Genome mining has potential uses in synthetic biology and drug discovery

By Samantha Black, PhD, ScienceBoard editor in chief

July 18, 2019 -- Researchers from Howard Hughes Medical Institute and the University of Illinois at Urbana-Champaign discovered a cluster of genes in Pseudomonas syringae which infects plants. The results of this research were published in Science on July 19th. However, this natural product produced belongs to a special class of ribosomally synthesized and posttranslationally modified peptides. This technology and methodology is becoming increasingly important in the life sciences, where many of our members work.

This research is in the emerging field of genome mining. This approach allows researchers to find secondary metabolites of bacteria that might be used in other targeted ways. It allows for the prediction isolation of natural compounds based only on genetic information, without knowing structure. Growth in this field has been enabled through sequencing technology.

The cluster of genes from Pseudomonas syringae included one that held the information for a peptide made by a ribosome, while another coded for an enzyme that could add another amino acid onto the peptide chain. In this way, the enzyme can be used as a scaffold to make products over and over again. This can happen because once the peptide is added, it is modified in a series of steps and then broken off, returning to the original peptide form. In this process, first amino acids are transferred to the carboxyl terminus of the peptide through adenosine triphosphate and amino acyl-tRNA–dependent chemistry that is independent of the ribosome. Then oxidative rearrangement, carboxymethylation, and proteolysis of a terminal cysteine yields an amino acid–derived small molecule.

In order to determine molecular structure, electron microscopy on flash-frozen microcrystals of purified sample, a technique called microcrystal electron diffraction, was used. Better classification of structure allows researchers to more fully understand the natural product and its synthesis. Because researchers understand the mechanisms of this natural product, they were able to identify other examples with similar mechanisms. One example is the production of an anti-tumor compound produced by a soil microbe. Researchers hope to find ways to use this pathways in synthetic biology (discovery of new antibiotics) and drug discovery.

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