Biosynthesis, of alkaloids

Some of the more significant advances which have been made during 1972 appear in Section 2 of this review. In these yearly reviews it is not possible to discuss the biosynthesis of all classes of alkaloids in depth. It is the plan to select different topics each year so that a more complete story can be told on the individual alkaloids. In Section 3 the biosynthesis of tropic acid is reviewed. Some progress is being made on the isolation of enzymes responsible for the biosynthesis of alkaloids and this appears in Section 4. The use of tissue cultures of various plant organs in studying alkaloid biosynthesis is covered in Section S. 

Discussion of the synthesis of alkaloids in the laboratory under so-called physiological conditions , also referred to as biomimetic synthesis , has been omitted. 

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V. Aldol Reactions of Heterocyclic Enamines and Their Importance for the Biosynthesis of Alkaloids... 

McCoy E, O Connor SE, Directed biosynthesis of alkaloid analogs in the medicinal plant Catharanthus roseus, J Am Chem Soc 128 14276-14277, 2006. 

Nowacki, E. 1963. Inheritance and biosynthesis of alkaloids in lupin. Genetica Polonica, 4 161-202. 

Zenk, M. H. 1989. Biosynthesis of alkaloids using plant cell cultures. Recent... 

Robins, R. J. 1998. The Biosynthesis of Alkaloids in Root Cultures. In Alkaloids. Biochemistry, Ecology, and Medicinal Applications (Roberts, M. F. and Wink, M., eds), pp.199-218. New York - London Plenum Press. 

The biosynthesis of alkaloids has been extensively studied, and although for a time it was thought that alkaloids arose primarily from amino acid precursors, strong evidence now is available that ethanoate also is involved. The mode of alkaloid biosynthesis is not yet as well understood as that of the terpenes and steroids. One experimental problem is the difficulty of feeding suitably labeled precursors to plants. 

Misra N, Luthra R, Singh KL and Kumar S (1999) Recent advances in biosynthesis of alkaloids. Comprehensive Natural Products Chemistry, Vol 4. Elsevier, Amsterdam, pp 25-59. 

During the last two decades, the use of enzyme-catalysed reactions in the total chemical synthesis and in the biological formation of alkaloids has been rapidly developed and a large number of enzymes and genes (cDNAs) involved in the biosynthesis of alkaloids have become available. 

The benzylisoquinoline alkaloids are widely distributed in nature and are intermediates in the biosynthesis of alkaloids of this family (2, 3). It is not surprising therefore that several groups (6, 7, 15, 23) have examined their spectra. Among the alkaloids that have been studied are reticuline (26) (7), norlaudanosine (27) (7), laudanosine (28) (6, 15), and the cis- and trans-N-oxides of laudanosine, 29 and 30, respectively (7). The chemical shifts of laudanosine are recorded in Table IV and the structures of the alkaloids may be found in Fig. 4. 

This observation was explained by the assumption that a portion of the protoberberine was formed via norreticuline (96) present in the same incubation mixture and derived from enzymic demethylation of reticuline. Reaction of 96 with an unlabeled one-carbon fragment and subsequent ring closure would then lead to C-8 unlabeled protoberberines. The authors suggest that this one-carbon fragment may be derived from S-adenosyl-methionine, and that the product of its combination with 96 may be converted directly to 91 or 94 without the intermediacy of free reticuline (99). If their assumption is correct, the conversion of norreticuline to the protoberberine alkaloids may not involve the formation of reticuline itself, a suggestion that is at variance with the known intermediacy of reticuline in the biosynthesis of alkaloids of this group. 

Tetracyclization. The Heathcock group1 has described a remarkably short and efficient synthesis of the skeleton of Daphniphyllum alkaloids (2) by reaction of the dialdehyde 1 with gaseous ammonia and then dissolution in acetic acid at 70°. The yield is 77%, based on the diol precursor to 1. The azadiene a and the imine b have both been isolated and identified. The conversion of a to b is an intramolecular Diels-Alder type reaction. The tetracyclization may well be involved in the biosynthesis of alkaloids such as Daphnilactone A (3). 

The established practice of including references to earlier Reports in this series for background information is continued. Two comprehensive reviews are also cited.1,2 An authoritative account of the biosynthesis of fungal metabolites has been published,3 as has an introductory text which includes a survey of the biosynthesis of alkaloids and nitrogenous microbial metabolites.4... 

The first intermediate beyond ornithine in the biosynthesis of tropane alkaloids has been deduced to be (S-A-methylornithine (2). Recently, (2) was identified as a natural constituent for the first time in a plant, namely Atropa belladonna, which produces tropane bases.5 The (2) was labelled by radioactive ornithine (1), but, unfortunately, the alkaloids were not, so correlation between the formation of (2) and the biosynthesis of alkaloids has not yet been achieved. 

In accord with a general body of evidence on the biosynthesis of alkaloids as against that of pipecolic acid (see above), L-lysine has been shown to be the preferred precursor for lupanine (27) and D-lysine the preferred precursor for l-pipecolic acid (24) in Lupinus angustifolia,36 A high retention of tritium, present at C-4 and C-5 in the lysine, on formation of (27) is to be noted. 

Further work on the biosynthesis of alkaloids by fractions of the latex of seed capsules of P. somniferum has been published.39... 

Steroidal Alkaloids.—In the biosynthesis of alkaloids such as solasodine (128), from cholesterol (129), it appears that the cholesterol side-chain is first functionalized at C-26 with the introduction of a hydroxy-group (cf. Vol. 8, p. 28 Vol. 7, p. 32). The 26-amino-compound, (25i )-26-aminocholesterol (130), has been found to act as a significant precursor for solasodine (128) in Solarium laciniatum, whereas (25i )-26-aminocholest-5-ene-3/ ,16/ -diol (131) was poorly utilized.105 This indicates that replacement of the hydroxy-group at C-26 by an amino-group may occur before further oxygenation elsewhere in the steroid nucleus (particularly at C-16). It may also be concluded from this and other evidence (cf. Vol. 9, p. 27) that oxidation at C-22 precedes hydroxylation at C-16. 

Biosynthesis of Polyketides Phenolic Compounds derived from Shikimate The Biosynthesis of C5—C20 Terpenoid Compounds Triterpenoids, Steroids, and Carotenoids Non-protein Amino-acids, Cyanogenic Glycosides, and Glucosinolates Biosynthesis of Alkaloids. 

The association of cytochrome P450s with organelles other than the ER may have important implications for the biosynthesis of alkaloids. It may help to explain why biochemical localization studies have shown that certain reactions in a pathway occur within the chloroplast. In the case of Catharanthus alkaloids, the 3 rd to last step in vindoline biosynthesis involves a chloroplast thylakoid associated N-methyltransferase.22 The arguments for participation of chloroplasts in this reaction include the possibility that the previous step involving hydration of the 2,3 double bond might require a chloroplast based oxidation reaction (Fig 8.6). The conclusive identification of specific cytochrome P4S0 enzymes in chloroplasts suggests that this hypothesis should be tested. 

In the next chapter you will see how hydroxylation of benzene rings plays an important part in the biosynthesis of alkaloids and other aromatic natural products. 

Some of the most interesting applications of organic structural theory to the elucidation of biosynthetic pathways were stimulated by efforts to formulate mechanisms for the biosynthesis of alkaloids. Conversely, consideration of implied biogenetic relations have occasionally helped structural determination. An important aspect of theories concerning alkaloid biosynthesis has been the assumed role of the aromatic amino acids in their formation. Only limited experimental evidence is available in this area. The incorporation of tyrosine- 8-C into morphine has been shown to be in accordance with a theory for its formation from 3,4-dihydroxyphenyl-alanine plus 3,4-dihydroxyphenylacetaldehyde. A stimulating theory of the biosynthesis of indole alkaloids, based on a condensation between trypt-amine and a rearrangement product of prephenic acid, has recently been published. The unique stereochemistry of C15 of these alkaloids had an important part in the formulation of the theory. Experimental proof of this theory would be valuable for several areas of alkaloid chemistry and biosynthesis. 

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