Is artemisinic acid a precursor of artemisinin?

Two competing chemotypes

Already twenty years ago the possibility of two chemotypes for Artemisia annua had been suggested ( HJ Woerdenbag et al., Flavour and Fragrance Journal 8, 1993, 131-137) distinguishing between a Chinese and a Vietnamese chemotype, the former containing 0.17 artemisinin, the latter 1.0%.
D Fulzele et al. ( Phytotherapy Research , 5, 1991, 149-153) found that plants from Europe produced the highest level of artemisin and those from Lucknow produced the highest level of arteannuin-B.
L Maes, F Van Nieuwerburgh from Gent University et al., ( J of Chromatography A 1118, 2006, 180.187) studied the influence of different enzymes on the production of arteannuin B and artemisinin in the two chemotypes , those from the National Botanical Garden at Meise poor in artemisinin and rich in B-arteannuin and those from Pedro de Magalhaes, Brazil rich in artemisinin and poor in B-arteannuin. It is very difficult to detect any arteannuin-B in Brazilian artemisia annua from Campinas, at least by HPLC-ELSD. Very often the arteannuin-B peak overlaps with the peaks of degradation products of artemisinin (CA Peng et al., J of Chromatography, 1133, 2006, 254-8).

Huge differences were also found in the work of L. Al-Soweimel , (BS thesis, Worcester, 2009) concerning the content in artemisinin and arteannuin-B between strains from Yugoslavia and China. They relate this to differences in the precursors artemisinic acid and dihydroartemisinic acid. The author finds surprisingly high concentrations of artemisinic acid in both chemotypes. The Chinese ( W Wu et al., Planta Med, 77, 2011, 1048-53 ) have recently confirmed considerable differences in artemisinic acid and dihydroartemisinic acid between two chemotypes within the species Artemisia annua. The two chemotypes use the two different pathways employed in plants for the production of isoprenoids, the one localized in the plastid, the other in the cytosol.
Arteannuin-B was detected by Efferth in Chinese samples but not in Anamed samples (T Efferth et al Phytomedicine, 18, 2011, 959-969). He finds also that it is as cytotoxic against cancer cells as artemisinin.
L.Olofson et al., ( BMC Plant biology, 11, 2011, 45) state that the conversion of dihydroartemisinic acid to artemisinin is believed to be a non enzymatic spontaneous reaction. In a similar way artemisinic acid is converted to arteannuin-B . The genetic variation within A. annua appears to be high. One chemotype shows high content of dihydroartemisinic acid DHAA and artemisinin, while the second chemotype shows high content of artemisinic acid and arteannuin-B. Based on results obtained by Jorge Ferreira (personal communication) the plant keeps a healthy reservoir of the precursor DHAA even while the precursor is transformed into artemisinin. Sun and oxygen are sufficient for this transformation, no enzyme is required. This is confirmed by GD Brown (Molecules, 2010, 15, 7603-98) and by P Weathers (Phytochem Rev 19 Feb 2010).
Artemisinic acid even appears to inhibit the transformation of dihydroartemisinic acid into artemisinin, by inhibition of the CYP transcription. (PR Arsenault et al., Plant Pysiol 154 oct 2010). Chenfei Ma et al., (J of Chromatography A 1186, 2008, 412-19) also studied two chemotypes and find that in one of the samples at the flowering stage artemisinin had no significant increase , but arteannuin-B increased significantly. High arteannuin-B creates a bottle-neck in the production of artemisinin. A similar concept had been developed by TE Wallart et al., ( Planta Med 66. 2000, 57-62).

It is possible however that a decoction of the artemisia annua herb might lead to an in vivo transformation of certain precursors into artemisinin.
Very few investigations have been devoted to a comparison between artemisinin and artemisinic acid. Several studied the phytotoxicity. It was found ( L.Stiles et al., Journal of Chemical Ecology, April 1994, 20:4, 969-978) that both molecules induced almost the same effect at a concentration of 5 µM for artemisisin versus 10 µM for artemisinic acid. Similar studies were made on seeds (GD Baghi et al., Phytochemistry, 45:6, 1997, 1131-33). Artemisinin has an EC50 of 10ng/ml against plasmodium compared to 1000 for arteannuin-B (Nguyen Tien Ban 1999 http://www.proseanet.org). Against human and plant pathogenic fungi only arteannuin B shows activity whereas artemisinin shows none ( HQ Tang et al., Planta Medic 66, 2000. 391-393)

J Ferreira (J Agric Food Chem 58, 2010, 1691-98) also finds that during the drying process of Artemisia annua herb only dihydtroartemisinic acid is transformed into artemisinin, artemisinic acid stays stable in the leaves. The same author also claims that the two different chemotypes of artemisia annua are very different in their polyphenol composition ( Molecules. 2010. 15)

In light of this the biosynthesis of artemisinic acid by many research groups for the production of artemisinin appears to be a complicated process.
Artemisinic acid is a dead end product which cannot be converted into artemisinin. That does not mean that it is useless: although having less efficacy than artemisinin, it has a variety of pharmacological activity, such as antimalarial, antipyretic, antibacterial, antitumor (J Kong et al., RSC Adv, 01 Feb 2013). Recently it has been shown that it is a regulator of adipocyte differentiation, that it reduces IL-6 secretion, thus influencing insulin resistance and the inflammatory state characterizing obesity (J Lee et al., J Cell Biochem, 2012, 113:7. 2488-99) Research at Basel ( Molecules, 2010 November) has firmly confirmed this: dihydroartemisinic acid is a late-stage precursor to artemisinin and the closely related metabolite artemisinic acic is not. They have also found that some derivatives from artemisinic acid, the arteannuin-B precursor, have shown in vitro higher antimalarial activities against Plasmodium falciparum than artemisinin. The discovery of novel derivatives of artemisinic acid will begin a new era in natural drug formulation pathway. (Pooja Singh, 01/2011; Proceedings of: 80th annual Symposium of biological chemists).

lutgenp@gms.lu


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