Introduction of Research Area “Sulfur Biology”

Purpose of the Research Project

 Sulfur has been an essential element for living organisms on the earth during the long history of evolution (Figure 1).

Figure 1. Elements utilized by living organisms on the earth during evolution. Sulfur has been playing an essential role in the biosphere.

 Unique chemical properties of sulfur include redox-sensitive nature and ability to catenate only by itself. The latter allows generation of a wide variety of sulfur-containing molecules that are rather fragile due to the former. We define “supersulfides” as metabolites and proteins possessing sulfur catenation (Figure 2). Because supersulfides are so sensitive to redox perturbation and easily degraded or altered during the sample processing, their presence in biological contexts has been overlooked for a long time. Thanks to a recent technical advancement in the analytical chemistry, substantial amount of supersulfides, such as glutathione persulfide and cysteine persulfide, have been found in various organisms.

Figure 2. Supersulfides are present in the form of low molecular weight metabolites and in cysteine residue side chains of proteins.

 Low-molecular weight supersulfides are now recognized as universal metabolites and play critical roles in energy production, antioxidant function, and anti-inflammatory function. Supersulfidated proteins are expected to be involved in the protein folding, proteostasis regulation, signal transduction, and regulation of various other protein functions (Figure 3). Essential roles of supersulfides are expected to be well conserved among various species.

Figure 3. Various functions of supersulfides. Low molecular weight supersulfides and protein supersulfides are widely utilized in miscellaneous biological processes.

 Based on these emerging biological functions of sulfur, we aim at creating and establishing innovative sulfur biology by further clarifying chemical, physical and biological characteristics of supersulfides and interdisciplinary research network among wide range of scientific fields, including chemistry, physics, geoscience, biology, mathematics and so on.

 Here are three goals of our Research Area.
 (1)Development of quantification methods for supersulfides in terms of high sensitivity, high fidelity, and high reproducibility.
 (2)Discovery of life principles from a viewpoint of supersulfides in electron transfer and signal transduction.
 (3)Application of supersulifdes for contribution to the SDGs

Content of the Research Project

 The most fundamental themes of our research field are clarification of chemical properties and metabolism as well as quantification and visualization of supersulfides (Figure 4). Based on these knowledge and technology, we will clarify biological electron transfer mediated by supersulfides in various cellular compartment, such as mitochondria, chloroplast, cytoplasm, endoplasmic reticulum and plasma membrane. We will also clarify contribution of supersulfides to signal transduction and proteostasis in various organisms.

Figure 4. Multiple approaches for clarification of chemical properties, metabolism, and roles of supersulfides in various biological processes including electron transfer and signal transduction.

Research Group A01) Analysis, quantification, and visualization of supersulfides (Figure 5)

Figure 5. Members of research group A01.

 Structure and physiochemical properties of supersulfides are one of the most important and fundamental research topics. Supersulfides have dual chemical reactivities, both electrophilic and nuclepphilic, which properties are guaranteed and augmented by hydrolysis equilibrium among supersulfide species (Figure 6). Visualization of supersulfides at atomic resolution is a little challenging but worth pursuing. Donor and quencher reagents of supersulfides.
 Another important task of our research area is to establish and propagate methods and techniques for detection and quantification of supersulfides, which is done by mass spectrometry. We also challenge introducing new technology for visualization of supersulfides, including raman imaging and mass imaging. Fluorescent probes and chemical probes for specific detection of supersulfides will further accelerate the spreading of supersulfide biology.

Figure 6. Hydrolysis equilibrium among supersulfides. This unique property generates molecular diversity and dynamism of supersulfides. (Sawa et al., Antioxidant and Redox Signaling 2021. DOI: 101089/ars.2021.0170

Research Group A02) Electron flux mediated by supersulifdes (Figure 7)

Figure 7. Members of research group A02.

 Electron transfer in mitochondria and chloroplasts for energy metabolism and photosynthesis is one of the major topics. Electron transfer in the endoplasmic reticulum (ER) gives an important clue to understanding of regulatory mechanisms of protein folding and proteostasis.
 Electron transfer via NADPH oxidase (NOX) and nitric oxide synthetase (NOS) is most likely to remodel sulfur catenation and be involved in the supersulfide turnover. With these studies, contribution of supersulfides to biological redox reaction in general will be clarified.

Research Group A03) Signal transduction utilizing supersulfides (Figure 8)

Figure 8. Members of research group A03

 Signal transduction often utilizes cysteine residues in proteins. For example, KEAP1 serving as a cytoplasmic redox sensor, TRP channels transducing temperature changes and mechanical stress, and GPCR family and G proteins mediating miscellaneous signals, all possess critical cysteine residues that are responsible for the signal transduction. Involvement of supersulfides in already known signal transduction and in so-far unrecognized signal transduction will be clarified.

Expected Research Achievements and Scientific Significance

 Emergence of biological supersulfides is innovating fundamental concept of life science. The impact will spread as far as medical practice by developing new diagnostics and therapeutics, food security by elevating photosynthesis efficiency, and geoengineering by modulating biogenic sulfur emission. Our research area will evoke discussion and stimulate emergence of new research field on global sulfur cycle beyond sulfur biology (Figure 9).

Figure 9. Supersulfides and other sulfur-containing molecules in the global sulfur cycle.