Two-Enzyme Pathway Links L-Arginine to Nitric Oxide in N-Nitroso Biosynthesis
Two-Enzyme Pathway Links L-Arginine to Nitric Oxide in N-Nitroso Biosynthesis
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DOI：
10.1021/jacs.8b13049
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发表时间：
2019-03-06
影响因子：
15
通讯作者：
Ryan, Katherine S.
中科院分区：
文献类型：
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作者：
He, Hai-Yan;Henderson, Alyssa C.;Ryan, Katherine S.
一氧化氮（NO）在生物学中具有广泛的作用，但对其在构建化学多样性中的作用知之甚少。在这里，我们报告了一个新的途径NO从生物合成途径的N-亚硝基化合物链佐星。我们表明，链脲霉素的N-亚硝基来自L-精氨酸的生物合成重组，胍基氮形成氮-氮键。为了理解这个生物合成过程，我们确定了链脲佐菌素的生物合成基因簇，并证明了游离L-精氨酸是N-甲基化的StzE给N-ω-单甲基-L-精氨酸。我们表明，该产品然后被氧化的StzF，一种非血红素铁依赖性酶无关的已知的一氧化氮合酶，产生尿素化合物和NO。我们的工作意味着，NO的形成和捕获是可能的途径N-亚硝基形成在体内。总之，我们的工作揭示了一种新的酶对从L-精氨酸生产NO，并为了解N-亚硝基天然产物的生物合成途径奠定了基础。
Nitric oxide (NO) has wide-ranging roles in biology, but less is known about its role in building chemical diversity. Here we report a new route to NO from the biosynthetic pathway to the N-nitroso compound streptozocin. We show that the N-nitroso group of streptozocin comes from the biosynthetic reassembly of L-arginine, with the guanidino nitrogens forming a nitrogen-nitrogen bond. To understand this biosynthetic process, we identify the biosynthetic gene cluster of streptozocin and demonstrate that free L-arginine is N-methylated by StzE to give N-omega-monomethyl-L-arginine. We show that this product is then oxidized by StzF, a nonheme iron-dependent enzyme unrelated to known nitric oxide synthases, generating a urea compound and NO. Our work implies that formation and capture of NO is the likely route to N-nitroso formation in vivo. Altogether, our work unveils a new enzyme pair for the production of NO from L-arginine and sets the stage for understanding biosynthetic routes to N-nitroso natural products.