Researchers have uncovered hundreds of thousands of natural products,many of which contribute to med-icine,materials,and agriculture.However,missing knowledge about the biosynthetic pathways of these products hinders ...Researchers have uncovered hundreds of thousands of natural products,many of which contribute to med-icine,materials,and agriculture.However,missing knowledge about the biosynthetic pathways of these products hinders their expanded use.Nucleotide sequencing is key to pathway elucidation efforts,and an-alyses of the molecular structures of natural products,although seldom discussed explicitly,also play an important role by suggesting hypothetical pathways for testing.Structural analyses are also important in drug discovery,for which many molecular representation systems—methods of representing molecular structures in a computer-friendly format—have been developed.Unfortunately,pathway elucidation inves-tigations seldom use these representation systems.This gap likely occurs because those systems are pri-marily built to document molecular connectivity and topology rather than the absolute positions of bonds and atoms in a common reference frame,which would enable chemical structures to be connected with potential underlying biosynthetic steps.Here,we expand on recently developed skeleton-based molecular representation systems by implementing a common-reference-frame-oriented system.We tested this sys-tem using triterpenoid structures as a case study and explored its applications in biosynthesis and struc-tural diversity tasks.The common-reference-frame system can identify structural regions of high or low variability on the scale of atoms and bonds and enable hierarchical clustering that is closely connected to underlying biosynthesis.Combined with information on phylogenetic distribution,the system illuminates distinct sources of structural variability,such as different enzyme families operating in the same pathway.These characteristics outline the potential of common-reference-frame molecular representation systems to support large-scale pathway elucidation efforts.展开更多
基金supported by grant no.T32-GM110523 from the National Institute of General Medical Sciences of the National Institutes of HealthD.M.acknowledges funding from an NSF-IMPACTS training grant(DGE-1828149)+1 种基金NSF Dimensions of Biodiversity(DEB 1737898)Jeff Schell Bayer Foundation Fellowship 2022(application no.JS-2022-029).
文摘Researchers have uncovered hundreds of thousands of natural products,many of which contribute to med-icine,materials,and agriculture.However,missing knowledge about the biosynthetic pathways of these products hinders their expanded use.Nucleotide sequencing is key to pathway elucidation efforts,and an-alyses of the molecular structures of natural products,although seldom discussed explicitly,also play an important role by suggesting hypothetical pathways for testing.Structural analyses are also important in drug discovery,for which many molecular representation systems—methods of representing molecular structures in a computer-friendly format—have been developed.Unfortunately,pathway elucidation inves-tigations seldom use these representation systems.This gap likely occurs because those systems are pri-marily built to document molecular connectivity and topology rather than the absolute positions of bonds and atoms in a common reference frame,which would enable chemical structures to be connected with potential underlying biosynthetic steps.Here,we expand on recently developed skeleton-based molecular representation systems by implementing a common-reference-frame-oriented system.We tested this sys-tem using triterpenoid structures as a case study and explored its applications in biosynthesis and struc-tural diversity tasks.The common-reference-frame system can identify structural regions of high or low variability on the scale of atoms and bonds and enable hierarchical clustering that is closely connected to underlying biosynthesis.Combined with information on phylogenetic distribution,the system illuminates distinct sources of structural variability,such as different enzyme families operating in the same pathway.These characteristics outline the potential of common-reference-frame molecular representation systems to support large-scale pathway elucidation efforts.
