Toward the Dark Matter of Natural Products

Abstract

Considering the dynamic features of natural products, our access toward exploring the entire diversity of natural products has been quite limited. It is challenging to assess the diversity of natural products by using conventional analytical methods, even with tandem chromatographic techniques, such as LC-MS and GC-MS. This viewpoint is supported by the sequencing analyses of microbial genomes, which have unveiled the potential of secondary metabolite production far exceeding the number of isolated molecules. Recent advancements in metabolomics, in concert with genomics analyses, have further extended the natural product diversity, prompting growing awareness of the existence of reactive or short-lived natural molecules. This personal account introduces some examples of the discoveries of hitherto elusive natural products, due to physico-chemical or biological reasons, and highlights the significance of the dark matter of natural products.

Chemical cues for intraspecific chemical communication and interspecific interactions in aquatic environments: applications for fisheries and aquaculture

“…In addition to the current library of primary and secondary metabolites, more natural products should be identified. Labile natural product molecules that were not found using conventional methods can now be identified using new approaches, including bioinformatics (Wakimoto and Abe 2012;Wakimoto 2017;Berlinck et al 2019;Hughes 2021).…”

Accelerating Metabolite Identification in Natural Product Research: Toward an Ideal Combination of Liquid Chromatography–High-Resolution Tandem Mass Spectrometry and NMR Profiling, in Silico Databases, and Chemometrics

“…Moreover, it also shows that the unambiguous annotation of NPs, possibly in “all” detectable NP mixtures, is still far from reality, and interrogating what is called “dark matter” remains an important challenge. Dark matter essentially consists of chemical signatures that remain uncharacterized and encompasses compounds that remain invisible because they are not covered or detected by conventional isolation, bioactivity-based screening, or other analytical techniques . Furthermore, it has generally been stated that in metabolomics, less than 2% of the spectra in untargeted metabolomics can be annotated .…”

“…Dark matter essentially consists of chemical signatures that remain uncharacterized 23b and encompasses compounds that remain invisible because they are not covered or detected by conventional isolation, bioactivity-based screening, or other analytical techniques. 324 Furthermore, it has generally been stated that in metabolomics, less than 2% of the spectra in untargeted metabolomics can be annotated. 23b As discussed in this review, many powerful tools are emerging approaches that may have a large impact on improving this situation, but at present, rapid unambiguous annotation can only be performed using cross searches in experimental DBs with the same acquisition conditions, while generic in silico DBs will mainly help with confirming the structural elucidation processes in the near future.…”

Analysis of basidiomycete pigments in situ by Raman spectroscopy

“…While this is a positive development, usually the number of genetically identified natural product pathways exceeds the number of known compounds from the same species. Consequently, most natural products still remain "dark matter" [38]. Raman spectroscopy was useful in compound identification on agar plates and on isolated mushrooms.…”