Biocatalysis of Cycloastragenol by Syncephalastrum racemosum and Alternaria alternata to Discover Anti‐Aging Derivatives

Abstract

Cycloastragenol is ac ycloartane-type triterpenoid with significant telomerase-activating activities.Inthis paper, the biocatalysisofc ycloastragenol by two strains of filamentous fungi, namely Syncephalastrum racemosum AS 3.264 and Alternaria alternata AS 3.4578, was investigated. Scaled-up biotransformation reactions yielded 27 metabolites. Their structures were established on the basis of extensiveN MR and HR-ESI-MS data analyses,a nd 18 of them are new compounds.T he twof ungal strains exhibited distinct biocatalytic features. S. racemosum could catalyzer ing expansion ande poxidation reactions to form 3b,10b-epoxy-o r6 a ,19a-epoxy-9,10-seco-cycloartane structures,w hereas A. alternata preferredt oc atalyzea cetylation reactions,e specially at 3-OH, 6-OH and1 9-OH. These regio-ands tereoselective reactions are difficult to achieve by chemical means,b ut could be realized under mild conditions by biocatalysis.F urthermore,w ef ound that some acetylated derivatives at 50 mMc ould significantly extend the lifespan of Caenorhabditise legans from 16.93 AE 0.70 do ft he control group to 20.01 AE 0.75 d (P < 0.01), versus 18.54 AE 0.67 df or cycloastragenol. These biotransformed derivatives of cycloastragenol could be potential anti-aginga gents.

Biotransformation of cyclocanthogenol by the endophytic fungus Alternaria eureka 1E1BL1

“…In addition, compounds 7 and 8 were the rearrangement products of CCG resulting from the cleavage of 9,19-cyclopropane ring followed by methyl migration. This unique transformation was reported previously in the biotransformation of CA and CCG by Cunninghamella blakesleeana NRRL 1369, Syncephalastrum racemosum AS 3.264 and Alternaria alternata AS 3.4578 (Bedir et al, 2015;Feng et al, 2015;Kuban et al, 2010;Yang et al, 2012).…”

“…Additionally, downfield shift of C-3 signal suggested that an oxygen bridge involving C-3 atom was present in the framework. Resemblance of the spectral data of 4 with those of previously reported compounds (Feng et al, 2015) together with the long-distance correlation of the quaternary carbon at 88.3 ppm with H-3 (d 3.73) provided evidence for the oxygen bridge between C-3 and C-10 carbons. The orientation of 3(10)epoxy bridge was confirmed by inspecting the ROESY spectrum of 4 and calculating its minimized energy conformer by MM2 molecular mechanics program.…”

“…Apart from the monohydroxylation reactions, A. eureka 1E1BL1 catalyzed ring expansion and epoxidation reactions on CCG (4, 5 and 6) to form 3(10)b-epoxy-9,10-seco-cycloartane structure. The microbial-catalysis of the B ring expansion reactions have been observed in the transformation of cycloastragenol to give 9,10-secocycloartane skeleton by the fungus Syncephalastrum racemosum AS 3.264 (Feng et al, 2015;Yang et al, 2012). However, a reaction mechanism was not proposed for this unique biotransformation.…”

The role of Cycloastragenol at the intersection of Nrf-2/ARE, telomerase, and proteasome activity

“…Previously, CA was suggested to ameliorate the decrease in Nrf-2 expression caused by TNF-α treatment in vascular smooth muscle cells. In another study, 50 μM CA slightly increased the Nrf-2 transcription in HepG2 cancer cells (Feng et al, 2015), which has much higher intrinsic telomerase expression compared to normal human cells (Sakaguchi et al, 2017; Watanabe et al, 2011). In this study, we found that CA not only increased Nrf-2 protein expression but also enhanced the nuclear localization of Nrf-2, leading to ARE-promotor activity and consequently increasing the levels of cytoprotective enzymes such as HO-1, GR, and GCLC to protect cells against oxidative stress ( Figure 1 ).…”

Anti-Inflammatory 18β-Glycyrrhetinin Acid Derivatives Produced by Biocatalysis

“…Biotransformation, as an alternative method for structural modification, catalyzes many important reactions, especially in structurally complex natural products [16]. This method exhibited many advantages such as stereo-or region-selectivity, mild reaction conditions and avoiding complex protection, and deprotection steps over chemical synthesis [17][18][19].…”