研究等業績 - 原著論文 - 松永 哲郎
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Chemistry and metabolism of supersulfides: Perspective for supersulfide biology and omics medicine
Takaaki Akaike, Tetsuro Matsunaga, Tsuyoshi Takata
Seikagaku 93 ( 5 ) 708 - 716 2021年
研究論文（学術雑誌）
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Rational Design of a Dual-Reactivity-Based Fluorescent Probe for Visualizing Intracellular HSNO.
Wei Chen, Tetsuro Matsunaga, Deshka L Neill, Chun-Tao Yang, Takaaki Akaike, Ming Xian
Angewandte Chemie (International ed. in English) 58 ( 45 ) 16067 - 16070 2019年11月 [査読有り]
研究論文（学術雑誌）
Thionitrous acid (HSNO), the smallest S-nitrosothiol, is emerging as a potential key intermediate in cellular redox regulation linking two signaling molecules H S and NO. However, the chemical biology of HSNO remains poorly understood. A major hurdle is the lack of methods for selective detection of HSNO in biological systems. Herein, we report the rational design, synthesis, and evaluation of the first fluorescent probe TAP-1 for HSNO detection. TAP-1 showed high selectivity and sensitivity to HSNO in aqueous media and cells, providing a useful tool for understanding the functions of HSNO in biology. 2
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Akira Nishimura, Ryo Nasuno, Yuki Yoshikawa, Minkyung Jung, Tomoaki Ida, Tetsuro Matsunaga, Masanobu Morita, Hiroshi Takagi, Hozumi Motohashi, Takaaki Akaike
The Journal of Biological Chemistry ( AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC ) 294 ( 37 ) 13781 - 13788 2019年09月 [査読有り]
研究論文（学術雑誌）
Eukaryotes typically utilize two distinct aminoacyl-tRNA synthetase isoforms, one for cytosolic and one for mitochondrial protein synthesis. However, the genome of budding yeast (Saccharomyces cerevisiae) contains only one cysteinyl-tRNA synthetase gene (YNL247W, also known as CRS1). In this study, we report that CRS1 encodes both cytosolic and mitochondrial isoforms. The 5' complementary DNA end method and GFP reporter gene analyses indicated that yeast CRS1 expression yields two classes of mRNAs through alternative transcription starts: a long mRNA containing a mitochondrial targeting sequence and a short mRNA lacking this targeting sequence. We found that the mitochondrial Crs1 is the product of translation from the first initiation AUG codon on the long mRNA, whereas the cytosolic Crs1 is produced from the second in-frame AUG codon on the short mRNA. Genetic analysis and a ChIP assay revealed that the transcription factor heme activator protein (Hap) complex, which is involved in mitochondrial biogenesis, determines the transcription start sites of the CRS1 gene. We also noted that Hap complex- dependent initiation is regulated according to the needs of mitochondrial energy production. The results of our study indicate energy-dependent initiation of alternative transcription of CRS1 that results in production of two Crs1 isoforms, a finding that suggests Crs1's potential involvement in mitochondrial energy metabolism in yeast.
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Hisyam Abdul Hamid, Akira Tanaka, Tomoaki Ida, Akira Nishimura, Tetsuro Matsunaga, Shigemoto Fujii, Masanobu Morita, Tomohiro Sawa, Jon M Fukuto, Péter Nagy, Ryouhei Tsutsumi, Hozumi Motohashi, Hideshi Ihara, Takaaki Akaike
Redox Biology 21 101096 - 101096 2019年02月 [査読有り]
研究論文（学術雑誌）
The physiological importance of reactive sulfur species (RSS) such as cysteine hydropersulfide (CysSSH) has been increasingly recognized in recent years. We have established a reactive sulfur metabolomics analysis by using RSS metabolic profiling, which revealed appreciable amounts of RSS generated endogenously and ubiquitously in both prokaryotic and eukaryotic organisms. The chemical nature of these polysulfides is not fully understood, however, because of their reactive or complicated redox-active properties. In our study here, we determined that tyrosine and a hydroxyphenyl-containing derivative, β-(4-hydroxyphenyl)ethyl iodoacetamide (HPE-IAM), had potent stabilizing effects on diverse polysulfide residues formed in CysSSH-related low-molecular-weight species, e.g., glutathione polysulfides (oxidized glutathione trisulfide and oxidized glutathione tetrasulfide). The protective effect against degradation was likely caused by the inhibitory activity of hydroxyphenyl residues of tyrosine and HPE-IAM against alkaline hydrolysis of polysulfides. This hydrolysis occurred via heterolytic scission triggered by the hydroxyl anion acting on polysulfides that are cleaved into thiolates and sulfenic acids, with the hydrolysis being enhanced by alkylating reagents (e.g. IAM) and dimedone. Moreover, tyrosine prevented electrophilic degradation occurring in alkaline pH. The polysulfide stabilization induced by tyrosine or the hydroxyphenyl moiety of HPE-IAM will greatly improve our understanding of the chemical properties of polysulfides and may benefit the sulfur metabolomics analysis if it can be applied successfully to any kind of biological samples, including clinical specimens.
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Shahzada Khan, Shigemoto Fujii, Tetsuro Matsunaga, Akira Nishimura, Katsuhiko Ono, Tomoaki Ida, Khandaker Ahtesham Ahmed, Tatsuya Okamoto, Hiroyasu Tsutsuki, Tomohiro Sawa, Takaaki Akaike
Cell Chemical Biology ( CELL PRESS ) 25 ( 11 ) 1403 - 1413.e4 2018年11月 [査読有り]
研究論文（学術雑誌）
Reactive persulfides such as cysteine persulfide and glutathione persulfide are produced by bacteria including Salmonella during sulfur metabolism. The biological significance of bacterial reactive persulfides in host-pathogen interactions still warrants investigation. We found that reactive persulfides produced by Salmonella Typhimurium LT2 regulate macrophage autophagy via metabolizing 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP), an electrophilic product of reactive oxygen species and nitric oxide signaling. 8-Nitro-cGMP signaling was required for efficient autophagy-mediated clearance of Salmonella from infected macrophages. In the infected cells, 8-nitro-cGMP caused cGMP adduct formation (S-guanylation) of bacterial surface proteins, which triggered recruitment of autophagy-related proteins p62 and LC3-II to the intracellular bacteria. We also found that Salmonella-produced reactive persulfides downregulated this autophagy by decreasing cellular 8-nitro-cGMP content, thereby inhibiting electrophilic signaling. These data reveal a pathogenic role of bacteria-derived reactive persulfides via suppression of anti-bacterial autophagy. Khan et al. found that reactive persulfides produced by Salmonella inhibit autophagy-mediated bacterial clearance by regulating electrophilic signaling. These data reveal a pathogenic role of bacteria-derived reactive persulfides via suppression of anti-bacterial autophagy.
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Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics
Takaaki Akaike, Tomoaki Ida, Fan Yan Wei, Motohiro Nishida, Yoshito Kumagai, Md Morshedul Alam, Hideshi Ihara, Tomohiro Sawa, Tetsuro Matsunaga, Shingo Kasamatsu, Akiyuki Nishimura, Masanobu Morita, Kazuhito Tomizawa, Akira Nishimura, Satoshi Watanabe, Kenji Inaba, Hiroshi Shima, Nobuhiro Tanuma, Minkyung Jung, Shigemoto Fujii, Yasuo Watanabe, Masaki Ohmuraya, Péter Nagy, Martin Feelisch, Jon M. Fukuto, Hozumi Motohashi
Nature Communications 8 ( 1 ) 1177 - 1177 2017年12月 [査読有り]
研究論文（学術雑誌）
Cysteine hydropersulfide (CysSSH) occurs in abundant quantities in various organisms, yet little is known about its biosynthesis and physiological functions. Extensive persulfide formation is apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is believed to result from post-translational processes involving hydrogen sulfide-related chemistry. Here we demonstrate effective CysSSH synthesis from the substrate l-cysteine, a reaction catalyzed by prokaryotic and mammalian cysteinyl-tRNA synthetases (CARSs). Targeted disruption of the genes encoding mitochondrial CARSs in mice and human cells shows that CARSs have a crucial role in endogenous CysSSH production and suggests that these enzymes serve as the principal cysteine persulfide synthases in vivo. CARSs also catalyze co-translational cysteine polysulfidation and are involved in the regulation of mitochondrial biogenesis and bioenergetics. Investigating CARS-dependent persulfide production may thus clarify aberrant redox signaling in physiological and pathophysiological conditions, and suggest therapeutic targets based on oxidative stress and mitochondrial dysfunction.
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Exposure to electrophiles impairs reactive persulfide-dependent redox signaling in neuronal cells
Hideshi Ihara, Shingo Kasamatsu, Atsushi Kitamura, Akira Nishimura, Hiroyasu Tsutsuki, Tomoaki Ida, Kento Ishizaki, Takashi Toyama, Eiko Yoshida, Hisyam Abdul Hamid, Minkyung Jung, Tetsuro Matsunaga, Shigemoto Fujii, Tomohiro Sawa, Motohiro Nishida, Yoshito Kumagai, Takaaki Akaike
Chemical Research in Toxicology ( AMER CHEMICAL SOC ) 30 ( 9 ) 1673 - 1684 2017年09月 [査読有り]
研究論文（学術雑誌）
Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitrocGMP), accompanied by depletion of reactive persulfide species and 8-SHcGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles.