5ze4
The structure of holo- structure of DHAD complex with [2Fe-2S] cluster
Structural highlights
FunctionILVD_ARATH Catalyzes the dehydration of 2,3-dihydroxy-3-isovalerate or 2,3-dihydroxy-3-methylvalerate to the 2-oxo acids 3-methyl-2-oxobutanoate (3MOB) or 3-methyl-2-oxopentanoate (3MOP).[1] Publication Abstract from PubMedBioactive natural products have evolved to inhibit specific cellular targets and have served as lead molecules for health and agricultural applications for the past century(1-3). The post-genomics era has brought a renaissance in the discovery of natural products using synthetic-biology tools(4-6). However, compared to traditional bioactivity-guided approaches, genome mining of natural products with specific and potent biological activities remains challenging(4). Here we present the discovery and validation of a potent herbicide that targets a critical metabolic enzyme that is required for plant survival. Our approach is based on the co-clustering of a self-resistance gene in the natural-product biosynthesis gene cluster(7-9), which provides insight into the potential biological activity of the encoded compound. We targeted dihydroxy-acid dehydratase in the branched-chain amino acid biosynthetic pathway in plants; the last step in this pathway is often targeted for herbicide development(10). We show that the fungal sesquiterpenoid aspterric acid, which was discovered using the method described above, is a sub-micromolar inhibitor of dihydroxy-acid dehydratase that is effective as a herbicide in spray applications. The self-resistance gene astD was validated to be insensitive to aspterric acid and was deployed as a transgene in the establishment of plants that are resistant to aspterric acid. This herbicide-resistance gene combination complements the urgent ongoing efforts to overcome weed resistance(11). Our discovery demonstrates the potential of using a resistance-gene-directed approach in the discovery of bioactive natural products. Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action.,Yan Y, Liu Q, Zang X, Yuan S, Bat-Erdene U, Nguyen C, Gan J, Zhou J, Jacobsen SE, Tang Y Nature. 2018 Jul;559(7714):415-418. doi: 10.1038/s41586-018-0319-4. Epub 2018 Jul, 11. PMID:29995859[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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