A Novel Anti-diabetic Metabolite from Plants: Biosynthesis, Gene Discovery, and Metabolic Engineering of Montbretin A
July 14-18, 2019
Plant specialized metabolites (i.e. secondary metabolites) have been employed by humans for centuries in traditional and modern medicine. They remain an important source for the discovery of new pharmaceuticals and nutraceuticals. Montbretin A (MbA) is a complex acylated flavonoid glycoside discovered in the below-ground storage organs (corms) of the ornamental plant montbretia (Crocosmia x crocosmiiflora). MbA a highly potent and selective inhibitor of the human pancreatic α-amylase (HPA), a key enzyme in starch degradation. MbA is being tested for the treatment of type-2 diabetes. However, due to low abundance of MbA in montbretia plants and due the complex chemical structure of MbA, natural product extraction and chemical synthesis are insufficient for MbA production. Our goal is to develop a heterologous plant production system or a microbial production system for MbA. This requires knowledge of the genes, enzymes and regulating factors of the MbA biosynthetic system in montbretia. We achieved the discovery of the complete biosynthetic pathway of MbA using an approach that combined knowledge of montbretia biology, metabolite profiling, differential transcriptome analysis, cDNA cloning, heterologous gene expression in E. coli, yeast and tobacco, and enzyme biochemistry. This includes the discovery of five new UDP-sugar dependent glycosyltransferases (UGTs) and a BAHD-acyltransferases (AT) which together catalyze the complete assembly of MbA from its different building blocks. To reconstruct MbA production in tobacco (Nicotiana benthamiana) we enhanced the biosynthesis of flavonol precursors using genes for myricetin biosynthesis and transcription factors from montbtretia, which were stacked with genes of the MbA assembly pathway. We will highlight both challenges and opportunities of exploring novel biosynthetic systems of plant specialized metabolites for the development of new drugs, and bioproducts in general.
Jörg Bohlmann; Sandra Irmisch; Seohyun Jo; Christopher R. Roach,; Sharon Jancsik; Macaire Man Saint Yuen; and Stephen G. Withers, "A Novel Anti-diabetic Metabolite from Plants: Biosynthesis, Gene Discovery, and Metabolic Engineering of Montbretin A" in "Biochemical and Molecular Engineering XXI", Christina Chan, Michigan State University, USA Mattheos Koffas, RPI, USA Steffen Schaffer, Evonik Industries, Germany Rashmi Kshirsagar, Biogen, USA Eds, ECI Symposium Series, (2019). https://dc.engconfintl.org/biochem_xxi/104