三嗪霉素生物合成特征为 N-羟三嗪药效团。
Biosynthesis of triacsin featuring an N-hydroxytriazene pharmacophore.
机构信息
Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States.
Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
出版信息
Nat Chem Biol. 2021 Dec;17(12):1305-1313. doi: 10.1038/s41589-021-00895-3. Epub 2021 Nov 1.
Abstract
Triacsins are an intriguing class of specialized metabolites possessing a conserved N-hydroxytriazene moiety not found in any other known natural products. Triacsins are notable as potent acyl-CoA synthetase inhibitors in lipid metabolism, yet their biosynthesis has remained elusive. Through extensive mutagenesis and biochemical studies, we here report all enzymes required to construct and install the N-hydroxytriazene pharmacophore of triacsins. Two distinct ATP-dependent enzymes were revealed to catalyze the two consecutive N-N bond formation reactions, including a glycine-utilizing, hydrazine-forming enzyme (Tri28) and a nitrite-utilizing, N-nitrosating enzyme (Tri17). This study paves the way for future mechanistic interrogation and biocatalytic application of enzymes for N-N bond formation.
摘要
三嗪类化合物是一类具有独特生物活性的代谢产物，其结构中含有一个保守的 N-羟三嗪基团，这在其他任何已知天然产物中都未曾发现过。三嗪类化合物是脂质代谢中强效的酰基辅酶 A 合成酶抑制剂，但其生物合成途径一直不为人知。通过广泛的诱变和生化研究，我们在此报告了构建和安装三嗪类化合物 N-羟三嗪药效团所需的所有酶。研究揭示了两种截然不同的依赖于 ATP 的酶，它们催化两个连续的 N-N 键形成反应，包括一个利用甘氨酸、生成肼的酶（Tri28）和一个利用亚硝酸盐、进行 N-亚硝化的酶（Tri17）。这项研究为进一步探究酶在 N-N 键形成中的作用机制以及酶的生物催化应用铺平了道路。
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