A heme-dependent enzyme forms the hydrazine in the antibiotic negamycin

IF 12.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Menghua Wang, Zi-Wang Wei, Katherine S. Ryan
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引用次数: 0

Abstract

Negamycin, a hydrazine-containing dipeptide-like antibiotic, was first isolated in 1970 from three strains of Streptomyces purpeofuscus. Its pronounced antibacterial properties render it an appealing candidate for combating multi-drug-resistant Gram-negative bacteria. Additionally, the unique readthrough-promoting activity makes it a subject for research as a potential therapeutic agent for Duchenne muscular dystrophy and other hereditary diseases. Here we use the unusual (R)-β-lysine found in negamycin as a guide to identify the biosynthetic pathway of negamycin and then carry out gene deletion and chemical complementation, stable isotope feeding and enzyme assays to elucidate the key precursors for negamycin assembly. Our work identified NegB as a lysine-2,3-aminomutase that converts lysine into (R)-β-lysine and NegJ as a heme-dependent, N–N bond-forming enzyme. We show that NegJ, together with a ferredoxin encoded outside of the negamycin gene cluster, directly forms hydrazinoacetic acid from glycine and nitrite. NegJ is a novel biocatalyst for N–N bond formation, and our work highlights its potential for genome mining of N–N bond-containing natural products.

Abstract Image

一种依赖血红素的酶在抗生素负卡霉素中形成联氨
负霉素是一种含联氨的二肽类抗生素,于1970年首次从三株紫红链霉菌中分离出来。其显著的抗菌特性使其成为对抗多重耐药革兰氏阴性细菌的有吸引力的候选者。此外,其独特的促读活性使其成为杜氏肌营养不良症和其他遗传性疾病潜在治疗剂的研究对象。本研究以在负霉素中发现的不寻常的(R)-β-赖氨酸为指导,确定了负霉素的生物合成途径,然后通过基因缺失和化学互补、稳定同位素饲养和酶分析来阐明负霉素组装的关键前体。我们的研究发现,NegB是一种赖氨酸-2,3-氨基转氨酶,可将赖氨酸转化为(R)-β-赖氨酸,而NegJ是一种依赖血红素的N-N键形成酶。我们发现,NegJ与负霉素基因簇外编码的铁氧还蛋白一起,直接由甘氨酸和亚硝酸盐形成肼乙酸。NegJ是一种新型的N-N键形成生物催化剂,我们的工作强调了它在含有N-N键的天然产物的基因组挖掘中的潜力。
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来源期刊
Nature chemical biology
Nature chemical biology 生物-生化与分子生物学
CiteScore
23.90
自引率
1.40%
发文量
238
审稿时长
12 months
期刊介绍: Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.
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