L-PIPECOLIC ACID OXIDASE--ENZYMOLOGY, GENETICS, AND PEROXISOMAL DISORDERS

L-吡喃甲酸在泛发性过氧化物症等疾病中蓄积 Zellweger综合征和新生儿起病的肾上腺脑白质营养不良 其他几组患有进行性神经系统疾病的患者。 而L的一个缺陷是公认的--吡喃甲酸氧化 在患有全身性过氧化物症的儿童中，其原因是 缺陷是未知的。因为L有明显的神经学作用--哌替卡林 酸及其代谢物，L-吡哌酸的这种升高可能与 在这些疾病中发现了严重的精神发育迟滞。分解新陈代谢 L-吡喃甲酸氧化酶最新提纯至近 这种酶的同源性和多克隆抗体已经产生。 该项目将专注于对这种纯化酶的进一步研究。 主要焦点将包括对分布和相对活动的研究 在脑组织中的酶，进一步研究共价黄素- 含部分蛋白质、酶的克隆及测定 它的遗传特征，以及它的鉴定和研究 有酶缺陷的患者。这项工作将产生关于 正常的L-吡喃甲酸氧化途径也将有助于阐明 过氧酶体中L-吡喃甲酸氧化缺陷的病因 疾病，以及那些较罕见的其他形式的 高胆汁性酸血症。对这种蛋白质的进一步研究将使我们能够 确定该酶是否含有典型的羧基末端氨基 与酶靶向过氧化物体有关的酸序列。 利用抗体和部分氨基酸序列信息，它可以 应该有可能为该酶生产cdna克隆。这些克隆人 将是未来研究的工具，以表征高胆酸血症 并在遗传水平上寻找基因组克隆，从而共同 调整和同步上行数据段等特征 过氧化物酶的产生可以被区分开来。此外， L-吡喃甲酸穴位缺陷患者的鉴定 氧化将特别具有启发性，因为任何新陈代谢和 在这类患者中发现的神经变化只能归因于 叛逃。

L-Pipecolic acid accumulates in the generalized peroxisomal disorders such as Zellweger syndrome and neonatal-onset adrenoleukodystropy, as well as in several other groups of patients with progressive neurologic diseases. While a defect in L-pipecolic acid oxidation is recognized in the majority of children with generalized peroxisomal disorders, the cause of this defect is unknown. Because of the apparent neurologic role of L-pipecolic acid and its metabolites, this elevation of L-pipecolic acid may be related to the profound mental retardation found in these diseases. The catabolic enzyme for L-pipecolic acid oxidation has recently been purified to near homogeneity and a polyclonal antibody to the enzyme has been produced. This project will focus on further studies with this purified enzyme. Major foci will include a study of the distribution and relative activity of the enzyme in brain tissues, further study of the covalent flavin- containing portion of the protein, cloning of the enzyme and determination of its genetic characteristics, and identification of and studies of patients with defects in the enzyme. This work will yield information on the normal L-pipecolic acid oxidation pathway and will also help elucidate the etiology of the L-pipecolic acid oxidation defects in peroxisomal diseases, as well as in those rarer patients with other forms of hyperpipecolic acidemia. Further studies with the protein will allow us to identify whether the enzyme contains the typical carboxyl terminal amino acid sequences involved in the targeting of enzymes to the peroxisomes. With both the antibody and the partial amino acid sequence information, it should be possible to produce cDNA clones for the enzyme. These clones will be tools for future studies to characterize hyperpipecolic acidemia at the genetic level and to find a genomic clone, so that common characteristics such as upstream segments that regulate and synchronize peroxisomal enzyme production may be distinguished. In addition, the identification of patients with a point defect of L-pipecolic acid oxidation would be particularly enlightening because any metabolic and neurologic changes found in such patients can only be attributed to this defect.