Alkaloids as secondary metabolism molecules

The precursors of true alkaloids and protoalkaloids are aminoacids (both their precursors and postcursors), while transamination reactions precede pseudoalka-loids (Tables 1 and 10). It is not difficult to see that from all aminoacids only a small part is known as alkaloid precursors (Table 19). Both true and proto alkaloids are synthesized mainly from the aromatic amino acids, phenylalanine, tyrosine (isoquinoline alkaloids) and tryptophan (indole alkaloids). Lysine is the

Table 19 Amino acids and their participation in alkaloid synthesis

Group of Amino Acids/Amino acids

Alkaloid Type

Participation in Alkaloid Synthesis

Protein amino acids l-alanine l-arginine l-asparagine l-aspartic acid l-cysteine l-glutamine l-glutamic acid l-glycine l-histidine l-isoleucine l-leucine l-lysine l-methionine l-phenylalanine l-proline l-serine l-threonine l-tryptophan

Arginine-derived alkaloids

Histidine-derived alkaloids

Lysine-derived alkaloids

Phenylalanine-derived alkaloids

Tryptophan-derived alkaloids l-tyrosine

Tyrosine-derived alkaloids

True alkaloids Marine alkaloids

True alkaloids

Imidazole alkaloids Manzamine alkaloids

True alkaloids

Piperidine alkaloids Quinolizidine alkaloids Indolizidine alkaloids

True alkaloids

Phenylethylamino alkaloids Phenylisoquinoline alkaloids Amaryllidaceae alkaloids

True alkaloids Indole alkaloids Quinoline alkaloids ^-carboline alkaloids Pyrroloindole alkaloids Ergot alkaloids Iboga alkaloids Corynanthe alkaloids Aspidosperma alkaloids Protoalkaloids

Terpenoid indole alkaloids

True alkaloids

Phenylethylamino alkaloids Simple tetrahydroiso quinoline alkaloids

Alkaloid Chemistry Table 19 (Continued)

Group of Amino Acids/Amino acids

Alkaloid Type

Participation in Alkaloid Synthesis l-valine

Phenethylisoquinoline alkaloids Amaryllidaceae alkaloids


Phenylethylamino alkaloids

Non-protein aminoacids l-ornithine

Anthranilic acid

Nicotinic acid

Ornithine-derived alkaloids

Anthranilic acid-derived alkaloids

Nicotinic acid-derived alkaloids

True alkaloids

Pyrrolidine alkaloids Tropane alkaloids Pyrrolizidine alkaloids

True alkaloids

Quinazoline alkaloids Quinoline alkaloids Acridine alkaloids

True alkaloids Pyridine alkaloids Sesquiterpene pyridine alkaloids precursor for piperidine and quinolizidine alkaloid, and ornithine for pyrrolidine, pyrrolizidine and tropane alkaloids. Pseudoalkaloids are synthesized from other compounds, for example acetate in the case of piperidine alkaloids (coniine or pinidine). Alkaloids are derived from the amino acid in L-configuration (protein aminoacids) and from non-protein amino acids such as ornithine. However, it is important to note that alkaloids should be derived directly from the precursors of amino acids as, for example, in the case of anthranilic acid (the precursor of trypthophan from the shikimate pathway) or acetate (the precursor of lysine via a-ketoadipic acid and transamination in some algae and fungi). The precursors' substrata for alkaloids can also derive directly from the degradated parts of amino acids as, for example, in the case of nicotinic acid (Niacin or Vitamin B3), which is the precursor and a key part of coenzymes NAD+ and NADP+ in the degradation process of tryptophan. Alkaloid chemistry is clearly directly connected with the protein aminoacids, their precursors or postcursors in different pathways. It is difficult to find the exception to this rule. Although ornithine is a non-protein amino acid, in reality its precursor is L-glutamate (in plants) and L-arginine (in animals). The importance of ornithine as the precursor of alkaloids is not that this amino acid is non-protein, but just that it is postcursor of the protein amino acid (L-glutamate). Although the pathways of alkaloids are at present relatively well understood from the point of view of organic chemistry, there remain many questions relating to the biological nature of alkaloid synthesis. Mahler and Cordes212 considered and discussed three general examples of the synthesis of alkaloids from amino acids: (1) synthesis of the pyrroline ring and derived alkaloids from ornithine; (2) synthesis of the piperidine ring and derived alkaloids from lysine and (3) synthesis of isoquinolizidine alkaloids from tyrosine.

Nowadays a lot of new data is available on chemical alkaloid research, but the above-mentioned three classic examples are still important in the understanding of alkaloid synthesis. Certainly, the present trend in alkaloid chemistry is to underline the significance of the blocks, pathways and transamination reactions in alkaloid synthesis32. However, a presentation of chemical pathways and the synthesis of true alkaloids, protoalkaloids, and pseudoalkaloids is in many cases impossible without the characterization of their precursors. As already stated, protein amino acids, with their precursors and postcursors in different pathways, with or without transamination reactions, are generally substrates for alkaloids. This concept is very important because it highlights the probable role of alkaloids in metabolisms and underlines the significance of protein amino acids, their synthesis and degradation. Alkaloids exist in some kind of balance between distribution and degradation within amino acid production in the organisms producing them. This claim may provoke some controversy, but the connection between the amino acid pathway and the alkaloid synthesis is so evident that it cannot be omitted.

The similarity of the alkaloid to each molecule from the secondary metabolism is a consequence of the derivation process in the constructed active block. There are only four basic active blocks for the secondary compounds. Acetyl coenzyme A (acetyl CoA) is used in the acetate pathway, and shikimic acid in the shikimate pathway. The third block, mevalonic acid, is active in the mevalonate pathway, and the last, 1-deoxyxylulose 5-phosphate, key to the deoxyxylulose phosphate pathway (Figures 21-22). The theory of secondary compound synthesizing blocks is one of the most important in chemistry, as well as being interesting from a biological perspective. The establishment of the block needs the energy, and the primary metabolism is the source of it. On the other hand, the building blocks for the secondary metabolism are strongly regulated and this regulation seems to be genetically determined. The building blocks link the primary and secondary metabolisms. Acetyl CoA is derived from pyruvic acid (the product of a glycolytic pathway) and used in the acetate pathway (Figure 21). Pyruvate is derived primarily from glucose 6-phosphate. Another source of this three-carbon a-keto acid are the conversion reactions of oxaloacetate, lactate and alanine (Figure 22). Acetyl CoA is synthesized by the oxidative decarboxylation of peruvate and the ^-oxidation of fatty acids, as well as from ketogenic amino acids. A part of the acetyl CoA can be exported to the cytosol in the form of citrate, thus participating in the fatty acid synthesis.

Shikimic Acid
Figure 21. Secondary metabolism blocks and amino acid derivation. Note that shikimic acid can be derived directly from photosynthesis and glycolysis through the pentose phosphate cycle, or alternatively as a pyruvic acid postcursor.

However, in mammals acetyl CoA cannot be converted back into pyruvate. What is most important regarding alkaloid synthesis is that the pyruvate metabolism is a base for its alkaloid pathway precursors (Figure 22). As a group of specific molecules, part of the alkaloids is synthesized in the shikimic pathway. However, alkaloids are not the main product of this pathway, from which many phenols and lignans are also derived. Moreover, the shikimic pathway is only a source for aromatic amino acids such as phenylalanine, tyrosine and tryptophan. These amino acids are known to be the precursors of some alkaloids. Other amino acids are alkaloidal precursors from the different pathways. Ornithine is the postcursor of L-glutamic acid and L-lysine is postcursor of L-aspartic acid. Both glutamic and aspartic acids originate from the Krebs cycle. However, the shikimic and acetate pathways are very important as the original chain of alkaloids. Certainly, steroid alkaloids originate from the activity of mevalonate and deoxyxylulose phosphate pathways. This means that different alkaloids may derive from different secondary metabolism blocks and pathways. Alkaloid chemistry is, therefore, a part of the total secondary metabolism and has its roots

Secondary Metabolite Alkaloid Example

Figure 22. Pyruvate derivation and acetyl CoA synthesis. Observe that pyruvate, and subsequently the acetyl CoA pathway, has chain roots in the primary metabolism. Pyruvate can also be synthetized by conversion reactions. The secondary acetyl CoA is constructed as a building block on the pyruvate and glycolysis.

Figure 22. Pyruvate derivation and acetyl CoA synthesis. Observe that pyruvate, and subsequently the acetyl CoA pathway, has chain roots in the primary metabolism. Pyruvate can also be synthetized by conversion reactions. The secondary acetyl CoA is constructed as a building block on the pyruvate and glycolysis.

in the primary metabolism, photosynthesis and the Krebs cycle. The CoA and shikimic acid remain very important blocks for the alkaloids and their chemistry.

2. Synthesis and metabolism

Each biomolecule of a chemical nature in living organisms has its own synthesizing, transformational and interconverting processes. Therefore, the formation of the ring of the alkaloid molecule, and the flow of the nitrogen atom into this molecule, is the basic point for understanding alkaloid synthesis and its metabolism.

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks: the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid and 1-deoxyxylulose 5-phosphate (Figure 21). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthranilic acid as aromatized CoA ester (antraniloyl-CoA)). Shikimic acid is a product of the glycolytic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyruvate and erythrose 4-phosphate (Figure 21). The shikimic acid pathway is the source of such alkaloids as quinazoline, quino-line and acridine.

The mevalonate pathway is based on mevalonic acid (three molecules of acetyl-CoA) which is closely related to the acetate pathway, while the deoxyxy-lulose phosphate pathway is based on a combination of pyruvic acid and glycer-aldehyde 3-phosphate (both from the glycolytic pathway). Together, mevalonate and deoxyxylulose phosphate pathways produce terpenoid and steroid compounds. However, it is important to note that the Krebs cycle pathway is also key to many precursors of alkaloids. Ornithine, a postcursor of L-arginine in animals and of L-glutamate in plants, and, for example, L-lysine, a principal protein amino acid, deriving from the Krebs cycle pathway compound, are useful examples of the role of the Krebs cycle for alkaloid precursors (Figure 21). Moreover, there are other sources of alkaloid substrates, particularly in purine alkaloids. Figure 23 represents the general scope of alkaloid synthesis in the metabolic system of organisms and their energy production. Enzymatic activity is very important in the primary metabolism of glycolysis and the Krebs cycle. Pyruvic acid and CoA are key compounds in the synthesis of alkaloid precursors. Moreover, these precursors (amino acids) can be derived from different points in the glycolysis and Krebs cycles. Consequently, the synthesis of alkaloids as a secondary metabolic activity is a very challenging research subject. Generally, it is recognized in the literature that alkaloid metabolism in animals, and especially in mammals, is closely related to that of plants210. However, some exceptions exist. Figure 23 shows two means of L-ornithine synthesis.

In plants, this non-protein amino acid is derived from L-glutamate and in animals from L-arginine. Moreover, Figure 23 demonstrates that synthesis of alkaloids is complicated by the ability of the same amino acid to synthesize many different alkaloids.

Continue reading here: Skeleton diversity

Was this article helpful?

0 0


  • fidenzio
    Are alkaloids charged molecules?
    3 years ago