Biotransformation of artemisinic acid to bioactive derivatives by endophytic Penicillium oxalicum B4 from Artemisia annua L.


Tian H(1), Li XP(1), Zhao J(2), Gao HW(3), Xu QM(4), Wang JW(5).
Author information:
(1)College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
(2)National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Mississippi, 38677, USA.
(3)College of Pharmaceutical Sciences, Guangxi University of Chinese Medicine, Nanning, 530200, China.
(4)College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. Electronic address: [Email]
(5)College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. Electronic address: [Email]


As a biosynthetic precursor of the antimalarial drug artemisinin, artemisinic acid (AA) is abundant in Artemisia annua L. with a content of 8-10-fold higher than artemisinin, but less effective. In this study, the biotransformation of AA was carried out with an endophytic fungus Penicillium oxalicum B4 to extend its utility. After 10-day-culture of the endophyte with AA at 2 mg/mL, eight biotransformation metabolites were isolated from the culture broth, including five undescribed metabolites, namely 3α,14-dihydroxyartemisinic acid, 14-hydroxy-3-oxo-artemisinic acid, 15-hydroxy-3-oxo-artemisinic acid, 12, 15-artemisindioic acid and 1,2,3,6-tetradehydro-12, 15-artemisindioic acid. The fungal enzymes possess the selective capacity to hydroxylate, carbonylate and ketonize the allyl group of AA. The major biotransformation metabolite was the hydroxylated product 3-α-hydroxyartemisinic acid (33.3%) in the cultures of early stage (day 1-6), whereas most of the other biotransformation products were synthesized in the later stage (day 8-10). Compared with AA, some metabolites (3α,14-dihydroxyartemisinic acid, 15-hydroxy-3-oxo-artemisinic acid and 1,2,3,6-tetradehydro-12, 15-artemisindioic acid) possessed stronger cytotoxic activity to the human colon carcinoma cell line (LS174T) and promyelocytic leukemia cell line (HL-60). The metabolites 12, 15-artemisindioic acid and 3-α-hydroxyartemisinic acid exhibited significant inhibitory activity to the lipopolysaccharide-induced nitrite production of RAW 264.7 cells at 10.00 μM and 2.50 μM, respectively. The results demonstrated the potential of fungal endophytes on biotransforming AA to its bioactive derivatives.