Computational Mass Spectrometry Deepens The Understanding Of Metabolisms

Metabolomics aims at providing information about “metabolome,” the comprehensive small molecules of living organisms, which has been used for elucidating biochemical reactions, finding relationships between biological phenotypes, and linking metabolites to the upper omics hierarchies such as genomes, transcriptomes, and proteomes.

Recently, many studies have reported that metabolites themselves are deeply involved in physiological functions and homeostasis, including (1) oxylipins, an oxidized fatty acids group that acts as bioactive metabolites in inflammatory responses and defense systems, (2) oncometabolites, unexpected products from altered metabolism that are involved in tumorigenesis, (3) damaged metabolites, chemically-reactive compounds resulting from enzyme errors or spontaneous reactions that are normally regulated by damage-control systems, (4) microbiota metabolites, metabolites secreted by gut microbiota affecting the host physiology, and (5) phytochemicals, the plant specialized metabolites exerting various bioactivities on human metabolisms.

Therefore, metabolomics is an attractive research field, offering new biological insights to small molecules while there are still outstanding issues, especially in “informatics” to provide wider coverage of metabolomes.

Mass spectrometry is the popular platform in metabolomics to measure the small molecules by ionizing them, and the compound structure can be determined (mainly) by checking the “mass spectrum” pattern generated from the “mass fragmentation” of the ionized metabolite. Mass fragmentation occurs by adding energy (called collision energy) to a small molecule. The fragmentation scheme is very specific to the compound structure, enabling us to identify the unique metabolites in biological samples.

However, a long-term, outstanding issue in mass spectrometry-based metabolomics is that the complete prediction of mass fragmentation is not yet achieved, and, therefore, the identification of small molecules still depends on the confirmation of authentic standard compounds. The coverage of traceable metabolites is still limited to around 1,000 due to the lack of standard compounds, while it is believed that the small biomolecule world exceeds one million chemical species. Therefore, the next stage of metabolomics is to decode the physical/chemical phenomena of ionized metabolites as well as to handle the complicated “big data” from mass spectrometry. It‚Äôs no exaggeration to say that understanding mass fragmentations is linked to the deeper understanding of metabolisms.

To date, “computational mass spectrometry” is a growing research field assisting in the interpretation of mass fragmentations and elucidating unknown structures with metabolome databases and repositories. Here, two approaches, i.e. bottom-up and top-down approaches, are highlighted.

The feature of the bottom-up approach is to create the theoretical mass spectrum by extrapolating spectrum knowledge to structurally-similar or same-scaffold compounds (see figure). For example, lipids forming cellular membranes have a large variety of acyl chains in a lipid class, and the lipid diversity is involved in many physiological functions. In a mass spectrometer, the fragmentation scheme in a lipid class (e.g. phosphatidylcholine) is mostly universal in the acyl chain varieties: the ester bonds in higher polarity region are cleaved owing to the uneven distribution of collision energy in a molecule.

Once the fragmentation scheme of the lipid class has been interpreted, therefore, the diversity of certain lipid class can be grasped by creating the theoretical spectrum. This bottom-up approach is now expanded to wider metabolite classes, including oxidized phospholipids and plant specialized metabolites like phenylpropanoids, flavonoids, and glycoalkaloids, which are used to find alterations of lipid homeostasis linked to various diseases and to accelerate drug discoveries in natural product chemistry.

The feature of another approach, i.e. top-down approach, is to search reported molecular structures followed by a ranking of the structure candidates with evaluation techniques that untangle structure-spectrum relationships (see figure). Nowadays, we can utilize more than 200,000 mass spectral records from public repositories, and it can be used as a “training set” to construct fragmentation theory and machine learning for molecular structure predictions.

Figure 1: A bottom-up vs. top-down approach. Credit: Hiroshi Tsugawa

The accuracy of the top-down approach depends on the chemical spaces of interest, but the CASMI (critical assessment of small molecule identification) 2017 contest reported that the approach correctly assigned 37% (91/243), 61% (148/243), and 79% (193/243) of challenges as the top, top 3, and top 10 candidates, respectively.

This accuracy can be improved by database selections and curations in specific organs, tissues, and species. Especially in natural product research, taxonomical filters that apply information on species-chemical relationships efficiently exclude false-positive candidates. The practical use of the top-down approach is to narrow down the structure candidates finally determined by checking the authentic standards, and it can also enable us to identify novel modified metabolites removed from its canonical function in anabolism or catabolism by enzyme errors or chemical damage.

Improving bottom-up/top-down approaches and integrating these with additional approaches will facilitate the global identification of human, plant, and microbiota metabolomes. The final goal of computational mass spectrometry is the total understanding of mass fragmentation of small molecules, and for this purpose, updates on analytical chemistry with computational mass spectrometry are essential for the elucidation of new physiological function and biological mechanisms.

These findings are described in the article entitled, Advances in computational metabolomics and databases deepen the understanding of metabolisms, recently published in the journal Current Opinion in Biotechnology. This work was conducted by Hiroshi Tsugawa from the RIKEN Center for Sustainable Resource Science and the RIKEN Center for Integrative Medical Sciences.

About The Author

Hiroshi Tsugawa

Hiroshi Tsugawa is a researcher at RIKEN, Japan. The main project is to develop software tools for untargeted- and targeted metabolomics/lipidomics: Hiroshi is now managing MS-DIAL, MS-FINDER, MRMPROBS, Statistics tools as Excel Macro, and so on at computational MS-based metabolomics section of RIKEN Prime Web site ( Hiroshi is a basketball player from junior high school until the end of his college age, and he got his PhD at Osaka University (in Prof. Eiichiro Fukusaki lab, 2012). Since he started his research at RIKEN Masanori Arita team, he also learned a lot of things at UC Davis Oliver Fiehn laboratory in a collaboration work.

Speak Your Mind!


How The Messinian Salinity Crisis And Changes To The Mediterranean Sea Impacted The Myocricetodon Gerbil

Published by Raef Minwer-Barakat Institut Catal√† de Paleontologia Miquel Crusafont and Universidad de Granada These findings are described in the article entitled The European record of the gerbil Myocricetodon (Rodentia, Mammalia) and its bearing on the Messinian salinity crisis, recently published in the journal Palaeogeography, Palaeoclimatology, Palaeoecology (Palaeogeography, Palaeoclimatology, Palaeoecology 506 (2018) 168-182). This work […]

Ferrous Metals

Ferrous metals by definition contain iron in them whereas non-ferrous metals do not contain iron. The word iron is derived from the Latin word ferrum, hence the English¬†derivation ferrous to describe iron bearing metals. The main thing to know about metals is whether they are ferrous or non-ferrous. Once we have made the distinction, we […]

Unified Protocol For Treating Multiple Mental Health Concerns

Patients seeking treatment for mental health concerns often meet criteria for more than one disorder. Despite high rates of comorbidity, most evidence-based interventions are designed to address a single disorder (e.g., panic disorder, generalized anxiety disorder, major depressive disorder). This practice is problematic because it forces clinicians and patients to choose which disorder to focus […]

The Acceleration Formula (Equation) In Physics: How To Use It

The acceleration formula is one of the basic equations in physics, something you’ll want to make sure you study and practice. After all, acceleration is one of the building blocks of physics. A motion is said to be uniformly accelerated when, starting from rest, it acquires, during equal time-intervals, equal amounts of speed. –¬†Galileo Galilei,¬†Two […]

After 1,000 Years, Iceland Is Growing Forests Again

As time progresses, landscapes experience change owing to things like natural disasters, ice ages, and human settlements among many other factors. Humans have altered the landscape of many places across the world to the point that they barely resemble their former selves. New York City, one of the worlds booming metropolis, was once a swamp. […]

Electronegativity Trend

Electronegativity trend refers to a trend which can be seen across the periodic table. This trend is seen as you move across the periodic table from left to right, the electronegativity increases while it decreases as you move down a group of elements. While this is the basic definition of the electronegativity trend, to truly […]

How To Maximize Solar Output Where The Sun Hardly Shines

Electricity from solar photovoltaics (PVs) is the fastest-growing source of new electric power worldwide. The growth is due to the dramatic cost decrease of PV over the last several years and the surging demand for clean, renewable energy. However, the transition from fossil fuels to a completely clean, renewable energy economy requires an enormous expansion […]