ENZYMES OF POLYAMINE BIOSYNTHESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 S-腺苷蛋氨酸脱羧酶(ADO-MetDC)是多胺生物合成途径中的一个关键酶，依赖于丙酮酰基的脱羧基活性。多胺腐胺、亚精胺和精胺对细胞生长和分化很重要；某些类型的癌症和寄生虫病与多胺水平升高有关。通过调节多胺的生物合成途径来维持细胞内的多胺水平是一种很有前途的抗癌和抗寄生虫治疗工具。ADOMetDC催化S-腺苷蛋氨酸(ADOMet)转化为脱羧基S-腺苷蛋氨酸(DcADOMet)。DcADOMet的丙胺基转移成腐胺和亚精胺，分别形成亚精胺和亚精胺。ADOMetDC是该途径的一个关键分支点，dcADOMet致力于多胺的生物合成。多胺腐胺可激活ADOMetDC的自动加工和脱羧化反应。以前的晶体结构中有一个腐胺分子结合在腐胺结合部位，并识别与酶的关键相互作用。人的ADOMetDC与各种抑制剂结合后的晶体结构也得到了解决。该项目的主要目标是获得寄生虫中的ADOMetDC的晶体结构以及人的ADOMetDC与各种抑制剂的络合物，以寻找潜在的先导化合物用于药物设计。此外，突变体在人ADOMetDC的腐胺结合部位的晶体结构将为深入了解激活机制提供依据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation activity. The polyamines putrescine, spermidine and spermine are important for cell growth and differentiation; ertain types of cancer and parasitic diseases are associated with elevated levels of polyamines. Maintaining the polyamine levels in the cells by regulating the polyamine biosynthetic pathway is a promising tool for anti-cancer and anti-parasitic therapy. AdoMetDC catalyses the conversion of S-Adenosylmethionine (AdoMet) to decarboxylated S-Adenosylmethionine (dcAdoMet). The propylamine group of dcAdoMet is transferred to putrescine and spermidine to form spermidine and spermine respectively. AdoMetDC is at a key branch point in the pathway and dcAdoMet is committed to polyamine biosynthesis. The polyamine putrescine activates the autoprocessing and decarboxylation reactions of AdoMetDC. Previous crystal structures have a molecule of putrescine bound in the putrescine binding site and identify the key interactions with the enzyme. The crystal structures of human AdoMetDC bound to various inhibitors were also solved previously. The primary goal of the project is to obtain the crystal structure of AdoMetDC in parasites and the complexes of human AdoMetDC with various inhibitors in search of potential lead compounds for drug design. In addition, the crystal structures of the mutants in the putrescine binding site of human AdoMetDC would provide insights into the mechanism of activation.