Biochemistry and Structure of Lipid A Enzymes

脂质 A 酶的生物化学和结构

基本信息

批准号：
9230402
负责人：
Pei Zhou
金额：
$ 30.13万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9230402
关键词：
Adverse effects Alzheimer&apos s Disease Amyloid Anabolism Antibiotics Antimicrobial Resistance Attenuated Attenuated Vaccines Bacteria Binding Biochemical Biochemistry Biogenesis Biomedical Engineering Calcineurin Catalysis Chlamydia Chlamydia trachomatis Complement Complex Crystallization Cytosol Detergents Development Diphosphates Disaccharides Enzymes Escherichia coli Excision Family Francisella Francisella tularensis Future Genomic Library Glucosamine Goals Gram-Negative Bacteria Haemophilus influenzae Health Helicobacter Helicobacter pylori Hospitals Human Hydrolase Hydrophobicity Hypersensitivity Immune System Diseases Immune response Immunity Immunotherapeutic agent In Vitro Individual Infection Inflammatory Investigation Knowledge Life Lipid A Lipids Lipopolysaccharides Malignant Neoplasms Malignant neoplasm of cervix uteri Membrane Modification Molecular Molecular Probes Multi-Drug Resistance Mus Mutagenesis Neurodegenerative Disorders Open Reading Frames Orthologous Gene Pathogenesis Pathogenicity Pathway interactions Patients Peptides Peripheral Phagocytes Phosphoric Monoester Hydrolases Play Prevention Production Proteobacteria Public Health Reporting Role Salmonella Salmonella infections Septic Shock Structure Surface Vaccine Adjuvant Variant Virulence Virulence Factors base cancer therapy environmental change enzyme pathway human disease improved inhibitor/antagonist inorganic phosphate insight lipid X member membrane biogenesis monolayer mutant nervous system disorder novel novel therapeutics pathogen periplasm public health relevance pyrophosphatase response small molecule inhibitor structural biology sugar virtual

项目摘要

DESCRIPTION (provided by applicant): Lipid A, the hydrophobic membrane anchor of lipopolysaccharide, is a glucosamine-based saccharolipid that constitutes the outer monolayer of the outer membrane of Gram-negative bacteria and protects bacteria from the external damage of detergents and antibiotics. It is also the active component of lipopolysaccharide that causes life-threatening Gram-negative septic shock. Lipid A is synthesized by nine enzymes of the Raetz pathway in E. coli. The first six enzymes of lipid A biosynthesis are required for the viability of virtually all Gram-negative bacteria and are novel antibiotic targets. After lipid A i generated, it is flipped from the cytosolic surface of the inner membrane to the periplasmic surface, where it can be further transformed by lipid A modification enzymes that are specific to individual bacterial species. These modifications help bacteria evade the host immune response, adapt to environmental changes, and generate altered lipid A molecules that display diverse bioactivities. Although detailed structural analyses of several lipid A biosynthetic and modification enzymes have been carried out, providing rich information for structure-aided inhibitor development, others require further characterization. This proposal focuses on biochemical and structural studies of the essential lipid A biosynthetic enzymes that convert UDP-diacylglucosamine (UDP-DAGn) to 2,3- diacyl-GlcN-1-P (lipid X) and the lipid A modification enzyme LpxE that is important for bacterial virulence and production of monophosphorylated lipid A (MPLA), a widely used immunotherapeutic agent. These studies are expected to generate fundamental insights into the structure and mechanism of lipid A enzymes as well as the biogenesis and function of the bacterial outer membrane, and ultimately contribute to the development of novel therapeutics to improve human health.

描述（申请人提供）：脂质A是脂多糖的疏水膜锚，是一种基于葡萄糖胺的糖脂，构成革兰氏阴性菌外膜的外单层，保护细菌免受清洁剂和抗生素的外部损伤。脂多糖的活性成分会导致危及生命的革兰氏阴性败血性休克，脂质 A 是由九种酶合成的。大肠杆菌中的 Raetz 途径。脂质 A 生物合成的前六种酶是几乎所有革兰氏阴性细菌的生存所需，并且是新的抗生素靶标。脂质 A 生成后，会从内膜的细胞质表面翻转。到周质表面，它可以被特定于单个细菌物种的脂质 A 修饰酶进一步转化，这些修饰帮助细菌逃避宿主免疫反应，适应环境变化，并产生具有不同生物活性的改变的脂质 A 分子。尽管已经对几种脂质 A 生物合成和修饰酶进行了详细的结构分析，为结构辅助抑制剂的开发提供了丰富的信息，但其他建议还需要进一步表征，该提案重点关注转化 UDP 的必需脂质 A 生物合成酶的生化和结构研究。 -二酰基葡萄糖胺 (UDP-DAGn) 转化为 2,3-二酰基-GlcN-1-P（脂质 X）以及对细菌很重要的脂质 A 修饰酶 LpxE单磷酸化脂质 A (MPLA) 是一种广泛使用的免疫治疗剂，其毒力和产生有望对脂质 A 酶的结构和机制以及细菌外膜的生物发生和功能产生基础见解，并最终做出贡献。开发新疗法以改善人类健康。