Characterization of Panax ginseng UDP- Glycosyltransferases Catalyzing Protopanaxatriol and Biosyntheses of Bioactive Ginsenosides F1 and Rhl in Metabolically Engineered Yeasts

Ginsenosides, the main pharmacologically active natural compounds in ginseng （Panax ginseng）, are mostly the glycosylated products of protopanaxadiol （PPD） and protopanaxatriol （PPT）. No uridine diphosphate glycosyltransferase （UGT）, which catalyzes PPT to produce PPT-type ginsenosides, has yet been reported. Here, we show that UGTPgl, which has been demonstrated to regio-specifically glycosylate the C20-OH of PPD, also specifically glycosylates the C20-OH of PPT to produce bioactive ginsenoside FI. We report the characterization of four novel UGT genes isolated from P. ginseng, sharing high deduced amino acid identity （〉84%） with UGTPgl. We demonstrate that UGTPgl00 specifically glycosylates the C6-OH of PPT to produce bioactive ginsenoside Rhl, and UGTPgl01 catalyzes PPT to produce F1, followed by the generation of ginsenoside Rgl from FI. However, UGTPgl02 and UGTPgl03 were found to have no detectable activity on PPT. Through structural modeling and site-directed mutagenesis, we identified several key amino acids of these UGTs that may play important roles in determining their activities and substrate regio-specificities. Moreover, we constructed yeast recombinants to biosynthesize F1 and Rhl by introducing the genetically engineered PPT-producing pathway and UGTPgl or UGTPgl00. Our study reveals the possible biosynthetic pathways of PPT-type ginsenosides in Panax plants, and provides a sound manufacturing approach for bioactive PPT-type ginsenosides in yeast via synthetic biology strategies.

Amphiphilic drug-drug conjugate for cancer therapy with combination of chemotherapeutic and antiangiogenesis drugs

The progression and metastasis of solid tumors strongly rely on the process of forming nascent blood vessels.However,using angiogenesis inhibitors alone does not meet the cancer treatment needs.Herein,we used the amphiphilic drug-drug conjugate(ADDC)strategy to fabricate a new drug conjugate with the combination of chemotherapeutic drug and antiangiogenesis drug together.With one-step esterification of hydrophilic floxuridine(FUDR)and hydrophobic pseudolaric acid B(PAB),the conjugate was synthesized.The amphiphilic property of FUDR-PAB conjugate induced the self-assembly to form nanoparticles in water.From further in vitro and in vivo experiments,this FUDR-PAB conjugate does not only have a high antitumor effect,but also shows efficient antianiogenesis property.These results offer a promising ADDC strategy for designing drugs with combination of chemotherapeutic drug and antiangiogenesis drug together.

Clerodenoids A-F:C-ring Aromatized and/or Rearranged Abietane Diterpenoids from Clerodendrum chinense var.simplex

Main observation and conclusion As part of our continuing efforts toward the discovery of the biologically active diterpenoids from medicinal plants,six new C-ring aromatized abietane diterpenoids,clerodenoids A-F(1-6),were isolated from Clerodendrum chinense.

Cipaferoids A-C, Three Limonoids Represent Two Different Scaffolds from Cipadessa baccifera

Three limonoids cipaferoids A-C （1-3） representing two different scaffolds were isolated from Cipadessa baccifera. Their structures were completely assigned by spectroscopic data, CD exciton chirality method, and X-ray crystallography. Compounds 2 and 3 exhibited moderate antimalarial activity with IC50 values of 9.3±0.1 and 14.7±4.8 μmol·L^-1, respectively.