Department of Chemistry, North Carolina State University, 2620 Yarbrough Drive, Raleigh, NC, 27695, USA.
Graduate School of Chemical Sciences and Engineering, Hokkaido University, N13W8, Kita-ku, Sapporo, Hokkaido, 060-8628, Japan.
Angew Chem Int Ed Engl. 2022 Feb 7;61(7):e202113189. doi: 10.1002/anie.202113189. Epub 2021 Dec 27.
Hormaomycins and belactosins are peptide natural products that contain unusual cyclopropane moieties. Bioinformatics analysis of the corresponding biosynthetic gene clusters showed that two conserved genes, hrmI/belK and hrmJ/belL, were potential candidates for catalyzing cyclopropanation. Using in vivo and in vitro assays, the functions of HrmI/BelK and HrmJ/BelL were established. HrmI and BelK, which are heme oxygenase-like dinuclear iron enzymes, catalyze oxidation of the ϵ-amino group of l-lysine to afford l-6-nitronorleucine. Subsequently, HrmJ and BelL, which are iron- and α-ketoglutarate-dependent oxygenases, effectively convert l-6-nitronorleucine into 3-(trans-2-nitrocyclopropyl)-alanine through C4-C6 bond installation. These observations disclose a novel pathway of cyclopropane ring construction and exemplify the new chemistry involving metalloenzymes in natural product biosynthesis.
霍马霉素和贝拉妥菌素是含有不寻常环丙烷部分的肽类天然产物。相应生物合成基因簇的生物信息学分析表明，两个保守基因 hrmI/belK 和 hrmJ/belL 是催化环丙烷化的潜在候选基因。通过体内和体外测定，确定了 HrmI/BelK 和 HrmJ/BelL 的功能。HrmI 和 BelK 是血红素加氧酶样双核铁酶，催化 l-赖氨酸的 ε-氨基氧化生成 l-6-硝基正亮氨酸。随后，HrmJ 和 BelL 是铁和 α-酮戊二酸依赖性加氧酶，通过 C4-C6 键安装有效地将 l-6-硝基正亮氨酸转化为 3-(反式-2-硝基环丙基）-丙氨酸。这些观察结果揭示了一种新的环丙烷环构建途径，并例证了涉及金属酶的天然产物生物合成中的新化学。
