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

摘要 硫肽类抗生素是一类新兴的天然产物，具有强大的抗肿瘤活性。 耐药、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，具有不同的中心含氮六元环 三取代或四取代的饱和度。其他修改包括多个噻唑或 恶唑环和脱氢氨基酸。这些抗生素是由一种前体多肽产生的，这种多肽 核糖体合成，然后用一些剪裁酶修饰。其中一种酶， NOSN是一种参与诺西肽生物合成的C类RS甲基酶，催化诺西肽的甲基化。 3-甲基吲哚酸(MIA)分子中的一个碳原子，与硫肽结合 框架。这种反应发生的机制尚不清楚，也是许多研究的焦点。 拟议中的工作。此外，MIA部分连接到硫肽的时间 框架是未知的，将类似地通过概括 硫肽的体外实验。

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.