Relations of a New Metabolic Pathway and Immunosuppressive Effects of Urocanic Acid to its Isomerization by Exposure of Skin to Ultraviolet Light

尿刊酸的新代谢途径和免疫抑制作用与其皮肤暴露于紫外线引起的异构化的关系

• 批准号: 08836008
• 负责人: KUNUTA Masahiro
• 金额: $ 1.34万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08836008/
• 关键词: Urocanic Acid; Glutathione; Imidazole Compounds; gamma-Glutamyltransferase; Enzyme Inhibition; Capillary Electrophoresis; Diastereomer Separation; Ultraviolet Light; グルタチオン抱合体; 立体異性体; 紫外線防御; 含硫アミノ酸代謝

In the skin, only trans-urocanic acid is formed from L-histidine by histidine ammonia-lyase and then accumulated in epidermis because of the absence of urocanate hydratase from the skin. The epidermal urocanic acid isomerized to the cis isomer by ultraviolet light. However, physiological functions of the accumulation and of the isomerization have not been elucidated. This research deals with a new pathway of urocanic acid metabolism, which is initiated by the adduction of glutathione to urocanic acid to form a glutathione S-conjugated imidazole compound (I), and also with its physiological roles. We previously suggested that the metabolism related to the trans-cis isomerization and the elimination of the epidermal urocanic acid under conditions of sunlight irradation. New knowledges and results obtained are as follows : 1, Three additional metabolites of compound I were specified, and the new metabolic pathway has been established completely ; 2, Compound I and its metabolites located in the pathway have an asymmetric beta-carbon atom on the skeletal imidazolepropanoate part of their molecules, i.e., the existance of two diastereomers of each metabolite ; 3, The two diastereomers of each metabolite were prepared, purified by ion-exchangers, and characterizad by physicochemical analyzes ; 4, A new method for simultaneous determination of the diastereomers was developed by capillary electrophoresis, and this method achieved characterization of the enzymatic recognition of stereoisomerism on the beta-carbon atom of their molecules ; 5, A great inhibitory effect of compound I on gamma-glutamyltransferase activity was elucidated and this involves a physiological importance of the formation of compound I under conditions of sunlight irradiation probably to increase intracellular and/or extracellular levels of glutathione, and to protect from oxidative stresses or damages in tissues caused by sunlight.

在皮肤中，只有反式尿刊酸通过组氨酸氨裂解酶由L-组氨酸形成，然后在表皮中积累，因为皮肤中缺乏尿刊酸水合酶。表皮尿刊酸通过紫外光异构化为顺式异构体。然而，积累和异构化的生理功能尚未阐明。本研究涉及一种新的尿刊酸代谢途径，该途径是由谷胱甘肽加合到尿刊酸以形成谷胱甘肽S-缀合的咪唑化合物（I）而启动的，并且还涉及其生理作用。我们以前认为，代谢有关的反式-顺式异构化和消除表皮尿刊酸在阳光照射的条件下。获得的新认识和结果如下：1、确定了化合物I的另外三种代谢产物，并完整地建立了新的代谢途径; 2、化合物I及其代谢产物位于其分子的咪唑丙酸骨架部分，即，3、制备了两种非对映异构体，用离子交换法纯化了两种非对映异构体，并进行了理化分析：4、建立了毛细管电泳法同时测定两种非对映异构体的新方法，该方法实现了酶对它们分子β-碳原子上立体异构体的识别; 5.阐明了化合物I对γ-谷氨酰转移酶活性的巨大抑制作用，这涉及在阳光照射条件下形成化合物I的生理重要性，可能增加细胞内和/或细胞外谷胱甘肽水平，并保护组织免受阳光引起的氧化应激或损伤。

项目成果

Kinuta, M.^*, Shimizu, H.et al.: "Identification of S-〔2-carboxy-1-(1H-imidazol-4-yl)ethyl〕-3-mercaptopyruvic acid with a metabolic intermediate between S-〔2-carboxy-1-(1H-imidazol-4-yl)ethyl〕-L-cysteine and S-〔2-carboxy-1-(1H-imidazol-4-yl)ethyl〕-3-merca

Kinuta, M.^*, Shimizu, H.et al.：“用 S-[2-羧基-1-(1H-咪唑-4-基)乙基]-3-巯基丙酮酸与 S-之间的代谢中间体进行鉴定[2-羧基-1-(1H-咪唑-4-基)乙基]-L-半胱氨酸和S-[2-羧基-1-(1H-咪唑-4-基)乙基]-3-merca

Shimizu, H.and Kinuta, M.^*: "Inhibitory effects in vitro of S-〔2-carboxy-1-(1H-imidazol-4-yl)ethyl〕 glutathione,a proposed metabolite of L-histidine,on γ-glutamyltransferase activity" Biochimica et Biophysica Acta. (in press). (1998)

Shimizu, H. 和 Kinuta, M.^*：“S-〔2-羧基-1-(1H-咪唑-4-基)乙基〕谷胱甘肽（L-组氨酸的拟议代谢物）对 γ 的体外抑制作用-谷氨酰转移酶活性”Biochimica et Biophysicala Acta.（印刷中）。（1998）

Kinuta, M.^*, Shimizu, H.et al.: "Determination of chiral catabolites from S-〔2-carboxy-1-(1H-imidazol-4-yl)ethyl〕 glutathione,a proposed metabolite of L-histidine,by capillary electrophoresis" Journal of Chromatography A. 802 (1). 133-141 (1998)

Kinuta, M.^*, Shimizu, H.et al.：“测定 S-[2-羧基-1-(1H-咪唑-4-基)乙基]谷胱甘肽（一种 L-组氨酸的拟议代谢物）的手性分解代谢物，通过毛细管电泳”《色谱杂志》A. 802 (1). 133-141 (1998)

Kinuta, M., Shimizu, H.and Ubuka, T.: "Analyzes of S- [2-carboxy-1- (1H-imidazol-4-yl) ethyl] glutathione metabolites by capillary electrrophoresis." Seikagaku. 69 (7) (abstract). 675 (1997)

Kinuta, M.、Shimizu, H. 和 Ubuka, T.：“通过毛细管电泳分析 S-[2-羧基-1-(1H-咪唑-4-基)乙基]谷胱甘肽代谢物。”

Kinuta,M.et al.: "Isolation and characterization of N-acetyl-S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine,a new metabolite of histidine,from normal human urine and its formation from S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-L-cysteine" Biochimica et

Kinuta，M.等人：“N-乙酰基-S-[2-羧基-1-(1H-咪唑-4-基)乙基]-L-半胱氨酸，一种组氨酸的新代谢物，从正常细胞中分离和表征