Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways - PubMed (original) (raw)

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Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways

Kou-San Ju et al. J Ind Microbiol Biotechnol. 2014 Feb.

Abstract

Phosphonate natural products have proven to be a rich source of useful pharmaceutical, agricultural, and biotechnology products, whereas study of their biosynthetic pathways has revealed numerous intriguing enzymes that catalyze unprecedented biochemistry. Here we review the history of phosphonate natural product discovery, highlighting technological advances that have played a key role in the recent advances in their discovery. Central to these developments has been the application of genomics, which allowed discovery and development of a global phosphonate metabolic framework to guide research efforts. This framework suggests that the future of phosphonate natural products remains bright, with many new compounds and pathways yet to be discovered.

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Figures

Figure 1

Figure 1. Timeline of the discovered phosphonate natural products since 1959

The biosynthetic genes for several compounds have been discovered (blue). Genome mining has thus far yielded the discovery of two new natural products (orange). Compounds that have reached clinical testing, been developed into commercial antibiotics, or biotechnological products are highlighted (red asterisks).

Figure 2

Figure 2. Pathways for phosphonate natural product biosynthesis

Genetic and biochemical characterization of phosphonate producing strains have resulted in the identification of five core biosynthetic pathways common to these natural products. PnPy and PnAA are converted into PMM, 2-keto-4-hydroxy-5-phosphonpentanoic acid (KHPTA), 2-HEP, PnAc, or 2-AEP. Dashed arrows indicate pathways newly discovered as a result of genome mining.

Figure 3

Figure 3. PepM maximum-likelihood tree, nucleotidyl transferases and taxonomy

A maximum-likelihood tree of full-length PepM sequences found in all bacterial genomes in NCBI as of February 2013 is shown. This tree was made using FastTreeMP with the Gamma20 option [50] and altered with the Python library ETE [23]. The inner circle next to the tree is colored based on the presence of an N- or C-terminal nucleotidyltransferase fusion with PepM, along with the presence or absence of a nucleotidyl transferase on a separate ORF. The outer circle shows the phylum level taxonomic designation for each strain. The tree is rooted on the sequence for methylisocitrate lyase from E. coli, indicated with an asterisk.

Figure 4

Figure 4. PepM maximum-likelihood tree, early biosynthetic steps, and taxonomy

The phylogenetic tree is the same as shown in Figure 3. Here the inner circle is colored according to the presence of phosphonopyruvate decarboxylase (Ppd), 2-AEP transaminase, phosphonoacetaldehyde reductase (PhpC) and FrbC. The outer circle is the same as in Figure 3 and shows the phylum level taxonomic designation for each strain. Sequences that correspond to known compounds are: 1, bialaphos; 2, cyanophos; 3, dehydrophos; 4, fosfazinomycin; 5, FR-900098; 6, rhizocticin; and 7, fosfomycin. The tree is rooted on the sequence for methylisocitrate lyase from E. coli, indicated with an asterisk.

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