Biosynthesis of Caffeine

Several studies have investigated the biosynthesis of caffeine in tea. The results of a study by Suzuki and Takahashi27 30 suggest a pathway for caffeine biosynthesis in tea from 7-methylxanthine to theobromine and then to caffeine. Additionally they suggest that theophylline is synthesized from 1-methylxanthine. Another study by Ogutuga and Northcote31 proposes a pathway through 7-methylxanthosine to theobromine followed by caffeine. 

Roberts, M.F. and Waller, G.R., N-methyltransferases and 7-methyl-N9-nucleo-side hydrolase activity in Coffea arabica and the biosynthesis of caffeine, Phytochemistry, 18,451,1979. 

Suzuki, T. and Takahashi, E., Biosynthesis of caffeine by tea-leaf extracts, Biochemistry, 146,87,1975. 

Negishi, O., Ozzawa.T., and Imagawa, H., Biosynthesis of caffeine from purine nucleotides in tea plant, Bioscience, Biotechnology, and Biochemistry, 56,499,1992... 

Waller, G. R. and M. F. Roberts. N-methyltransferases and 7-methyl-N-nucleoside hydrolase activity in vitro of Coffea arabica fruits, and the biosynthesis of caffeine , and the in vivo metabolism of caffeine. Proc lUPAC 11th International Symp Chem Nat Prod 1978 4(2) 55-71. 

Figure 2.1 Sequence relationships in the form of a phylogentic tree of representative type 1, 2, and 3 MTs. The genus of each enzyme is listed. Type 1 (pink) family members include COMT, ChOMT, plant catechol OMT, and IOMT. Type 2 (light grey) includes catechol OMT from mammals and CCoAOMT (or CCOMT). Type 3 or SABATH (yellow) family members are predominantly carboxyl-directed MTs such as SAMT, BAMT, and JMT, but also include the NMTs involved in the biosynthesis of caffeine.

Ashihara, H. and Suzuki, T. (2004) Distribution and biosynthesis of caffeine in plants. 

The biosynthesis of caffeine begins with the methylation of xanthosine to yield N-methylxanthosine by the enzyme xanthosine N-methyltransferase (XMT) (also called 7-methy-Ixanthosine synthase) (171-173). N-methylxanthosine is converted to N-methylxanthine by methylxanthine nucleosidase, an enzyme that has not been cloned yet (174). N-methylxanthine is converted to theobromine by 7-methylxanthine-N-methyl-transferase (MXMT) (also called theobromine synthase), a second N-methyltransferase (171, 175). Theobromine is converted to caffeine by a final N-methyltransferase, dimethylxanthine-N-methyltransferase (DXMT) (also called caffeine synthase) (171). 

The biosynthesis of caffeine takes the same path up to xanthosine-5 -phosphate, which is here dephosphorylated and methylated at N-7. However, there are also reports that xanthosine-5 -phosphate can be methylated directly. [506] Afterthe sugar residue is cleaved off, two additional methylation steps take place via the intermediates 7-methykanthine and theobromine. [507]... 

The biosynthesis of caffeine was investigated through incorporation experiments using the stems of Cqffea and Camellia plants [17]. As a result, it became clear that methylation of the N-7 position occurred on xanthosine derived from XMP, which originated from AMP via IMP. Caffeine is then biosynthesized through 7-methyl xanthosine, 7-methyl xanthine, and theobromine, as shown in the figure. 

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). 

For a recent article on the biosynthesis of caffeine see Looser et al. (1974) and the references therein. 

Ashihara, H. et al. (1996) Biosynthesis of caffeine in leaves of coffee. Plant Physiol 111,... 

The biosynthesis of caffeine begins with xanthosine, which is converted into 7-methylxanthosine, 7-methylxanthine, theobromine and caffeine, in that order. The genes encoding three distinct A/ methyltransferase enzymes used to make caffeine from xanthosine have been isolated and then expressed in tobacco plants. The resulting caffeine-containing tobacco plants are unpalatable to tobacco cutworms (Spodoptera liturd). 

---