A new type of the gene-sharing on prostaglandin D synthases

前列腺素（PG） D2是在大鼠和人类中枢神经系统中产生的一种主要的前列腺素，参与多种中枢活动，如诱导睡眠和体温过低，调节气味和疼痛反应。PGD2也在肥大细胞中积极合成，并作为过敏和炎症介质。PGD合成酶有两种不同的类型，即定位于中枢神经系统、视网膜和男性生殖器官的脂脂素型酶和分布于外周组织的造血酶。我们证明，脂钙素型酶以β -痕量的形式分泌到脑脊液、光感受器间基质和精浆中，并结合小脂质物质，如类维生素a、甲状腺素和胆汁色素。因此，脂脂素型PGD合成酶被认为是一种双功能蛋白，既可以作为pgd2产生酶，又可以作为这些体液中疏水生物活性物质的转运蛋白。对造血PGD合成酶的cDNA克隆发现，其氨基酸序列与脂脂素型合成酶没有明显的同源性，表明这两种合成酶是从不同的祖先进化而来的。脂质钙素型PGD合成酶是脂质钙素基因家族的成员，而造血PGD合成酶是第一个被公认的谷胱甘肽s转移酶sigma类的脊椎动物同源物。我们制备了重组脂钙素型和造血酶，对这些酶进行结晶，并通过x射线晶体学分析确定了造血酶的结构。我们还培养了过量产生这些人类酶的转基因小鼠和缺乏脂钙素型酶基因的敲除小鼠。然后，我们检查了这些突变小鼠的控制神经系统、生殖系统和免疫反应的功能异常。

Prostaglandin (PG) D2 is a major prostanoid produced in the central nervous system of rats and humans, and is involved in a variety of central actions, i.e., it induces sleep and hypothermia and regulates odor and pain responses. PGD2 is also actively synthesized in mast cells and acts as an allergic and inflammatory mediator. There are two distinct types of PGD synthase, i.e., the lipocalin-type enzyme localized in the central nervous system, retina, and male genital organs and the hematopoietic enzyme distributed in the peripheral tissues. We demonstrated that the lipocalin-type enzyme is secreted as beta-trace into the cerebrospinal fluid, interphotoreceptor matrix, and seminal plasma and binds small liposhilic substances, such as retinoids, thyroids and bile pigments. Therefore, the lipocalin-type PGD synthase is considered to be a bifunctional protein which act as a PGD2-producing enzyme and also functions as a transporter protein for hydrophobic bioactive substances in those body fluids. The cDNA cloning of hematopoietic PGD synthase revealed that the amino acid sequence did not possess any significant homology with that of the lipocalin-type enzyme, indicating that these two enzymes have evolved from the unique ancestors distinct from one another. The lipocalin-type PGD synthase is a member of the lipocalin gene family, while the hematopoietic PGD synthase is the first recognized vertebtate homolog of the sigma class of glutathione S-transferase. We produced the recombinant lipocalin-type and hematopoietic enzymes, crystallized these enzymes, and determined the tartiary structure of the hematopoietic enzyme by X-ray crystallographic analysis. We also generated transgenic mice which overproduced each of those human enzymes and knockout mice lacking the gene for the lipocalin-type enzyme. We then examined the functional abnormality of the control nervous system, reproductive system, and immune responses of these mutant mice.