Microbial genome mining answers longstanding biosynthetic questions

Abstract

At the beginning of the genomic revolution, genomes were frequently described as the instruction manuals for an organism, but as the revolution progressed, many of these genomic instruction manuals resembled the frustratingly opaque descriptions that accompany so many new household gadgets, laboratory devices, and computer software. An important exception to this opacity has been in microbial natural product biosynthesis (1⇓⇓⇓⇓⇓–7), and in PNAS, Davison et al. (8) provide a striking example of how the biosynthetic genes for a biologically important class of small molecules were spotted and analyzed to resolve a 70-y-old puzzle. “Natural products” is the collective term for the wildly diverse families of small molecules produced by genetically encoded pathways. The natural products from fungi and bacteria have repeatedly transformed our understanding of biological systems and represent a substantial fraction of our current pharmaceuticals, especially those used as anticancer, antibiotic, or immunomodulatory agents (9). The biosynthetic pathways that give rise to natural products begin with the same small-molecule building blocks used by all of life, but they are joined together and modified into idiosyncratic molecules that differ dramatically from their universal forebears. Natural product biosynthetic pathways involve multiple genes, but in microbes the biosynthetic genes are most often clustered with regulatory and resistance genes on a contiguous stretch of the genome. With the right chemical, microbiological, or genetic tools, a natural product gene cluster can be connected to its cognate small-molecule product(s). In this way, natural product biosynthesis provides relatively easily studied multigenic phenotypes—the small-molecule products—that can be analyzed in a particularly informative way, because the contribution each gene makes to the final molecule can be determined. As microbial genomes become increasingly available, they are being mined both to discover new molecules with biomedical relevance and to find the answers to … [↵][1]1To whom correspondence should be addressed. E-mail: jon_clardy{at}hms.harvard.edu. [1]: #xref-corresp-1-1