PHOSPHONIC ACID BIOSYNTHETIC PATHWAYS

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In the previous grant period, our enzymology and synthetic chemistry studies complemented the genetic and biochemical efforts towards understanding the biosynthetic logic of natural product phosphonates. The program project team has made significant progress, developing effective methods to detect new phosphonate biosynthetic gene clusters and understanding in great detail the biosynthetic pathways leading towards commercially important phosphonates such as phosphinothricin and fosfomycin. As the genetic and biochemical studies became more efficient, a new bottleneck was idenyified that involves inefficient purification strategies and hence slow-down of structure elucidation of the products of newly discovered gene clusters. Part of the proposed studies in this subproject will focus on the development of efficient methods for purification and structural elucidation of those new compounds. In addition, the genome sequencing efforts of the past grant period identified cases in which the same natural product is made in different organisms by very different biosynthetic routes. We will investigate these examples of convergent evolution. Finally, many natural product phosphonates are produced as short peptides to promote uptake by peptide permeases in the target organisms. Whereas for some compounds small non-ribosomal pepfide synthetase (NRPS) clusters are responsible for peptide bond formation, many phosphonate containing peptides are assembled In different, often unidentified ways. We will attempt to provide more insight into this very important aspect with respect to possible future engineering efforts.