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Title: Absolute configuration of acremoxanthone C, a potent calmodulin inhibitor from Purpureocillium lilacinum

item MADARIAGA-MAZON, ABRAHAM - Universidad Nacional Autonoma De Mexico
item GONZALEZ-ANDRADE, MARTIN - Instituto Nacional De Medicina Genómica (INMEGEN), Secretaría De Salud, Distrito Federal, México C
item GONZALEZ, MARIA DELCARME - Universidad Nacional Autonoma De Mexico
item Glenn, Anthony - Tony
item CERDA-GARCIA-ROJAS, CARLOS - National Polytechnic Institute
item MATA, RACHEL - Universidad Nacional Autonoma De Mexico

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/26/2013
Publication Date: 7/22/2013
Publication URL:
Citation: Madariaga-Mazon, A., Gonzalez-Andrade, M., Gonzalez, M., Glenn, A.E., Cerda-Garcia-Rojas, C.M., Mata, R. 2013. Absolute configuration of acremoxanthone C, a potent calmodulin inhibitor from Purpureocillium lilacinum. Journal of Natural Products. 76(8):1454-1460.

Interpretive Summary: The fungus Purpureocillium lilacinum was isolated from soil collected in a cave in Juxtlahuaca in the state of Guerrero, Mexico. This fungus is a member of a family of fungi known for parasitizing insects and other fungi. It is also of interest for its possible utility for control of plant parasitic nematodes. Metabolites produced by this fungus in culture were extracted and screened to identify inhibitors of calmodulin. The identified metabolites are acremoxanthone C and acremonidin A. The two compounds were shown to bind to human calmodulin much more strongly (70-fold higher) than chlorpromazine, a commonly used inhibitor. As part of this work, a novel biosensor was developed to measure the interaction of these metabolites with calmodulin. Calmodulin interacts with many cellular targets to regulate their function, resulting in modulation of a large number of calcium-dependent signal transduction processes. The discovery of new and more potent CaM inhibitors, such as acremoxanthone C and acremonidin A, with novel binding properties could lead to the discovery of new research tools or drugs with unique pharmacological properties.

Technical Abstract: Bioassay-guided fractionation of an extract prepared from the culture medium and mycelium of Purpureocillium lilacinum allowed the isolation of two calmodulin (CaM) inhibitors, namely, acremoxanthone C (1) and acremonidin A (2). The absolute configuration of 1 was established as 2R, 3R, 1'S, 11'S, and 14'R through extensive NMR spectroscopy and molecular modeling calculations at the DFT B3LYP/DGDZVP level, which included the comparison between theoretical and experimental specific rotation, 3JC,H, and 3JH,H values. Compounds 1 and 2 bind to the human calmodulin (hCaM) biosensor hCaM M124C-mBBr, with dissociation constants (Kd) of 18.25 and 19.40 nM, respectively, 70-fold higher than that of chlorpromazine (Kd = 1.24 µM), used as positive control. Docking analysis using AutoDock 4.2 predicted that 1 and 2 bind to CaM at a similar site to that which KAR-2 binds, which is unusual. Furthermore, a novel, sensible, and specific fluorescent biosensor of hCaM, i.e., hCaM T110C-mBBr, was constructed; this device is labeled at a site where classical inhibitors do not interact and was successfully applied to measure the interaction of 1 with CaM. This is the first report of xanthone–anthraquinone heterodimers in species of Paecilomyces or Purpureocillium genera.