Integrating carbon-halogen bond formation into medicinal plant metabolism.
Halogenation, which was once considered a rare occurrence in nature, has now been observed in many natural product biosynthetic pathways. However, only a small fraction of halogenated compounds have been isolated from terrestrial plants. Given the impact that halogenation can have on the biological activity of natural products, we reasoned that the introduction of halides into medicinal plant metabolism would provide the opportunity to rationally bioengineer a broad variety of novel plant products with altered, and perhaps improved, pharmacological properties. Here we report that chlorination biosynthetic machinery from soil bacteria can be successfully introduced into the medicinal plant Catharanthus roseus (Madagascar periwinkle). These prokaryotic halogenases function within the context of the plant cell to generate chlorinated tryptophan, which is then shuttled into monoterpene indole alkaloid metabolism to yield chlorinated alkaloids. A new functional group-a halide-is thereby introduced into the complex metabolism of C. roseus, and is incorporated in a predictable and regioselective manner onto the plant alkaloid products. Medicinal plants, despite their genetic and developmental complexity, therefore seem to be a viable platform for synthetic biology efforts.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Weerawat
W
Runguphan
Xudong
X
Qu
Sarah E
SE
O'Connor
D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001688:Biological Products / Q000096:biosynthesis / Q000235:genetics; D001709:Biotechnology / Q000379:methods; D002244:Carbon / Q000737:chemistry / Q000378:metabolism*; D030008:Catharanthus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002713:Chlorine / Q000737:chemistry / Q000378:metabolism*; D054879:Halogenation; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000378:metabolism; D026121:Indole Alkaloids / Q000378:metabolism; D039821:Monoterpenes / Q000378:metabolism; D018517:Plant Roots / Q000378:metabolism; D030821:Plants, Genetically Modified; D010946:Plants, Medicinal / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D012231:Rhizobium / Q000235:genetics; D046948:Secologanin Tryptamine Alkaloids / Q000378:metabolism; D058615:Synthetic Biology / Q000379:methods; D046509:Tissue Culture Techniques; D019076:Transgenes; D014364:Tryptophan / Q000378:metabolism
C412590:19,20-dihydroakuammicine; D001426:Bacterial Proteins; D001688:Biological Products; D006576:Heterocyclic Compounds, 4 or More Rings; D026121:Indole Alkaloids; D039821:Monoterpenes; D046948:Secologanin Tryptamine Alkaloids; C005709:raubasine; D002713:Chlorine; D002244:Carbon; D014364:Tryptophan; D001142:Aromatic-L-Amino-Acid Decarboxylases