セレノシステイン含有ペプチドの合成と生化学的機能の研究

Selenium belongs to the Ⅵb group of the periodic table,and possesses both metallic and nonmetallic characteristics. Physicochemical properties of selenium resemble more or less those of sulfur,and selenium may be indiscriminately incorporated in place of sulfur in cellular constituents and disturb metabolism. Alkali disease and blind stagger disease of livestock are caused by selenium-polluted grass. Carcinogenic effect is also one of the marked biological properties of selenium. In spite of the toxic and carcinogenic effects,selenium is actually an essential trace element for bacteria,fish,and mammals. Life has exploied the high reactivity and unique characteristics of organoselenium compounds,especially in the form of selenoenzymes. Mammalian glutathione peroxidase(EC 1.11.1.9) has selenocysteine residue at the active site, and the enzyme plays a central role in the biological defense system against oxidative challenge by activated oxygens and radicals. The author has studied the low redox potential and high reactivity of selenium-containing compounds, and developed glutathione peroxidase mimics. Glutaselenone, a selenium analog of glutaheione, catalyzes a glutathione peroxidase like reaction in vitro. Studies on the mechanisum of glutaselenone-catalyzed reaction revealed that glutaselenone is converted to a selenosulfide conjugate with glutathione in its catalysis. Thioredoxins contain a conserved sequence,Cys-Gly-Pro-Cys, which is known to form intramolecular disulfide bond with consecutive β-turn conformations. THe peptide is expected to serve as an template for intramolecular selenosulfide bond formation when either the cysteine is replaced by selenocystein. A tetrapeptide,Secys-Gly-Pro-Cys, was synthesized chemically. It showed glutathione peroxidase-like activity three times as high as glutaselenone. The high catalytic activity is ascribed to an intramolecular selenosulfide bond formation in the catalytic reaction.

セレンは2-、0、2+、4+、6+と多彩な酸化還元状態をとるという点で金属的な性質を持つ。また有機セレン化合物として求核的・求電子的な反応性に関与できるという点で酸素や硫黄などの典型元素のような振る舞いをする。生命は進化の過程で、セレンのユニークな化学的特性をうまく利用し、グルタチオンペルオキシダーゼなどのセレン酵素を獲得してきたと考えられる。セレン酵素の研究に触発されて、セレン酵素化合物を医薬品として利用する研究が進められており注目を集めている。このような背景のもと、グルタセレノンとテトラペプチドを合成した。とくにテトラペプチドはグルタセレノンの反応機構研究から生まれたペプチドである。今後さらに高い活性を持つ人工酵素がデザインされ、合成されるだろう。その時、鋳型として蛋白質や核酸、オリゴ糖などある特定のコンフォメーションをとる生体物質が利用されると思われる。