Chiho Sumi-Ichinose

ジーンターゲッティング法を用いて6-ピルボイルテトラヒドロプテリン合成酵素(PTPS)遺伝子ノックアウトマウスの作成を行った.ホモ接合型マウスはほぼメンデルの法則にしたがって生まれたが,48時間以内に死亡した.ホモ接合型新生仔では脳に含まれるビオプテリン,カテコールアミン,セロトニンの量が極めて少なかった.変異マウスの生化学的測定ではホモ接合型マウスのチロシン水酸化酵素活性が著しく低下していた

Tetrahydrobiopterin ((6R)-L-erythro-tetrahydrobiopterin, BH4) is de novo synthesized from GTP. Enzymes involved in its synthesis are the rate limiting enzyme GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase (PTPS) and sepiapterin reductase. Abnormalities in the metabolism of BH4 have been demonstrated in some diseases affecting the central nervous systems such as atypical phenylketonuria, hereditary progressive dystonia (Segawa's disease). Furthermore, BH4 has been shown to be involved in vascular protection. It is suggested that the dysfunction of endothelial BH4 leads to atherosclerosis. Recently we established BH4-deficient mice by disrupting the PTPS gene to investigate the effects of BH4 depletion on the animals and the involvement of BH4 in regulating biological functions including neural systems. Investigation utilizing this model animal can contribute to the development of new therapeutic strategies toward various diseases involving neurological and vascular systems. Pterin derivatives other than biopterin may also be involved in the regulation of a variety of biological functions. We found that ciliated protozoan Tetrahymena pyriformis synthesizes tetrahydromonapterin, isomer of BH4, and its levels alter according to the progress of the cell cycle. How pterin derivatives are related to the human physiology and diseases is an interesting subject of investigation.