Editorial: Mass spectrometry of small molecules and natural products

The molecular characterization of our natural world with mass spectrometry is at a pivotal and exciting stage. We are at the start of major transformations that are going to take place in the analysis of natural products akin to the way our ability to sequence DNA has exponentially increased in the last two decades and revolutionized the life sciences as we know it. The revolutions are coming in the form of advances in instruments, better workflows and using mass spectrometry tools to perform structure elucidation. As more genomic information is becoming available, the scientific community is realizing the need to understand the function of this genetic information at the molecular level, including the functional understanding of natural products. Perhaps a more apt name for natural products is to use the term specialized metabolites highlighting their important functional role in driving biological processes that range from intracellular signals, serving as antibiotics, to driving microbial community formation, plant growth, host-guest interactions and shaping entire ecosystems. The objective of this themed issue is to inform and educate natural product scientists about the amazing capabilities of modern mass spectrometry in the context of analysis of small molecules and natural products. The issue covers topics such as a historical perspective on mass spectrometry used in the pharmaceutical industry to a more futuristic analysis of emerging and yet to be realized tools that one can expect to be developed over the next decade.

In the first article of this themed issue, Carter (DOI: 10.1039/C3NP70085B), a leading expert in the natural product characterization and a pioneer in the use of mass spectrometry in industry for several decades gives insight into how mass spectrometry was used in industry. The article highlights that industry was already leading in developing applications of mass spectrometry for use in dereplication and structure elucidation of complex natural products for many decades. Carter covers natural product analysis from the 1970s when mass spectrometry instruments took up entire basements to the modern desktop instruments and how this has impacted and transformed natural product analysis.

During the 1970s the use of mass spectrometry saw an enormous surge in the analysis of natural products, largely due to the ability to analyze volatile organic compounds. This had become a mainstay approach after McLafferty developed the GC-MS based workflows while working in industry in the late 1960s. As new ion sources such as ESI and MALDI became available and it became easier to detect intact biomolecules by mass spectrometry, there was a decreased interest in volatiles during the late 1980s and 1990s. The tide, however, is shifting once again as it is now increasingly being recognized that volatiles play critical roles in chemical ecology, human health, and defining the balance of entire ecosystems. Dickschat (DOI: 10.1039/C3NP70080A) provides a modern assessment of state-of-the-art analysis of volatile natural products. Specifically, Dickschat describes the details of sample collection processes and how the analysis of the fragmentation data can be used to gain insight into the structure of the molecules. The review highlights that volatiles are a potential source for the discovery of new molecules for decades to come. It should also be noted that the biosynthetic pathways for many, if not most, of the volatiles remain to be discovered.

Advances in ion sources enables the detection of a wider range of natural products, enable the discovery of new natural products that previously remained undetected and is advancing mass spectrometric analysis in both laboratory and non-laboratory settings. In this special issue, Bhardwaj and Hanley (DOI: 10.1039/C3NP70094A) cover the key advances in ion sources developed in mass spectrometry including their respective applications. The authors describe how to choose an ion source for a given application and highlight imaging mass spectrometry as a direction. Because the field of imaging mass spectrometry has rapidly expanded in the past decade and is beginning to be an indispensable tool in a modern natural products community, there are two comprehensive articles by leaders in this area. These articles cover two areas of active and exciting branches of natural product research, plants and microbes. The first contribution in imaging mass spectrometry by Bjarnholt, Li, D'Alvise and Janfelt (DOI: 10.1039/C3NP70100J) describes the imaging mass spectrometry tools that are used for plant metabolite and natural product analysis and it provides a vision of what is emerging in this area. The next imaging mass spectrometry article is a comprehensive review of the microbial imaging analysis by Shih, Chen, Liaw, Lai and Yang (DOI: 10.1039/C3NP70091G). They cover topics ranging from microbes in culture to entire ecosystems and the types of tools that are used in this field of research. From both of these reviews, it is becoming evident that the potential of imaging mass spectrometry has only been barely reached and that this is a leading field for decades to come because imaging mass spectrometry provides an informative real-time “snapshot” of natural products as they are distributed in nature.

While mass spectrometry has been used for decades in natural product research programs, imaging mass spectrometry approach is an emerging tool for natural product scientists. LC-MS based analysis is one such tool that has been used for decades in natural products research programs but at the same time this has significantly advanced in the last decade. There are two reviews by the leaders in this area; one comes from the plant NP community and the other from a leader in microbial secondary metabolomics. Ernst, D. Silva, R. Silva, Vêncio and Lopes (DOI: 10.1039/C3NP70086K) provides a detailed assessment and expert review on the current status of plant metabolite and natural product analysis while Krug and Müller (DOI: 10.1039/C3NP70127A) provide a picture of metabolite analysis from microbes and the recent advances that have been made in capturing chemical complexity of diverse natural products. One thing that is becoming clear is that one person or one lab can no longer handle the comprehensive characterization, particularly the structural characterization, for the molecules that are detected by mass spectrometry. In other words, mass spectrometers are becoming so widely accessible and routine in use that natural product science is entering the “Big Data” era. To improve dereplication and use mass spectrometry as a structure elucidation tool, the earliest iterations of algorithms are being developed. This is comparable to the earliest iterations of multiple sequence alignment algorithms that started the field of comparative genomics. Although a young field, Hufsky, Scheubert and Böcker (DOI: 10.1039/C3NP70101H) highlight the most recent advances in the area of computational mass spectrometry with respect to structural assessment of the molecules that are detected by mass spectrometry.

Not only is natural product mass spectrometry changing with respect to ion sources and algorithmic solutions, the mass spectrometers themselves are also advancing. Because of the advances in ion sources and hardware, Jarmusch and Cooks (DOI: 10.1039/C3NP70121B) highlight the fantastic developments in miniaturizing mass spectrometers that weigh just a few kilograms and can be deployed in the fieldwork itself. In other words, availability of cost-effective and portable mass spectrometers is just around the corner. Such advances and other advances are described in this review. Finally, Bouslimani, Sanchez and Garg from my lab (DOI: 10.1039/C4NP00044G) expand on Cooks’ exciting vision and describe a global viewpoint not only of current advances of mass spectrometry used in natural product research but also the directions natural product mass spectrometry can expect to be developed in the decades to come. It is expected that these advancements will encompass analysis of complex mixtures, development of more sensitive instruments, and algorithms making it easier and faster to quantify and dereplicate identical and related molecules, and to structurally characterize natural products that can be detected.

In summary, this special issue with its ten contributed manuscripts, is dedicated to showcase the current possibilities of mass spectrometry in natural product research. It also highlights the interface and commonalities between the metabolomics efforts and how natural products can make major revolutionary advances. As we enter the era of Big Data the field of natural products science is beginning to embrace disciplines such as computer science, mathematics and physics. This is a great development for a field that reaches all corners of biochemistry and biology. Finally, to develop a successful special issue such as this, it not only required the dedication of leaders to write the articles but also the willingness of dedicated investigators in the field to review the contributed articles. I would like to thank both the authors and reviewers for their contributions in making this issue a success.

Pieter C. Dorrestein

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