ENZYMES OF POLYAMINE BIOSYNTHESIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 S-腺苷甲硫氨酸脱羧酶（S-Adenosylmethionine decarboxylase，S-MetDC）是多胺生物合成途径中的关键酶，其脱羧活性依赖于腺苷酰基团。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。通过调节多胺生物合成途径来维持细胞中的多胺水平是用于抗癌和抗寄生虫治疗的有希望的工具。DMTMetDC催化S-腺苷甲硫氨酸（DMTMet）转化为脱羧S-腺苷甲硫氨酸（DMTMet）。 去甲硫氨酸的丙胺基被转移到腐胺和亚精胺上，分别形成亚精胺和精胺。DcMetDC处于途径中的关键分支点，并且dcMetDC致力于多胺生物合成。 多胺腐胺激活了CCLMetDC的自动加工和脱羧反应。先前的晶体结构具有结合在腐胺结合位点中的腐胺分子，并确定了与酶的关键相互作用。与各种抑制剂结合的人β-MetDC的晶体结构先前也已解决。该项目的主要目标是获得寄生虫中的CIMetDC的晶体结构以及人类CIMetDC与各种抑制剂的复合物，以寻找用于药物设计的潜在先导化合物。此外，在腐胺结合位点的突变体的晶体结构的人类cDNA-MetDC将提供见解的激活机制。

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.