論文 - 黒木 勝久
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Kurogi K., Sakakibara Y., Hashiguchi T., Kakuta Y., Kanekiyo M., Teramoto T., Fukushima T., Bamba T., Matsumoto J., Fukusaki E., Kataoka H., Suiko M.
PNAS Nexus 3 ( 3 ) 2024年3月
担当区分：筆頭著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PNAS Nexus
Cytosolic sulfotransferases (SULTs) are cytosolic enzymes that catalyze the transfer of sulfonate group to key endogenous compounds, altering the physiological functions of their substrates. SULT enzymes catalyze the O-sulfonation of hydroxy groups or N-sulfonation of amino groups of substrate compounds. In this study, we report the discovery of C-sulfonation of α,β-unsaturated carbonyl groups mediated by a new SULT enzyme, SULT7A1, and human SULT1C4. Enzymatic assays revealed that SULT7A1 is capable of transferring the sulfonate group from 3′-phosphoadenosine 5′-phosphosulfate to the α-carbon of α,β-unsaturated carbonyl-containing compounds, including cyclopentenone prostaglandins as representative endogenous substrates. Structural analyses of SULT7A1 suggest that the C-sulfonation reaction is catalyzed by a novel mechanism mediated by His and Cys residues in the active site. Ligand-activity assays demonstrated that sulfonated 15-deoxy prostaglandin J2 exhibits antagonist activity against the prostaglandin receptor EP2 and the prostacyclin receptor IP. Modification of α,β-unsaturated carbonyl groups via the new prostaglandin-sulfonating enzyme, SULT7A1, may regulate the physiological function of prostaglandins in the gut. Discovery of C-sulfonation of α,β-unsaturated carbonyl groups will broaden the spectrum of potential substrates and physiological functions of SULTs.
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Iwamoto W., Ikeda T., Nishikawa H., Hirano M., Kinoshita H., Ono M., Kurogi K., Sakakibara Y., Suiko M., Yasuda S.
Bioscience, Biotechnology and Biochemistry 88 ( 9 ) 1081 - 1089 2024年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Bioscience, Biotechnology and Biochemistry
Indoxyl sulfate (IS), a uremic toxin, is a physiologically active sulfated metabolite, specifically in kidney failure patients. Our previous studies have shown that IS downregulates phagocytic immune function in a differentiated HL-60 human macrophage cell model. However, it remains unclear whether IS exerts similar effects on macrophage function in other cell types or in lipopolysaccharide (LPS)-sensitive immune cell models. Therefore, this study aimed to investigate the effects of IS on intracellular oxidation levels and phagocytic activity in a differentiated U937 human macrophage cell model, both in the absence and presence of LPS. Our results demonstrated that IS significantly increases intracellular oxidation levels and decreases phagocytic activity, particularly in cells activated by LPS. Furthermore, we found that 2-acetylphenothiazine, an NADH oxidase inhibitor, attenuates the effects of IS in LPS-activated macrophage cells. Representative antioxidants, trolox, α-tocopherol, and ascorbic acid, significantly mitigated the effects of IS on the macrophages responding to LPS.
DOI： 10.1093/bbb/zbae077
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Evolution and multiple functions of sulfonation and cytosolic sulfotransferases across species 査読あり 国際誌
Kurogi K., Suiko M., Sakakibara Y.
Biosci Biotechnol Biochem 88 ( 4 ) 368 - 380 2024年3月
担当区分：筆頭著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Bioscience, Biotechnology and Biochemistry
Organisms have conversion systems for sulfate ion to take advantage of the chemical features. The use of biologically converted sulfonucleotides varies in an evolutionary manner, with the universal use being that of sulfonate donors. Sulfotransferases have the ability to transfer the sulfonate group of 3'-phosphoadenosine 5'-phosphosulfate to a variety of molecules. Cytosolic sulfotransferases (SULTs) play a role in the metabolism of low-molecular-weight compounds in response to the host organism's living environment. This review will address the diverse functions of the SULT in evolution, including recent findings. In addition to the diversity of vertebrate sulfotransferases, the molecular aspects and recent studies on bacterial and plant sulfotransferases are also addressed.
DOI： 10.1093/bbb/zbae008
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高速液体クロマトグラフィーを用いたアセトアミノフェン O- 硫酸体とチロシン O- 硫酸体の UV 検出による測定法 査読あり
森田千紘、元山優作、谷口玲央真、上田裕人、木下英樹、小野政輝、黒木勝久、榊原陽一、水光正仁、安田伸
東海大学紀要 42 1 - 8 2023年3月
記述言語：日本語 掲載種別：研究論文（大学，研究機関等紀要）
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プロテオミクス基盤技術を活用したブランド豚肉と個体識別の検討 招待あり 査読あり
黒木 勝久, 秋山 克樹, 榊原 陽一
電気泳動 66 ( 2 ) 97 - 102 2022年11月
担当区分：筆頭著者 記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：日本電気泳動学会
黒毛和牛やブランド豚肉を始めとした高付加価値食肉は系統種の交配と飼育条件の工夫により開発される．食肉偽装などの問題もあり，遺伝的・環境的要因を一度に解析できる手法を確立することで，効率的な優良育種とブランド肉の偽装鑑定への応用に期待できる．その一つとして，我々はプロテオミクス基盤技術を活用した解析を行っている．本稿では，豚肉に焦点を当てブランド肉鑑定および優良種豚選抜法への可能性を二次元電気泳動と質量分析計を用いて検討した結果を報告する．プロテオーム解析の結果，ブランド豚肉では解糖系に関するタンパク発現が大きく変動しており，環境要因が糖代謝に与える影響を見出すことが出来たと共に，ブランド豚肉を判別できるマーカータンパク質・ペプチドの候補を見出すことが出来た．さらに，優良育種に用いられるデュロック種と大ヨークシャー種の血清サンプルを用いた解析より，従来の系統的な選抜方法とは異なる新たな個体識別方法への可能性が示された．
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Kurogi K., Cao Y., Segawa K., Sakakibara Y., Suiko M., Uetrecht J., Liu M.C.
Biochemical Pharmacology 204 2022年10月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical Pharmacology
Nevirapine (NVP) is an effective drug for the treatment of HIV infections, but its use is limited by a high incidence of severe skin rash and liver injury. 12-Hydroxynevirapine (12-OH-NVP) is the major metabolite of nevirapine. There is strong evidence that the sulfate of 12-OH-NVP is responsible for the skin rash. While several cytosolic sulfotransferases (SULTs) have been shown to be capable of sulfating 12-OH-NVP, the exact mechanism of sulfation in vivo is unclear. The current study aimed to clarify human SULT(s) and human organs that are capable of sulfating 12-OH-NVP and investigate the metabolic sulfation of 12-OH-NVP using cultured HepG2 human hepatoma cells. Enzymatic assays revealed that of the thirteen human SULTs, SULT1A1 and SULT2A1 displayed strong 12-OH-NVP-sulfating activity. 1-Phenyl-1-hexanol (PHHX), which applied topically prevents the skin rash in rats, inhibited 12-OH-NVP sulfation by SULT1A1 and SULT2A1, implying the involvement of these two enzymes in the sulfation of 12-OH-NVP in vivo. Among five human organ cytosols analyzed, liver cytosol displayed the strongest 12-OH-NVP-sulfating activity, while a low but significant activity was detected with skin cytosol. Cultured HepG2 cells were shown to be capable of sulfating 12-OH-NVP. The effects of genetic polymorphisms of SULT1A1 and SULT2A1 genes on the sulfation of 12-OH-NVP by SULT1A1 and SULT2A1 allozymes were investigated. Two SULT1A1 allozymes, Arg37Asp and Met223Val, showed no detectable 12-OH-NVP-sulfating activity, while a SULT2A1 allozyme, Met57Thr, displayed significantly higher 12-OH-NVP-sulfating activity compared with the wild-type enzyme. Collectively, these results contribute to a better understanding of the involvement of sulfation in NVP-induced skin rash and provide clues to the possible role of SULT genetic polymorphisms in the risk of this adverse reaction.
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Morita C., Tokunaga Y., Ueda Y., Ono M., Kinoshita H., Kurogi K., Sakakibara Y., Suiko M., Liu M.C., Yasuda S.
Journal of Toxicological Sciences 47 ( 10 ) 421 - 428 2022年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Toxicological Sciences
Acetaminophen (APAP) and p-aminophenol (p-AP) are the analogous simple phenolic compounds that undergo sulfate conjugation (sulfation) by cytosolic sulfotransferases. Sulfation is gener-ally thought to lead to the inactivation and disposal of endogenous as well as xenobiotic compounds. This study aimed to investigate the antioxidative effects of O-sulfated form of APAP and p-AP, i.e., APAPS and p-APS, in comparison with their unsulfated counterparts. Using a 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay, the antioxidant capacity of APAPS was shown to be approximately 126-times low-er than that of APAP. In contrast, p-APS displayed comparable activity as unsulfated p-AP. Similar trends concerning the suppressive effects of these chemicals on cellular O-2 radical generation were found using an activated granulocytic neutrophil cell model. Collectively, these results indicated that, depending on the presence of an additional “active site”, sulfation may not always decrease the antioxidant activities of phenolic compounds.
DOI： 10.2131/jts.47.421
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Yamamoto K., Yamada N., Endo S., Kurogi K., Sakakibara Y., Suiko M.
PLoS ONE 17 ( 8 August ) 2022年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PLoS ONE
Polyphenols in plants are important for defense responses against microorganisms, insect herbivory, and control of feeding. Owing to their antioxidant, anti-cancer, and anti-inflammatory activities, their importance in human nutrition has been acknowledged. However, metabolism of polyphenols derived from mulberry leaves in silkworms (Bombyx mori) remains unclear. Sulfotransferases (SULT) are involved in the metabolism of xenobiotics and endogenous compounds. The purpose of this study is to investigate the metabolic mechanism of polyphenols mediated by B. mori SULT. Here, we identified a novel SULT in silkworms (herein, swSULT ST3). Recombinant swSULT ST3 overexpressed in Escherichia coli effectively sulfated polyphenols present in mulberry leaves. swSULT ST3 showed high specific activity toward genistein among the polyphenols. Genistein-7-sulfate was produced by the activity of swSULT ST3. Higher expression of swSULT ST3 mRNA was observed in the midgut and fat body than in the hemocytes, testis, ovary, and silk gland. Polyphenols inhibited the aldo-keto reductase detoxification of reactive aldehydes from mulberry leaves, and the most noticeable inhibition was observed with genistein. Our results suggest that swSULT ST3 plays a role in the detoxification of polyphenols, including genistein, and contributes to the effects of aldo-keto reductase in the midgut of silkworms. This study provides new insight into the functions of SULTs and the molecular mechanism responsible for host plant selection in lepidopteran insects.
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Acetaminophen 硫酸体の有機合成 査読あり
森田千紘・谷口玲央真・吉田実央・德永祐希・木下英樹 小野政輝・黒木勝久・榊原陽一・水光正仁・安田伸
東海大学紀要 41 39 - 46 2022年3月
記述言語：日本語 掲載種別：研究論文（大学，研究機関等紀要）
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Kurogi K., Manabe Y., Liu M.C., Suiko M., Sakakibara Y.
Bioscience, Biotechnology and Biochemistry 85 ( 10 ) 2113 - 2120 2021年9月
担当区分：筆頭著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Bioscience, Biotechnology and Biochemistry
Cytosolic sulfotransferase SULT1C subfamily is one of the most flexible gene subfamilies during mammalian evolution. The physiological functions of SULT1C enzymes still remain to be fully understood. In this study, common marmoset (Callithrix jacchus), a promising primate animal model, was used to investigate the functional relevance of the SULT1C subfamily. Gene database search revealed 3 intact SULT1C genes and a pseudogene in its genome. These 4 genes were named SULT1C1, SULT1C2, SULT1C3P, and SULT1C5, according to the sequence homology and gene location. Since SULT1C5 is the orthologous gene for human SULT1C2P, we propose, here, to revisit the designation of human SULT1C2P to SULT1C5P. Purified recombinant SULT1C enzymes showed sulfating activities toward a variety of xenobiotic compounds and thyroid hormones. Kinetic analysis revealed high catalytic activities of SULT1C1 and SULT1C5 for 3,3′-T2. It appears therefore that SULT1C isoforms may play a role in the thyroid hormone metabolism in common marmoset.
DOI： 10.1093/bbb/zbab141
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Effects of genetic polymorphisms on the sulfation of doxorubicin by human SULT1C4 allozymes 査読あり 国際共著
Gohal S.A., Rasool M.I., Bairam A.F., Alatwi E.S., Alherz F.A., Abunnaja M.S., El Daibani A.A., Kurogi K., Liu M.C.
Journal of Biochemistry 170 ( 3 ) 419 - 426 2021年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Biochemistry
Doxorubicin is a chemotherapeutic drug widely utilized in cancer treatment. An enzyme critical to doxorubicin metabolism is the cytosolic sulfotransferase (SULT) SULT1C4. This study investigated the functional impact of SULT1C4 single nucleotide polymorphisms (SNPs) on the sulfation of doxorubicin by SULT1C4 allozymes. A comprehensive database search was performed to identify various SULT1C4 SNPs. Ten nonsynonymous SULT1C4 SNPs were selected, and the corresponding cDNAs, packaged in pGEX-2TK expression vector, were generated via site-directed mutagenesis. Respective SULT1C4 allozymes were bacterially expressed and purified by affinity chromatography. Purified SULT1C4 allozymes, in comparison with the wild-type enzyme, were analysed for sulphating activities towards doxorubicin and 4-nitrophenol, a prototype substrate. Results obtained showed clearly differential doxorubicin-sulphating activity of SULT1C4 allozymes, implying differential metabolism of doxorubicin through sulfation in individuals with distinct SULT1C4 genotypes.
DOI： 10.1093/jb/mvab055
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The crystal structure of mouse SULT2A8 reveals the mechanism of 7α-hydroxyl, bile acid sulfation 査読あり
Teramoto T., Nishio T., Kurogi K., Sakakibara Y., Kakuta Y.
Biochemical and Biophysical Research Communications 562 15 - 20 2021年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
Bile acids play essential roles in facilitating the intestinal absorption of lipophilic nutrients as well as regulation of glucose, lipid, and energy homeostasis via activation of some receptors. Bile acids are cytotoxic, and consequently their concentrations are tightly controlled. A critical pathway for bile acid elimination and detoxification is sulfation. The pattern of bile acid sulfation differs by species. Sulfation preferentially occurs at the 3α-OH of bile acids in humans, but at the 7α-OH in mice. A recent study identified mouse cytosolic sulfotransferase 2A8 (mSULT2A8) as the major hepatic 7α-hydroxyl bile acid-sulfating enzyme. To elucidate the 7α-OH specific sulfation mechanism of mSULT2A8, instead of 3α-OH specific sulfation in humans, we determined a crystal structure of mSULT2A8 in complex with cholic acid, a major bile acid, and 3′-phosphoadenosine-5′-phosphate, the sulfate donor product. Our study shows that bile acid-binding mode of mSULT2A8 and how the enzyme holds the 7α-OH group of bile acids at the catalytic center, revealing that the mechanism underlying 7α-OH specific sulfation. The structure shows the substrate binds to mSULT2A8 in an orientation perpendicular to that of human 3α-hydroxyl bile acid-sulfotransferase (hSULT2A1). The structure of the complex provides new insight into species different bile acid metabolism.
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SULT genetic polymorphisms: physiological, pharmacological and clinical implications 査読あり 国際共著
Kurogi K., Rasool M.I., Alherz F.A., El Daibani A.A., Bairam A.F., Abunnaja M.S., Yasuda S., Wilson L.J., Hui Y., Liu M.C.
Expert Opinion on Drug Metabolism and Toxicology 17 ( 7 ) 767 - 784 2021年7月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Expert Opinion on Drug Metabolism and Toxicology
Introduction: Cytosolic sulfotransferases (SULTs)-mediated sulfation is critically involved in the metabolism of key endogenous compounds, such as catecholamines and thyroid/steroid hormones, as well as a variety of drugs and other xenobiotics. Studies performed in the past three decades have yielded a good understanding about the enzymology of the SULTs and their structural biology, phylogenetic relationships, tissue/organ-specific/developmental expression, as well as the regulation of the SULT gene expression. An emerging area is related to the functional impact of the SULT genetic polymorphisms. Areas covered: The current review aims to summarize our current knowledge about the above-mentioned aspects of the SULT research. An emphasis is on the information concerning the effects of the polymorphisms of the SULT genes on the functional activity of the SULT allozymes and the associated physiological, pharmacological, and clinical implications. Expert opinion: Elucidation of how SULT SNPs may influence the drug-sulfating activity of SULT allozymes will help understand the differential drug metabolism and eventually aid in formulating personalized drug regimens. Moreover, the information concerning the differential sulfating activities of SULT allozymes toward endogenous compounds may allow for the development of strategies for mitigating anomalies in the metabolism of these endogenous compounds in individuals with certain SULT genotypes.
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Impact of Human SULT1E1 Polymorphisms on the Sulfation of 17β-Estradiol, 4-Hydroxytamoxifen, and Diethylstilbestrol by SULT1E1 Allozymes 査読あり
El Daibani AA, Alherz FA, Abunnaja MS, Bairam AF, Rasool MI, Kurogi K, Liu MC
Eur J Drug Metab Pharmacokinet. 46 ( 1 ) 105 - 118 2021年1月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Effects of indole and indoxyl on the intracellular oxidation level and phagocytic activity of differentiated HL-60 human macrophage cells. 査読あり
Tsutsumi S, Tokunaga Y, Shimizu S, Kinoshita H, Ono M, Kurogi K, Sakakibara Y, Suiko M, Liu MC, Yasuda S.
J Toxicol Sci. 45 ( 9 ) 569 - 579 2020年9月
記述言語：英語 掲載種別：研究論文（学術雑誌）
DOI： 10.2131/jts.45.569.
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Functional analysis of novel sulfotransferases in the silkworm Bombyx mori 査読あり
Bairam AF, Kermasha ZW, Liu MC, Kurogi K, Yamamoto K.
Arch Insect Biochem Physiol 104 ( 3 ) e21671 2020年7月
記述言語：英語 掲載種別：研究論文（学術雑誌）
DOI： 10.1002/arch.21671.
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Investigation of the effects of indoxyl sulfate, a uremic toxin, on the intracellular oxidation level and phagocytic activity using an HL-60-differentiated human macrophage cell model 査読あり
Tsutsumi S, Tokunaga Y, Shimizu S, Kinoshita H, Ono M, Kurogi K, Sakakibara Y, Suiko M, Liu MC, Yasuda S.
Biosci Biotechnol Biochem 84 ( 5 ) 1023 - 1029 2020年5月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Effect of SULT2B1 genetic polymorphisms on the sulfation of dehydroepiandrosterone and pregnenolone by SULT2B1b allozymes. 査読あり
Alherz FA, El Daibani AA, Abunnaja MS, Bairam AF, Rasool MI, Sakakibara Y, Suiko M, Kurogi K, Liu MC.
Molecular and Cellular Endocrinology 496 110535 2019年10月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Impact of SULT1A3/SULT1A4 genetic polymorphisms on the sulfation of phenylephrine and salbutamol by human SULT1A3 allozymes. 査読あり
Bairam AF, Rasool MI, Alherz FA, Abunnaja MS, El Daibani AA, Gohal SA, Alatwi ES, Kurogi K, Liu MC.
Pharmacogenetics and genomics. 29 99 - 105 2019年7月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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レトルト加工および保蔵期間が鶏肉のイミダゾールジペプチド含有量に及ぼす影響 査読あり
神力（長友）はるな，近藤知巳，永濵清子，福井敬一，黒木勝久，水光正仁，榊原陽一
日本食品科学工学会誌 66 210 - 214 2019年6月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
DOI： 10.3136/nskkk.66.210