TY - JOUR
T1 - Deploying Microbial Synthesis for Halogenating and Diversifying Medicinal Alkaloid Scaffolds
AU - Bradley, Samuel Alan
AU - Zhang, Jie
AU - Jensen, Michael Krogh
PY - 2020
Y1 - 2020
N2 - Plants produce some of the most potent therapeutics and have been used for thousands of years to treat human diseases. Today, many medicinal natural products are still extracted from source plants at scale as their complexity precludes total synthesis from bulk chemicals. However, extraction from plants can be an unreliable and low-yielding source for human therapeutics, making the supply chain for some of these life-saving medicines expensive and unstable. There has therefore been significant interest in refactoring these plant pathways in genetically tractable microbes, which grow more reliably and where the plant pathways can be more easily engineered to improve the titer, rate and yield of medicinal natural products. In addition, refactoring plant biosynthetic pathways in microbes also offers the possibility to explore new-to-nature chemistry more systematically, and thereby help expand the chemical space that can be probed for drugs as well as enable the study of pharmacological properties of such new-to-nature chemistry. This perspective will review the recent progress toward heterologous production of plant medicinal alkaloids in microbial systems. In particular, we focus on the refactoring of halogenated alkaloids in yeast, which has created an unprecedented opportunity for biosynthesis of previously inaccessible new-to-nature variants of the natural alkaloid scaffolds.
AB - Plants produce some of the most potent therapeutics and have been used for thousands of years to treat human diseases. Today, many medicinal natural products are still extracted from source plants at scale as their complexity precludes total synthesis from bulk chemicals. However, extraction from plants can be an unreliable and low-yielding source for human therapeutics, making the supply chain for some of these life-saving medicines expensive and unstable. There has therefore been significant interest in refactoring these plant pathways in genetically tractable microbes, which grow more reliably and where the plant pathways can be more easily engineered to improve the titer, rate and yield of medicinal natural products. In addition, refactoring plant biosynthetic pathways in microbes also offers the possibility to explore new-to-nature chemistry more systematically, and thereby help expand the chemical space that can be probed for drugs as well as enable the study of pharmacological properties of such new-to-nature chemistry. This perspective will review the recent progress toward heterologous production of plant medicinal alkaloids in microbial systems. In particular, we focus on the refactoring of halogenated alkaloids in yeast, which has created an unprecedented opportunity for biosynthesis of previously inaccessible new-to-nature variants of the natural alkaloid scaffolds.
U2 - 10.3389/fbioe.2020.594126
DO - 10.3389/fbioe.2020.594126
M3 - Journal article
C2 - 33195162
SN - 2296-4185
VL - 8
JO - Frontiers in Bioengineering and Biotechnology
JF - Frontiers in Bioengineering and Biotechnology
M1 - 594126
ER -