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 硫代肽抗生素是一类新兴的天然产品，表现出强大的活性 抗药性，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 - 肺炎链球菌和万古霉素抗肠球菌的抗性链球菌。这些天然产品高度高 经过修饰的，富含硫的环状肽，具有含氮的中央六元环的不同 三或四取代的饱和度。其他修改包括多个噻唑或 恶唑环和脱氢氨基酸。这些抗生素是由前体肽产生的 合成核糖体，然后通过许多调整酶进行修饰。这些酶之一， NOSN是参与脱氧肽的生物合成的C rs甲基化酶，催化了甲基化的甲基化 3-甲基吲哚酸（MIA）分子的碳原子，该分子与硫代肽相连 框架。这种反应发生的机制尚不清楚，并且是很多重点 拟议的工作。另外，将MIA部分固定到硫代肽的时机 框架是未知的，将通过概括地点的生物合成来解决 体外硫代肽。