Morphine, biosynthesis structure

Moore, Stanford, 1030 Morphine, biosynthesis of, 969 specific rotation of, 296 structure of, 64 MR1, see Magnetic resonance imaging. 468-469 mRNA, see Messenger RNA MS, see Mass spectrometry Mullis, Kary Banks, 1117 Multiplct (NMR), 460 table of, 462... 

Alkaloids, like terpenoids, are a large and diverse class of compounds, with more than 12,000 examples known at present. They contain a basic amine group in tbeir structure and are derived biosyntbetically from amino acids. WeTl look at morphine biosynthesis as an example in Section 25.3. 

The structure of morphine was first determined in 1925 by Sir Robert Robinson (1886— 1975) and John Masson Gulland (1898-1947). A total synthesis of morphine was achieved in 1952 at the University of Rochester by Marshall D. Gates (1915—2003) and his co-worker Gilg Tschudi. Since its first synthesis, a number of other processes have been used to synthesize morphine in the laboratory, but none of these is economically viable. Therefore morphine continues to be obtained through biosynthesis from poppy plants. 

In order to understand the continuation of the biosynthesis of codeine and morphine from reticuline, the structure for (S)-reticuline can be written as follows ... 

Or they may be grouped according to the genus of their plant source (morphine and codeine, Section 23-2, are examples of opium alkaloids), or by their physiological effects (antimicrobials, antibiotics, analgesics), or by similarities in the route by which they are synthesized by the organism (biosynthesis). The structural and biosynthetic classifications make the most sense to the chemist and is the organization chosen here. 

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. 

Figure 2 Semisynthetic bulk drugs Ampicillin (antibacterial) from penicillin G. Modifications of biosynthetic structures are often created to improve the in vivo attributes of the original compound, utilizing the biosynthesis product as the starting material containing most, if not all, of the structural complexity that provides the basic biological activity. Similarly, codeine (analgesic), although found in opium from Papaver plants, is most economically made by methylation of morphine, which is more efficiently isolated from opium.

Despite the detection of COR and other known morphinan branch pathway enzymes in opium poppy cell cultures (63-65,67), morphine and codeine are not produced. The inability of cultured cells to accumulate morphine might reflect the absence of other relevant enzymes or structural proteins that preclude the formation of a requisite metabolic channel. Nevertheless, the efficient operation of the sang-uinarine pathway indicates that cultured opium poppy cells possess the essential regulatory, eellular, and metabolic components to support the biosynthesis and... 

Several studies have reported the production in microorganisms of plant enzymes that are involved in alkaloid biosynthesis [29, 99-102], In this sense, Unterlinner et al. [100] have cloned and expressed in Escherichia coli four cDNAs encoding for different isoforms of the Codeinone reductase NADPH-dependent enzyme isolated from Papaver somniferum. In this report has been investigated the substrate specificity of the enzyme and the structural analysis, being the first report about the cloning and expression of genes of the biosynthetic pathway of morphine [90],... 

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... 

It is because, in the event, secondary metabolites derive from but a handful of primary metabolites along pathways involving generally the simplest reactions in organic chemistry and little rearrangement, that speculation about their biosynthesis can be so accurate. Also invaluable in this regard, is the identification of metabolites of similar structure in the same, or related, species. Thus benzyl-isoquinoline alkaloids [as (2.7)] and morphine (2.2) are both found in Papaver species. It follows reasonably that morphine derives from a compound type of (2.7) (Section 6.3.4). 

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). ... 

The appropriate time in the biosynthesis for the methylation reaction to occur and, of course, the correct position of the methyl group in the molecule, have important influences on modifying the skeleton. This is particularly true for the isoquinoline skeleton, especially in alkaloids of the morphine and aporphine groups (see p. 204 for structures). Methylation is considered to be a type of detoxication reaction. Thus Pohm (1966) has observed that in seedlings of Cytisus laburnum with removed cotyledons, cultivated in appropriate feeding solution, addition of small amounts of cytisine was inhibitory, whereas 50 times as much methylcytisine had no effect. Moreover, it seemed that methylcytisine acted as a type of antagonist toward cytisine. Generally methylation is considered to diminish the reactivity of a compound (Mothes, 1965, 1966). 

Horn JS, Paul AG, Rapoport H (1978) Biosynthetic conversion of thebaine to codeinone. Mechanism of ketone formation from enol ether in vivo. J Am Chem Soc 100 1895-1898 Kametani T, Ihara M, Honda T (1970) The alkaloids of Corydalis pallida var. tenuis (Yatabe) and the structures of pallidine and kikemanine. J Chem Soc (C) 1060—1064 Kirby GW, Massey SR, Steinreich P (1972) Biosynthesis of unnatural morphine derivatives in Papaver somniferum. J Chem Soc Perkin Trans 1 1642-1647 Kleinschmidt G, Mothes K (1959) Physiology and biosynthesis of alkaloids in Papaver somniferum. Z Naturforsch 14b 52-56... 

Research in the field of plant alkaloid biochemistry began with the isolation of morphine in 1806. Remarkably, the structure of morphine was not elucidated until 1952 due to the stereochemical complexity of the molecule. Since then, extensive chemical, biochemical and molecular research over the last half-century have led to an unprecedented understanding of alkaloid biosynthesis in plants (Facchini 2001). In this chapter, we review the biosynthesis, ethnobotany and pharmacology of the major groups of alkaloids produced in plants with a focus on the role of important alkaloids in diet and human health. 

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