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The l-Alanosine Gene Cluster Encodes a Pathway for Diazeniumdiolate Biosynthesis.
ChemBioChem ( IF 2.6 ) Pub Date : 2019-12-19 , DOI: 10.1002/cbic.201900565
Tai L Ng 1 , Monica E McCallum 1 , Christine R Zheng 1 , Jennifer X Wang 2 , Kelvin J Y Wu 1 , Emily P Balskus 1
Affiliation  

N-Nitroso-containing natural products are bioactive metabolites with antibacterial and anticancer properties. In particular, compounds containing the diazeniumdiolate (N-nitrosohydroxylamine) group display a wide range of bioactivities ranging from cytotoxicity to metal chelation. Despite the importance of this structural motif, knowledge of its biosynthesis is limited. Herein we describe the discovery of a biosynthetic gene cluster in Streptomyces alanosinicus ATCC 15710 responsible for producing the diazeniumdiolate natural product l-alanosine. Gene disruption and stable isotope feeding experiments identified essential biosynthetic genes and revealed the source of the N-nitroso group. Additional biochemical characterization of the biosynthetic enzymes revealed that the non-proteinogenic amino acid l-2,3-diaminopropionic acid (l-Dap) is synthesized and loaded onto a free-standing peptidyl carrier protein (PCP) domain in l-alanosine biosynthesis, which we propose may be a mechanism of handling unstable intermediates generated en route to the diazeniumdiolate. These discoveries will facilitate efforts to determine the biochemistry of diazeniumdiolate formation.

中文翻译:

l-Alanosine基因簇编码二醇二氮烯鎓生物合成的途径。

含N-亚硝基的天然产物是具有抗菌和抗癌特性的生物活性代谢产物。尤其是,包含二醇二氮烯鎓(N-亚硝基羟胺)基团的化合物表现出从细胞毒性到金属螯合的广泛生物活性。尽管该结构基序很重要,但对其生物合成的了解仍然有限。在本文中,我们描述了在负责生产二醇二氮烯二酸酯天然产物1-丙氨酸的丙氨酸链霉菌ATCC 15710中生物合成基因簇的发现。基因破坏和稳定的同位素饲喂实验确定了必不可少的生物合成基因,并揭示了N-亚硝基基团的来源。生物合成酶的其他生化特性表明,非蛋白原氨基酸1-2 合成3-二氨基丙酸(1-Dap)并将其加载到I-丙氨酸生物合成中的独立式肽基载体蛋白(PCP)结构域中,我们提出这可能是处理在生成二氮杂二氮烯酸途中生成的不稳定中间体的机制。这些发现将有助于确定二醇二氮烯鎓盐形成的生物化学的努力。
更新日期:2019-12-19
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