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.

摘要 硫肽类抗生素是一类新兴的天然产物， 耐药性革兰氏阳性病原体，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、富硫的环肽，其特征在于中心含氮的六元环具有不同的 三或四取代的饱和度。另外的修饰包括多个噻唑或 唑环和脱氢氨基酸。这些抗生素是由一种前体肽产生的， 在核糖体中合成，然后被许多裁剪酶修饰。其中一种酶， NosN是一种参与那西肽生物合成的C类RS甲基化酶， 3-甲基吲哚酸（MIA）分子的碳原子，与硫肽连接 框架.这种反应发生的机制尚不清楚，也是许多研究的焦点。 的拟议工作。另外，MIA部分与硫肽的连接的时机也是确定的。 框架是未知的，并将通过重述的生物合成类似地解决， 体外硫肽。