Polyketide and nonribosomal peptide retro-biosynthesis and global gene cluster matching.
Polyketides (PKs) and nonribosomal peptides (NRPs) are profoundly important natural products, forming the foundations of many therapeutic regimes. Decades of research have revealed over 11,000 PK and NRP structures, and genome sequencing is uncovering new PK and NRP gene clusters at an unprecedented rate. However, only ∼10% of PK and NRPs are currently associated with gene clusters, and it is unclear how many of these orphan gene clusters encode previously isolated molecules. Therefore, to efficiently guide the discovery of new molecules, we must first systematically de-orphan emergent gene clusters from genomes. Here we provide to our knowledge the first comprehensive retro-biosynthetic program, generalized retro-biosynthetic assembly prediction engine (GRAPE), for PK and NRP families and introduce a computational pipeline, global alignment for natural products cheminformatics (GARLIC), to uncover how observed biosynthetic gene clusters relate to known molecules, leading to the identification of gene clusters that encode new molecules.
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Chris A
CA
Dejong
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Gregory M
GM
Chen
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Haoxin
http://orcid.org/0000-0002-0476-6201
H
Li
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Chad W
CW
Johnston
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Mclean R
MR
Edwards
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Philip N
PN
Rees
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Michael A
MA
Skinnider
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Andrew L H
AL
Webster
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry and Chemical Biology, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Nathan A
NA
Magarvey
D000465:Algorithms; D005810:Multigene Family / Q000235:genetics; D046908:Peptide Biosynthesis, Nucleic Acid-Independent / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D061065:Polyketides / Q000737:chemistry / Q000378:metabolism*
D010455:Peptides; D061065:Polyketides
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