Small molecule signaling serves important functions at all levels of organismal organization. Biogenic small molecules (BSMs) function as intracellular signals, as hormones or second messengers connecting different cells or tissues of one organisms, or as pheromones and quorum sensing signals facilitating communication between individuals of the same or several different species. As a result, an organism’s metabolome essentially comprises a collection of small molecules with potentially useful affinities for specific molecular targets. Not surprisingly, BSM’s constitute the most important source of lead structures for drug development. Given the importance of BSM' as information carries and reporters, it is striking that the metabolomes of traditional animal model systems - the nematode Caenorhabditis elegans, Drosophila, and mouse - until recently have remained largely unexplored.
Our research aims to complement the highly developed genomics and proteomics of Caenorhabditis elegans, one of the most important biomedical model organisms, with a comprehensive structural and functional annotation of its metabolome: a vast universe of >10,000 different small molecules, most of which have not been chemically identified or biologically characterized. Their identification will greatly enhance our understanding of many signaling pathways that are of direct relevance for human disease, e.g., control of development and metabolism via conserved nuclear receptor signaling, the role of sirtuins in mediating stress resistance and longevity, or mechanisms that connect neuronal small-molecule perception and primary metabolism. The analytical tools we develop to identify structures and functions of biogenic small molecules will be transferable to other animal models, setting the stage for a functional annotation of mammalian metabolomes. Given that biogenic small molecules have evolved to serve specific biological functions, it is very likely that many of the thus identified metabolites provide new opportunities for drug development.
Separately, the finding that a specific group of small molecules, the ascarosides, is highly conserved among nematodes, including plant- and animal-parasites, may result in significant new opportunities to treat and cure human disease. Parasitic nematodes are responsible for several neglected tropical diseases, and ascarosides as nematode pheromones may provide means to interfere with nematode reproduction and host finding. In addition we have started a project directed at investigating the chemical ecology of microorganisms in search of leads for new antibiotics. Complementing our interests in analytical chemistry, biosynthesis, and small-molecule signaling, we pursue development of efficient syntheses for newly identified compounds and derivatives for receptor identification via click chemistry approaches.
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Biogenic small molecules (BSMs) play important roles in most biological processes and represent the most important source for new drug leads, especially for the treatment of infectious disease and cancer. Detailed knowledge of small-molecule structures, their biosyntheses, and their interactions with other biomolecules is essential for advancing drug development as well as for the understanding of disease-relevant interactions of microorganisms with their human, animal, or plant hosts.
A Universe of Unexplored Chemical Diversity. High-resolution MS/MS analyses indicate that the vast majority of metabolites produced by man, mouse, or the model organism C. elegans remain uncharacterized. In C. elegans, the ascarosides, steroids, ethanolamides, and other compounds that we and others recently identified constitute no more than the “tip of an iceberg”. In fact, it is likely that the number of metabolites in humans or C. elegans greatly exceeds the number of genes in these organisms. Correspondingly, the human and C. elegans genomes code for a vast number of putative enzymes, GPCRs, and other membrane and nuclear receptors that appear to participate in biosynthesis and sensing of yet unidentified chemical signals.
Structural and Functional Annotation via Comparative Metabolomics. Recently developed comparative metabolomics, based on analysis of mass spectrometric (MS) or NMR spectroscopic data, permits direct identification of BSMs whose biosynthesis is up- or downregulated in a specific genotype (see Fig. 3), and thereby greatly accelerates functional annotation of newly identified metabolites.This approach has enabled the rapid identification of several 100 new BSMs in C. elegans and other nematodes, including parasitic species. These new metabolites are derived from modular assembly of building blocks from all major metabolic pathways, presenting a new paradigm of small molecule biosynthesis in metazoans. Many of these compounds have entirely unexpected structures and biological activities, and current efforts in my lab focus on the elucidation of the biosynthesis of these compounds and their role in regulating conserved endocrine signaling.
In combination with mutant and RNAi screens, genome editing, proteomic analyses, chemical synthesis and bioassays, the further development of comparative metabolomics and associated bioinformatic strategies forms a major goal of the our work. Ongoing studies focus on the biosynthesis of the modular ascaroside library, mechanisms of small-molecule sensing, as well as elucidation of the biosynthesis of ligands of nuclear hormone receptors related to the human vitamin-D receptor.
New Antibiotics from Microbial Metabolomic "Dark Matter". Complementing our work on nematodes, we apply 2D NMR-based comparative metabolomics as a new strategy to identify the small-molecule products of cryptic PKS and NRPS gene clusters in bacteria and fungi, focusing in particular on the identification of virulence factors and antimicrobial compounds. BSMs of microbial origin represent the most important source for new drug leads, especially for the treatment of infectious disease and cancer. Recent technical advances that further accelerate detection and characterization of new structural entities include the development of algorithms for the partially automated comparative analysis of high-resolution 2D NMR spectra and the use of heterologous expression of gene clusters in A. nidulans.
As a necessary component of our chemical biology-oriented research, we develop novel strategies for the syntheses of newly identified compounds with particular structural or biological significance.
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