Baumgart Florian, Rodríguez-Crespo Ignacio
Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Spain.
FEBS J. 2008 Jul;275(14):3538-45. doi: 10.1111/j.1742-4658.2008.06517.x.
It has been recently established that in various brain regions D-serine, the product of serine racemase, occupies the so-called 'glycine site' within N-methyl D-aspartate receptors. Mammalian brain serine racemase is a pyridoxal-5' phosphate-containing enzyme that catalyzes the racemization of L-serine to D-serine. It has also been shown to catalyze the alpha,beta-elimination of water from L-serine or D-serine to form pyruvate and ammonia. Serine racemase is included within the group of type II-fold pyridoxal-5' phosphate enzymes, together with many other racemases and dehydratases. Serine racemase was first purified from rat brain homogenates and later recombinantly expressed in mammalian and insect cells as well as in Escherichia coli. It has been shown that serine racemase is activated by divalent cations like calcium, magnesium and manganese, as well as by nucleotides like ATP, ADP or GTP. In turn, serine racemase is also strongly inhibited by reagents that react with free sulfhydryl groups such as glutathione. Several yeast two-hybrid screens for interaction partners identified the proteins glutamate receptor interacting protein, protein interacting with C kinase 1 and Golga3 to bind to serine racemase, having different effects on its catalytic activity or stability. In addition, it has also been proposed that serine racemase is regulated by phosphorylation. Thus, d-serine production in the brain is tightly regulated by various factors pointing at its physiologic importance. In this minireview, we will focus on the regulation of brain serine racemase and d-serine synthesis by the factors mentioned above.
最近已经确定，在大脑的各个区域，丝氨酸消旋酶的产物D-丝氨酸占据了N-甲基-D-天冬氨酸受体中的所谓“甘氨酸位点”。哺乳动物脑丝氨酸消旋酶是一种含磷酸吡哆醛-5′的酶，它催化L-丝氨酸消旋化为D-丝氨酸。研究还表明，它能催化L-丝氨酸或D-丝氨酸进行α,β-脱水反应生成丙酮酸和氨。丝氨酸消旋酶属于II型折叠磷酸吡哆醛酶家族，与许多其他消旋酶和脱水酶同属该家族。丝氨酸消旋酶最初是从大鼠脑匀浆中纯化出来的，后来在哺乳动物细胞、昆虫细胞以及大肠杆菌中进行了重组表达。研究表明，丝氨酸消旋酶可被钙离子、镁离子和锰离子等二价阳离子以及ATP、ADP或GTP等核苷酸激活。反过来，丝氨酸消旋酶也会被与游离巯基反应的试剂如谷胱甘肽强烈抑制。通过酵母双杂交筛选出了几种相互作用蛋白，确定谷氨酸受体相互作用蛋白、与C激酶1相互作用的蛋白以及高尔基体蛋白3与丝氨酸消旋酶结合，它们对丝氨酸消旋酶的催化活性或稳定性有不同影响。此外，也有人提出丝氨酸消旋酶受磷酸化调节。因此，大脑中D-丝氨酸的产生受到多种因素的严格调控，这表明其具有重要的生理意义。在这篇综述中，我们将重点关注上述因素对脑丝氨酸消旋酶和D-丝氨酸合成的调控。
