Ornithinederived alkaloids

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Ornithine is a metabolically quite active amino acid, and the important precursor of pyrrolidine nucleus, which is found in pyrrolizidine alkaloids. Ornithine itself is a non-protein amino acid formed mainly from L-glumate in plants, and synthesized from the urea cycle in animals as a result of the reaction catalyzed by enzymes in arginine.

.C02H

Indole nucleus

/3-carboline nucleus

Indole C2N skeleton

Quinoline nucleus after transformation from indole

Quinoline CgN skeleton

Pyrroloindole nucleus

Pyrroloindole nucleus

Pyrroloindole C10N2 skeleton

Iboga nucleus

Iboga Cg skeleton

Corynanthe nucleus

Corynanthe Cg skeleton

Aspidosperma nucleus

Aspidosperma C9 skeleton Figure 32. The L-tryptophan-supplied nucleus during synthesis.

The synthesis of alkaloids from L-ornithine starts with decarboxylation by the Pyridoxal Phosphate (PLP) to putrescine (Figure 33) and putrescine metylation by S-Adenosylmethionine (SAMe) to N-methylputrescine. The SAM is a naturally occurring reaction, when the departing groups convert

Carboline C8NC3N skeleton

Diamine oxidase
Figure 33. Synthesis of alkaloids from ornithine. Alkaloids are derived via putrescine or glutamic semialdehyde. At least two enzymes, ODL (Ornithine decarboxylase) or PDL (Pyrroline decarboxylase), are needed.

L-methionine to S-adenosylmethionine. In this process a positively charged sulphur is produced and facilitates the nucleophilic reaction. By the activity of diamine oxidase, the N-methyl-A1-pyrrolinium cation is formed and after that the first alkaloid, hygrine. From hygrine, by way of acetyl CoA, hydrolysis and intramolecular Mannich reactions, other pyrrolidine and tropane alkaloids are synthesized: cuscohygrine, hyoscyamine or tropinone, tropine and cocaine. The Mannich reaction involves the combination of an amine, an aldehyde or a ketone with a nucleophilic carbon. This reaction is typical in alkaloid synthesis, and can be written as follows:

The synthesis of tropine from tropinione requires dehydrogenase NADPH+. Similarly, the synthesis of cocaine requires the Mannich reaction, SAM and NADPH+. Putrescine is a biogenic amine. Other biogenic amines also participate in alkaloid synthesis, for example cadaverine in the case of lysine alkaloids. Aniszewski et al.214 drew attention to the fact that the various biogenic amines

Moles Chemistry Conversion Chart
Figure 34. Synthesis pathway of the pyrrolizidine alkaloids from L-ornithine or L-arginine.

that actively participate in the biosynthetic process of alkaloids play a role in the equilibrium between basic nitrogen compounds. Moreover, enzyme participation in pyrrolidine and tropane alkaloid synthesis has also been noted. From the L-ornithine, and alternatively also from L-arginine pyrrolizidine alkaloids are synthesized (Figure 34). The L-arginine, alternative pyrrolizidine precursor is based on its ability to change into L-ornithine, and alternatively into putrescine, via coenzyme pyridoxal phosphate (PLP) and agmatine. In the synthetic pathway to homospermidine, which is the first pyrrolizidine alkaloid in this synthesis chain, two molecules of putrescine are condensed by the enzyme NAD+ into imine before NADH converts it to homospermidine. From homo-spermidine, the synthesis chain continues across oxidative and base formation, and the Mannich reactions, to synthesize other alkaloids, such as retronecine and its diester senecionine. This synthesis pathway is also characteristic for heliotri-dine, laburine, lycopsamine and indicine-N-oxide. All these alkaloids contain the pyrrolidine nucleus, which is derived from ornithine or its precursors and postcursors.

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