PURINE AND PYRIMIDINE METABOLISM

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。列出的机构是 中心，不一定是研究者的机构。 嘧啶和嘌呤核苷酸是合成核酸的基本构件，也可以参与能量转移和储存、蛋白质合成和信号传导。 由于这些分子的重要性，其代谢途径中的酶代表了用于治疗许多疾病的潜在药物靶标，包括癌症和几种类型的寄生虫感染。 我们已经进行了各种酶的结构研究，这些酶在嘧啶和嘌呤的代谢中发挥作用。 腺苷激酶（Adenosine kinase，AK）是寄生虫嘌呤代谢的关键酶，是弓形虫感染的潜在化疗靶点，可催化ATP依赖的腺苷磷酸化。 嘌呤核苷磷酸化酶（PNP）是一种重要的嘌呤核苷酸抢救酶，催化核糖核苷和2 '-脱氧核糖核苷可逆地磷酸化为游离碱和（2'-脱氧）核糖-1-磷酸。 RutA是一种FMN依赖性单加氧酶，参与最近发现的嘧啶降解途径，在E.杆菌 尿苷磷酸化酶（UP）催化尿苷的可逆磷酸解，形成核糖-1-磷酸和尿嘧啶。 乳清酸核苷-5 '-磷酸脱羧酶乳清酸磷酸核糖基转移酶（OMPDC-OPRT）是催化尿苷-5'-单磷酸（UMP）合成的最后两步的双功能酶。 除了它们的许多细胞用途之外，一些生物体可以代谢核苷酸作为氮源。 最近两个研究小组对克雷伯氏菌的研究揭示了一个基因簇，该基因簇负责表达利用嘌呤作为该生物体唯一氮源的酶。 为了更好地理解这一有趣的途径，我们对肺炎克雷伯氏菌中催化次黄嘌呤分解为尿囊素的几种酶进行了结构表征。

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. Pyrimidine and purine nucleotides are essential building blocks for the synthesis of nucleic acids and can also take part in energy transfer and storage, protein synthesis and signaling. Because of the importance of these molecules, the enzymes in their metabolic pathways represent potential drug targets for the treatment of many conditions including cancer and several types of parasitic infections. We have undertaken structural studies of various enzymes that play roles in the metabolism of pyrimidines and purines. Adenosine kinase (AK), a key enzyme in purine metabolism in parasites and a potential chemotherapeutic target for the treatment of Toxoplasma gondii infections, catalyzes the ATP dependent phosphorylation of adenosine. Purine nucleoside phosphorylase (PNP), which catalyzes the reversible phosphorolysis of ribonucleosides and 2'- deoxyribonucleosides to the free base and (2'-deoxy)ribose-1-phosphate, is an important enzyme for the salvage of purine nucleotides. RutA is a FMN dependent mono-oxygenase involved in a recently discovered pyrimidine degradation pathway that converts uracil (or thymine) to 3-hydroxypropionate (or 2-methyl-3-hydroxypropionate) in E. coli. Uridine phosphorylase (UP) catalyzes the reversible phosphorolysis of uridine with the formation of ribose-1-phosphate and uracil. Orotidine-5'-phosphate decarboxylase orotate phosphoribosyltransferase (OMPDC-OPRT) is a bifunctional enzyme that catalyzes the last two steps in the synthesis of uridine-5'-monophosphate (UMP). In addition to their many cellular uses, some organisms can metabolize nucleotides as a nitrogen source. Recent studies by two groups on Klebsiella sp. have revealed a gene cluster that is responsible for expressing the enzymes for utilizing purines as a sole nitrogen source in this organism. We have structurally characterized several of the enzymes that catalyze the breakdown of hypoxanthine to allantoin in Klebsiella pneumoniae in order to better understand this interesting pathway.