Purine alkaloid biosynthesis

Ashihara H, Sano H, Crozier A. Caffeine and lelaled purine alkaloids biosynthesis, catabolism, function and gmetic engineering. Phytochemistry 2008 69(4) 841-56. 

Purine alkaloid biosynthesis Xanthine, l,3,7-tiimethylxanthme(caffeine), 3,7-dimethylxanthme(theobnHnme), 1,3-dimethylxanthine (theophylline)... 

Keywords alkaloid biosynthesis alkaloid genes nicotine tropane alkaloids pyrrolizidine alkaloids benzylisoquinoline alkaloids monoterpene indole alkaloids ergot alkaloids acridone alkaloids purine alkaloids taxol betalains... 

Caffeine, a purine alkaloid, is one of the most widely known natural products. Caffeine is ingested as a natural component of coffee, tea, and cocoa, and the impact of caffeine on human health has been studied extensively. The biosynthetic pathway of caffeine has been elucidated recently on the genetic level. Caffeine biosynthesis has been studied most widely in the plant species Coffea (coffee) and Camellia (tea) (168, 169). 

Scheme 4. Biosynthesis of the purine alkaloids caffeine and theobromine. Molecular clones have been isolated for all enzymes shown. Abbreviations CS, caffeine synthase MXN, 7-methyIxanthosine nucleosidase MXS, 7-methyIxanthosine synthase.

Other Sources of Imidazole Alkaloids Lythraceae alkaloids Maytansinoids Antitumor Activity Other Biological Activity Muscarine Alkaloids Naphthylisoquinoline Alkaloids Peptide Alkaloids Purine or Xanthine Alkaloids Biosynthesis... 

Camellia (Thea) sinensis (tea) and Cqffea arabica (coffee) plants. Caffeine was formed rapidly by extracts of green coffee berries, but little by more mature ones, and not at all by seedlings. Biosynthesis of caffein proceeds from 7-methylxanthosine in the presence of an active purine nucleoside phosphorylase or 7-methyl-A -nucleoside hydrolase. Methionine and 5-adenosylmethionine serve as precursors for the methyl groups of purine alkaloids. These act in the presence of methyltransferases on 7-methylxanthine (38) and theobromine (31) to produce caffeine. A pathway for the origin of these compounds in coffee and tea plants has been proposed (Suzuki et al., 1992 Waller and Dermer, 1981) (Fig. 37.10). 

Thus, from the Solanaceae, hyoscyamine, a tropane alkaloid, which we now know to be derived from ornithine and/or arginine (Arg, R, Scheme 12.7), and nicotine, derived from a combination of nicotinic acid (see Scheme 12.103, et seq.) and ornithine, serve as examples of alkaloids based on nonaromatic amino adds. In the benzylisoquinoline alkaloids, only morphine, arguably the first alkaloid isolated in purified form and known to be derived from tyrosine (Tyr, T), itself a prephenic acid derivative, is discussed. For the indole alkaloids, the single example of this rich family to be illustrated is vinblastine, a (relatively) recently isolated base of some medicinal value and which is shown to be composed of two different expressions of tryptophan (Trp, W) and mevalonate (Scheme 11.40). Finally, caffeine is chosen as the member of the purine alkaloids, a relatively small family of compounds but one of major commercial import and one whose biosynthesis is closely tied to the library of life. 

Xanthosine, the initial substrate of purine alkaloid synthesis, is supplied by at least four different pathways de novo purine biosynthesis de novo route), degradation of adenine nucleotides (AMP route), the SAM cycle (SAM route), and guanine nucleotides (GMP route) [1, 38]. The pathways leading to xanthosine formation are illustrated in Fig. 29.2. 

Information on cellular metabolic organization of caffeine biosynthesis and catabolism links to purine nucleotide metabolism, intercellular translocation, and accumulation mechanisms at specific cellular sites, such as chloroplasts and vacuoles, have yet to be fully revealed. Cell-, tissue-, and organ-specific synthesis and possibly catabolism of purine alkaloids may be regulated by unique and unknown developmental- and environmental-specific control mechanisms. A great deal of fascinating purine alkaloid biology in plants still remained to be discovered. 

Ashihara H, Crozier A (1999) Biosynthesis and metabolism of caffeine and related purine alkaloids in plants. Adv Bot Res 30 117-205... 

Only the main features of the biosynthesis of the three purine alkaloids mentioned are known. It is likely that the starting material is, again, inosine-5 -phosphate which is first converted into xanthosine-5 -phosphate. This nucleotide contains the purine base xanthine. It is possible that the base is first liberated aad then methylated to give the purine alkaloids. 

Caffeine synthase, the majority of SAH hydrolase activity, and parts of the adenine-salvage pathway are localized to chloroplasts. In coffee SAM synthase is confined to the cytosol and SAM synthase genes fi-om tobacco and parsley lack a transit peptide. However, SAM synthase from tea is a chloroplastic enzyme, encoded by a nuclear gene (Koshiishi et al. 2001). The proposed model for the subcellular localization of caffeine biosynthesis begins with the production of homocysteine and its conversion to methionine in the chloroplasts. Methionine is then converted to SAM in the cytosol and transported back into the chloroplast to serve as the methyl donor in caffeine biosynthesis. Purine alkaloids are stored in vacuoles where they are thought to form complexes with chlorogenic acids (Mosli-Waldhauser and Baumann 1996). 

Several purine derivatives are found in nature, e.g. xanthine, hypoxanthine and uric acid. The pharmacologically important (CNS-stimulant) xanthine alkaloids, e.g. caffeine, theobromine and theophylline, are found in tea leaves, coffee beans and coco. The actual biosynthesis of purines involves construction of a pyrimidine ring onto a pre-formed imidazole system. 

Until now, these corrinoid derivatives were not usually described in alkaloid terms, and were often classified and discussed with purines and pyrimidines as primary metabolites related to life. However, at the beginning of the biosynthesis of porphyrin in the mitochondrion, a C4 unit is attached to an activated glycine, and during this biosynthetic step decarboxylation is accomplished. 

To date, biosynthetic pathway for four classes of plant alkaloids has been characterized to some extent the benzylisoquinoline, monoterpenoid indole, purine, and tropane alkaloids. Benzylisoquinoline alkaloids (BIAs) are derived from tyrosine and are comprised of 2,500 defined structures found mainly in the Papaveraceae, Ranunculaceae, Berberidaceae, and Menispermaceae [11]. First step of BIA biosynthesis begins with the stereoselective Pictet-Spengler condensation of dopamine and 4-hydroxyphenylacetaldehyde to form (5)-norcoclaurine. Subsequently, through a series of methylations and hydroxylations, (5)-norcoclaurine gets converted into (5)-reticuline, which is the pivotal intermediate for many pharmaceutically important BIAs formed further down in the pathway (i.e., downstream pathways) (Fig. 8.6) [3]. 

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