METABOLISM OF UNSATURATED AND HYDROXY FATTY ACIDS

不饱和脂肪酸和羟基脂肪酸的代谢

• 批准号: 3734448
• 负责人: HORST H SCHULTZ
• 金额: --
• 依托单位: CITY COLLEGE OF NEW YORK
• 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/3734448
• 关键词: HMG coA reductases; animal tissue; enzyme complex; fatty acid metabolism; fibroblasts; hormone regulation /control mechanism; hydroxy fatty acid; laboratory rat; lymphoblast; methylmalonyl coA epimerase; mitochondria; molecular cloning; nucleic acid sequence; stereochemistry; unsaturated fatty acids

This project is designed to answer a number of questions and provide information important for developing a detailed understanding of the beta-oxidation of polyunsaturated fatty acids. The focus of this study will be on 2,4-dienoyl-CoA reductase and 3-hydroxyacyl-CoA epimerase which are key enzymes in the reductase-dependent and epimerase-dependent pathways of PUFA beta-oxidation, respectively. Biochemical and genetic approaches will be used to study the beta-oxidation systems of mammals and E. coli. An important aspect of this study is an assessment of the importance of 3-hydroxyacyl-CoA epimerase in the beta-oxidation of hydroxy fatty acids like D-5-hydrooxyeicosatetraenoic acid (5-HETE) in mammals and D-3-hydroxymyristic acid in E. coli. Also, the mechanism of the E. coli 3-hydroxyacyl-CoA epimerase will be elucidated as will be the location of delta3-cis-delta2-trans-enoyl-CoA isomerase on the multienzyme complex of fatty acid oxidation from E. coli. The identification of a human disorder due to a deficiency of 2,4- dienoyl-CoA reductase prompts further studies of this enzyme including (a) the development of a more sensitive assay to measure reductase activities in fibroblasts and lymphoblasts; (b) the purification of the peroxisomal reductase from rat liver; (c) the cloning, sequencing and overexpression of the E. coli reductase gene; (d) a stereochemical study of the reduction catalyzed by mammalian 2,4-dienoyl-CoA reductase and (e) the hormonal regulation of this enzyme and its effect on PUFA beta- oxidation. Finally, the beta-oxidation of cis and trans unsaturated fatty acids in mitochondria will be studied with the aim of detecting and explaining differences in their degradation. Altogether, this project will provide a more complete view of the beta-oxidation of polyunsaturated fatty acids and of some hydroxy fatty acids in normal and diseased organisms including humans. The above outlined project was approved and is funded from 9/91-8/95 by NIH Grant HL30847.

该项目旨在回答一些问题并提供 对于详细了解非常重要的信息 多不饱和脂肪酸的β-氧化。 本研究的重点 将作用于 2,4-二烯酰基-CoA 还原酶和 3-羟酰基-CoA 差向异构酶 它们是还原酶依赖性和差向异构酶依赖性的关键酶 PUFA β-氧化途径，分别。 生化和遗传 方法将用于研究哺乳动物的β-氧化系统 和大肠杆菌。 这项研究的一个重要方面是评估 3-羟酰辅酶A差向异构酶在β-氧化中的重要性 羟基脂肪酸，如 D-5-羟基二十碳四烯酸 (5-HETE) 哺乳动物和大肠杆菌中的 D-3-羟基肉豆蔻酸。 另外，其机制 大肠杆菌 3-羟酰基-CoA 差向异构酶将被阐明 δ3-顺式-δ2-反式烯酰辅酶A异构酶在 大肠杆菌脂肪酸氧化的多酶复合物。 鉴定由于缺乏 2,4- 导致的人类疾病 二烯酰辅酶A还原酶促进了对该酶的进一步研究，包括 (a) 开发更灵敏的还原酶测定方法 成纤维细胞和淋巴母细胞的活性； (b) 纯化 来自大鼠肝脏的过氧化物酶体还原酶； (c) 克隆、测序和 大肠杆菌还原酶基因的过度表达； (d) 立体化学研究 哺乳动物 2,4-二烯酰基-CoA 还原酶催化的还原反应和 (e) 该酶的激素调节及其对 PUFA β- 的影响 氧化。 最后，顺式和反式不饱和的β-氧化 将研究线粒体中的脂肪酸，目的是检测和 解释它们退化的差异。 总而言之，这个项目 将提供更完整的β-氧化视图 多不饱和脂肪酸和一些羟基脂肪酸在正常和 患病的生物体，包括人类。 上述项目是 批准并由 NIH 拨款 HL30847 于 9/91-8/95 资助。