REGULATION OF CYCLIC NUCLEOTIDE METABOLISM

环核苷酸代谢的调节

• 批准号: 3919996
• 负责人: J MOSS
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3919996
• 关键词: 3'5' cyclic nucleotide phosphodiesterase; ADP ribosylation; Escherichia coli; G protein; adenine phosphoribosyltransferase; adenylate cyclase; aldehyde lyase; arginine; cholera toxin; cyclic nucleoside monophosphate; enterotoxins; enzyme complex; enzyme induction /repression; enzyme mechanism; hormone regulation /control mechanism; human tissue; hydrolase; immunochemistry; laboratory mouse; monoclonal antibody; nucleotide metabolism; pertussis toxin; protein sequence; receptor coupling; transducin

The hormone-sensitive adenylyl cyclase system is the target of bacterial toxins that alter its activity by catalyzing the ADP- ribosylation of critical guanine nucleotide-binding (G) regulatory proteins that couple hormone receptors to the cyclase catalytic unit. An inhibitory G protein (Gi) is ADP-ribosylated by pertussis toxin, an etiological agent in whooping cough, whereas a stimulatory G protein (Gs) is ADP-ribosylated by cholera toxin (CT) and E. coli heat-labile enterotoxins (LT), etiological agents in cholera and "travelers' diarrhea", respectively. The ADP- ribosyltransferase activities of CT and the LTs are enhanced by - 19 kDa soluble and membrane guanine nucleotide-binding proteins, known as ADP-ribosylation factors (ARFs); in the case of the LTs, it appears that although two of them, LT-IIa and LT-IIb, diverge in amino acid sequence from LT-I and CT, the sites involved in ARF- stimulated ADP-ribosylation have been conserved. CT and LT catalyze reactions similar to those of ADP-ribosyltransferases endogenous to animal cells. These transferases ADP-ribosylate arginine residues in proteins as well as free arginine. In animal tissues, ADP-ribosylarginine hydrolases exist that cleave the ADP- ribose-arginine linkage, regenerating the arginine residues; these enzymes are active as monomers of 39 kDa; it appears that the ADP- ribosylarginine hydrolase and the ADP-ribosyltransferase could catalyze opposing arms of an ADP-ribosylation cycle analogous to the kinases and phosphatases in protein phosphorylation cyclase. In addition, the ADP-ribosylarginine hydrolases, by reversing the toxin-catalyzed reactions, may promote recovery from disease.

激素敏感的腺苷酸环化酶系统是 细菌毒素通过催化 ADP- 改变其活性 关键鸟嘌呤核苷酸结合 (G) 调节的核糖基化 将激素受体与环化酶催化偶联的蛋白质 单元。 百日咳抑制性 G 蛋白 (Gi) 被 ADP 核糖基化 毒素，百日咳的病原体，而 刺激性 G 蛋白 (Gs) 被霍乱毒素 (CT) ADP 核糖基化 和大肠杆菌不耐热肠毒素（LT），病原体 分别是霍乱和“旅行者腹泻”。 ADP- CT 和 LT 的核糖基转移酶活性通过以下方式增强： 19 kDa 可溶性膜鸟嘌呤核苷酸结合蛋白， 称为 ADP-核糖基化因子 (ARF)；就 LT 而言， 看起来虽然其中两个 LT-IIa 和 LT-IIb 存在分歧 在LT-I和CT的氨基酸序列中，涉及ARF-的位点 受刺激的 ADP-核糖基化已被保留。 CT 和 LT 催化类似于 ADP-核糖基转移酶的反应 动物细胞内源性。 这些转移酶 ADP-核糖基 蛋白质中的精氨酸残基以及游离精氨酸。 在动物中 组织中，存在 ADP-核糖精氨酸水解酶，可裂解 ADP- 核糖-精氨酸连接，再生精氨酸残基；这些 酶以 39 kDa 的单体形式具有活性；看来 ADP- 核糖精氨酸水解酶和 ADP-核糖基转移酶可以 催化 ADP-核糖基化循环的相反臂，类似于 蛋白质磷酸化环化酶中的激酶和磷酸酶。 此外，ADP-核糖精氨酸水解酶通过逆转 毒素催化反应，可以促进疾病的康复。