Biosynthesis Of Artemisinin

Farnesyl pyrophosphate, the fundamental precursor of sesquiterpenes derived from mevalonic acid, (Akhila et al., 1987), is transformed into artemisinic acid, 13, one of the major constituents of A. annua through cyclisation and oxidation steps (Akhila et al., 1990). Although the biosynthetic pathway of artemisinin, 1, has not been completely established, there are two proposals:

The first is that arteannuin B, 3, another cadinolide of A. annua and 1 are generated sequentially from artemisinic acid, 13, (Akhila et al., 1990; Nair and Basile, 1992; 1993). Brown et al. (1994), isolated 4,5-secocadinane, 25, and dihydroxy-cadinanolide, 26, from A. annua. Following the isolation of the above the latter authors suggested a plausible biosynthetic route for the conversion of arteannuin B into artemisinin (Scheme 1). The mechanism proposed is that the epoxide ring of arteannuin B is first cleaved to yield 26 which then undergoes Grob fragmentation to yield the enol form of 25. The enol tautomer, 25a, subsequently rearranges to give

Scheme 1 Postulated biosynthesis of artemisinin from arteannuin B, 3.

the 1,2,4-trioxane system of 19 (artemisitene) via enzymic oxygenation at the enolic double bond (Acton and Klayman, 1985). Reduction of the 11-13 double bond completes the transformation to yield artemisinin; Woerdenbag et al. (1994), have reported the conversion of 19 into artemisinin. This proposed biosynthetic route is strongly supported by several partial or total chemical syntheses of artemisinin (Avery et al, 1992; Ravindranathan et al, 1990; Schmidt and Holfheinz, 1983; Xu et al, 1986; Ye and Wu, 1990; Zhou and Xu, 1994).

The second view is that 1 and 3 are biosynthesised independently from artemisinic acid, 13, (Sangwan et al, 1993; Wang et al, 1988, 1993). El-Feraly et al (1986), converted 13 into 3, whereas Kim and Kim, (1992), showed biotransformation of dihydroartemisinic acid 16, into 1 enzymatically in tumour homogenate. The latter authors did not observe the enzymic conversion 13 into 16 in vivo but as 16 is a constituent of A. annua the plant would be expected to have the enzymic system required for this bioconversion. Since artemisinic acid, 13, has been transformed chemically (non-enzymatically) into 1 via two steps, reduction and photo-oxidation by several workers, (Scheme 2) (Acton and Roth, 1992; Haynes and Vonwiller, 1990; Roth and Acton, 1989; 1991; 1991a), it is suggested that artemisinin, 1, could be generated by this route in vivo-, the latter authors have not reported the formation of arteannuin B, 3, following the incorporation of 16 in tumour homogenate.

From the above it is not clear whether 1 is biosynthesised directly from 13 or through intermediate 3. Thus, a detailed biosynthetic study is required to come to a definite conclusion.

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