of the basic ring system. No doubt the success of this investigation in the peyote cactus will stimulate further work in other systems. It is likely that the normal pattern will involve condensation of a phenethylamine with the appropriate pyruvic acid. However, reference has already been made to ipecoside (27) (Scheme 3) in which the isoquinoline system is formed by condensation of the phenethylamine with an aldehyde [secologanin]. Presumably the corresponding aldehyde, rather than a pyruvic acid, will be found to serve as precursor for the phenethylisoquinolines,3 5 and also for the isoquinoline alkaloids of the Lophophora cactus such as lopho-cerine (66). 

The apparent use of an aldehyde function to form the junction of the C5 unit with phenethylamine fragment in lophocerine biosynthesis makes an interesting contrast with the biosynthesis of the related alkaloids anhalamine (65) and anhalonidine (66), where the a-carbonyl acids, glyoxylic acid and pyruvic acid respectively, are very evidently intermediates. The analogous keto-acid for lophocerine is (64), simply... 

Since a-amino-acids serve as starting materials for the synthesis of protein and the elaboration of many plant alkaloids, there must be a sharing of any amino-acid which is required for both of these activities. The extent to which this happens has been the subject of a new study in one particular plant, Lophophora williamsii, which produces isoquinoline and j8-phenethylamine alkaloids. These bases are derived from the a-amino-acid tyrosine and the results from feeding L-[f/- C]tyrosine indicate that this amino-acid is incorporated into the alkaloids approximately three times more efficiently than into protein. Only the L-isomer was examined and one wonders what the results with D-tyrosine would be in the light of the known preference for particular optical isomers of lysine in pipecolic acid and piperidine alkaloid biosynthesis. 

Hidden in the old literature was the solution to the long-standing problem of the biosynthesis of the Cj unit (C-1 and C-9) of anhalonidine (12) and the C, unit (C-1) of anhalamine (13). Only recently was the original suggestion for the biosynthesis of these cactus alkaloids examined, with positive results. Thus the two acids (10) and (11) were found to be precursors for (12) and (13) respectively. They apparently derive in turn from the phenethylamine (9) and pyruvic acid or... 

Phenethylamines.— The biosynthesis of phenethylamines, e.g. mescaline (197), in cactus plants has been the subject of an exhaustive study. The pathways to these bases and the related isoquinolines, e.g. anhalonidine (12), is now well understood. 

It may be assumed that the biosynthesis of /3-phenethylamines in plant tissues follows a similar pattern. The general occurrence of decarboxylases, tyrosinases as well as melanization phenomena gives strong support to this hypothesis, although reliable experimental evidence, such as has been obtained in the case of animal metabohsm, is not yet available. 

Coclaurine.—Coclaurine (63) is an intermediate of some significance in the biosynthesis of benzylisoquinoline alkaloids, e.g. bisbenzylisoquinolines (see below). Its biosynthesis, in Annona reticulata, has been investigated and found to follow an orthodox pathway, from two molecules of tyrosine. Radioactive tyramine, dopa, and dopamine (54) labelled the phenethylamine portion of (63)... 

Normacromerine.—The /8-hydroxy-phenethylamines, e.g. normacromerine (36), are closely related biosynthetically to phenethylamines. Both tyrosine and tyramine serve as precursors for (36) in Coryphantha macromeris var. runyonii, and so do norepinephrine (34) and epinephrine (35). A role for these compounds as intermediates in normacromerine biosynthesis is supported by their detection as normal constituents of the plant.A two-fold difference in the level of incorporation of (34) and (35) was interpreted as indicating separate pathways via these bases to (36), but firm conclusions must await further work. 

Working with Litsea glutinosa (Lauraceae), and concentrating on the biosynthesis of reticuline, Bhakuni and co-workers have shown that dopa and dopamine contribute only to the formation of the phenethylamine portion of reticuline. The benzylic portion is biosynthesized from 3,4-dihydroxyphenyl-pyruvic acid not derived from dopa. Tyrosine, 4-hydroxy-, and 3,4-dihydroxy-phenylpyruvic acid all participate in the formation of both halves of the molecule. Norlaudanosoline carboxylic acid, norlaudanosoline, and didehydronor-laudanosoline are intermediates in the biosynthetic sequence 0-methylation precedes W-methylation. ... 

It has been established that the biosynthesis of morphine follows a path from tyrosine derivative 27 to laudanosine (30) via a Pictet-Spengler type cyclocondensation of phenethylamine 28 and aldehyde 29. Dimethylation of 30 then provides reticuline (31). 

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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