Takazawa Chisato, Fujimoto Kengo, Homma Daigo, Sumi-Ichinose Chiho, Nomura Takahide, Ichinose Hiroshi, Katoh Setsuko
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, Japan.
Biochem Biophys Res Commun. 2008 Mar 21;367(4):787-92. doi: 10.1016/j.bbrc.2008.01.028. Epub 2008 Jan 15.
Sepiapterin reductase (SPR) is an enzyme that acts in the third and final step of tetrahydrobiopterin (BH4) biosynthesis. The human Spr gene locates within the region of 2.5MB mapped to PARK3, an autosomal dominant form of familial Parkinson's diseases. In order to explore the role of SPR in the metabolism of BH4, we produced and analyzed Spr-deficient mice. Most of Spr-null mice survived beyond two weeks. Whereas the BH4 contents in the homozygous mutant mice were greatly decreased than those in wild-type and heterozygous mice, the substantial amounts of BH4 were remained even 17 days after delivery. Spr-null mice exhibited severe monoamine deficiencies and a tremor-like phenotype after weaning. The amount of TH protein in the brain of Spr-null mice was less than 10% of wild-type, while TH protein in the adrenal, phenylalanine hydroxylase protein in the liver, and nNOS in the brain were not altered. These data suggest an essential role of SPR in the biosynthesis of BH4, and that the SPR gene could be a candidate gene for PARK3.
蝶呤还原酶（SPR）是一种在四氢生物蝶呤（BH4）生物合成的第三步也是最后一步发挥作用的酶。人类Spr基因位于映射到PARK3的2.5MB区域内，PARK3是家族性帕金森病的常染色体显性形式。为了探究SPR在BH4代谢中的作用，我们制备并分析了Spr基因缺陷小鼠。大多数Spr基因敲除小鼠存活超过两周。虽然纯合突变小鼠体内的BH4含量比野生型和杂合小鼠大幅降低，但即使在出生后17天仍有大量BH4留存。Spr基因敲除小鼠断奶后表现出严重的单胺缺乏和震颤样表型。Spr基因敲除小鼠大脑中TH蛋白的量不到野生型的10%，而肾上腺中的TH蛋白、肝脏中的苯丙氨酸羟化酶蛋白以及大脑中的nNOS均未改变。这些数据表明SPR在BH4生物合成中起重要作用，并且Spr基因可能是PARK3的候选基因。
