Understanding the Biosynthesis of the 2,4-Dimethylindolic Acid Moiety in the Thiopeptide Antibiotic Nosiheptide

了解硫肽抗生素那西肽中 2,4-二甲基吲哚酸部分的生物合成

• 批准号: 9375024
• 负责人: SQUIRE J. BOOKER
• 金额: $ 18.9万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-18 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375024
• 关键词: Acids; Acyl Carrier Protein; Address; Amino Acids; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Biochemical; Carbon; Clinical; Complex; Crystallization; Cyclic Peptides; Drug resistance; Engineering; Enzymes; Esters; Exhibits; Future; Gastrointestinal tract structure; Genes; Goals; Gram-Positive Bacteria; Human; Hybrids; In Vitro; Measures; Methylation; Methyltransferase; Mind-Body Method; Modification; Natural Products; Nitrogen; Oxazoles; Pathway interactions; Penicillin Resistance; Peptides; Pharmacology; Property; Proteins; Reaction; Resolution; Ribosomes; Roentgen Rays; Role; Serine; Solubility; Streptococcus pneumoniae; Structure; Sulfur; Thiazoles; Thiostrepton; Tryptophan; Vancomycin resistant enterococcus; Work; aqueous; carbene; combat; functional group; improved; interest; methicillin resistant Staphylococcus aureus; methyl group; pathogen; protein structure; quinaldic acid; siomycin A; small molecule; sound; spectroscopic survey; thioester

Abstract The thiopeptide antibiotics are an emerging class of natural products that exhibit formidable activity against drug resistant, Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, penicillin- resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci. These natural products are highly modified, sulfur-rich, cyclic peptides that feature a central nitrogen-containing six-membered ring of differing degrees of saturation that is tri- or tetra-substituted. Additional modifications include multiple thiazole or oxazole rings, and dehydro-amino acids. These antibiotics are generated from a precursor peptide that is synthesized ribosomally and then modified by a number of tailoring enzymes. One of these enzymes, NosN, a Class C RS methylase involved in the biosynthesis of nosiheptide, catalyzes the methylation of a carbon atom of a 3-methylindolic acid (MIA) molecule that becomes attached to the thiopeptide framework. The mechanism by which this reaction takes place is unknown, and is the focus of much of the proposed work. Additionally, the timing of attachment of the MIA moiety to the thiopeptide framework is unknown and will be similarly addressed by recapitulating the biosynthesis of the thiopeptide in vitro.

抽象的 硫肽抗生素是一类新兴的天然产物，具有强大的抗细菌活性。 耐药的革兰氏阳性病原体，包括耐甲氧西林金黄色葡萄球菌、青霉素 耐药肺炎链球菌和耐万古霉素肠球菌。这些天然产品具有很高的 修饰的、富含硫的环肽，具有不同的中心含氮六元环 三取代或四取代的饱和度。其他修饰包括多个噻唑或 恶唑环和脱氢氨基酸。这些抗生素是由前体肽产生的，该前体肽是 核糖体合成，然后被许多剪裁酶修饰。其中一种酶， NosN 是一种 C 类 RS 甲基化酶，参与那西肽的生物合成，催化 3-甲基吲哚酸 (MIA) 分子的碳原子与硫肽相连 框架。该反应发生的机制尚不清楚，并且是许多研究的焦点 拟议的工作。此外，MIA 部分与硫肽连接的时间 框架是未知的，将通过重述生物合成来类似地解决 硫肽体外。