|RIVERA-CHAVEZ, JOSE - Universidad Nacional Autonoma De Mexico|
|GONZALEZ-ANDRADE, MARTIN - Instituto Nacional De Medicina Genómica (INMEGEN), Secretaría De Salud, Distrito Federal, México C|
|GONZALEZ, MARIA DELCARMEN - Universidad Nacional Autonoma De Mexico|
|Glenn, Anthony - Tony|
|MATA, RACHEL - Universidad Nacional Autonoma De Mexico|
Submitted to: Phytochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/16/2013
Publication Date: 6/26/2013
Publication URL: http://handle.nal.usda.gov/10113/58201
Citation: Rivera-Chavez, J., Gonzalez-Andrade, M., Gonzalez, M., Glenn, A.E., Mata, R. 2013. Thielavins A, J and K: alpha-glucosidase inhibitors from MEXU 27095, an endophytic fungus from Hintonia latiflora. Phytochemistry. 94:198-205.
Interpretive Summary: The plant Hintonia latiflora is noted in Mexico for its anti-diabetic medicinal properties. As part of a study isolating fungi that live within this plant (i.e., endophytes), an unidentified fungus was isolated and designated MEXU 27095. Metabolites produced by this fungus in culture were extracted and identified as thielavins A, J and K. Subsequent targeted studies were performed to evaluate the effectiveness of these compounds as inhibitors of the enzyme alpha-glucosidase. Cells use this enzyme to break apart complex carbohydrates to generate glucose, which is then absorbed by the cells. Inhibition of this enzyme is an important strategy for the treatment of diabetes, since slower absorption of glucose prevents spikes in blood sugar. Thus, there is much interest in identifying new, effective inhibitory compounds as possible new drugs for the treatment of diabetes. The data showed that the thielavins had high potential as inhibitors of alpha-glucosidase similar to acarbose, the compound currently used to treat diabetic individuals. Furthermore, the thielavins represent a new class of alpha-glucosidase inhibitors.
Technical Abstract: Bioassay-guided fractionation of the bio-active organic extract obtained from solid-media culture of MEXU 27095, an endophytic fungus isolated from the Mexican medicinal plant Hintonia latiflora (Rubiaceae), led to separation of three tridepsides which were identified as thielavins A, J and K. All three compounds inhibited Saccharomyces cerevisieae alpha-glucosidase (alphaGHY) in a concentration-dependent manner with IC50 values of 23.8, 15.8, and 22.1 uM, respectively. Their inhibitory action was higher than that of acarbose (IC50 = 545 uM), used as a positive control. Kinetic analysis established that the three compounds acted as non-competitive inhibitors with ki values of 27.8, 66.2 and 55.4 uM, respectively (alpha = 1.0, 1.2, 0.7, respectively); acarbose behaved as competitive inhibitor with a ki value of 156.1 uM. Thielavin J inhibited the activity of alpha-glucosidase from Bacillus stearothermophilus (alphaGHBs) with an IC50 of 30.5 uM, being less active than acarbose (IC50 = 0. 015 uM); in this case, compound (2) (ki = 20.0 uM and alpha = 2.9) and acarbose (ki = 0.008 uM and alpha = 1.9) behaved as non-competitive inhibitors. Docking analysis predicted that all three thielavins and acarbose bind to homologated alphaGHBs and to alphaGHY (PDB: 3A4A) in a pocket close to the catalytic site for maltose and isomaltose, respectively. The alpha-glucosidase inhibitory properties of thielavin K (3) were corroborated in vivo since it induced a noted antihyperglycemic action during an oral sucrose tolerance test (3.1, 10.0 and 31.6 mg/kg) in normal and nicotinamide–streptozotocin diabetic mice. In addition, at a dose of 10 mg/kg, it provoked a moderate hypoglycemic activity in diabetic mice.