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首页> 外文期刊>Acta crystallographica. Section D, Structural biology >Structural basis for the transformation of the traditional medicine berberine by bacterial nitroreductase
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Structural basis for the transformation of the traditional medicine berberine by bacterial nitroreductase

机译：细菌硝基还原酶转化传统药物小檗碱的结构基础

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The bacterial nitroreductases (NRs) NfsB and NfsA are conserved homodimeric FMN-dependent flavoproteins that are responsible for the reduction of nitroaromatic substrates. Berberine (BBR) is a plant-derived isoquinoline alkaloid with a large conjugated ring system that is widely used in the treatment of various diseases. It was recently found that the gut microbiota convert BBR into dihydroberberine (dhBBR, the absorbable form) mediated by bacterial NRs. The molecular basis for the transformation of BBR by the gut microbiota remains unclear. Here, kinetic studies showed that NfsB from Escherichia coli (EcNfsB), rather than EcNfsA, is responsible for the conversion of BBR to dhBBR in spite of a low reaction rate. The crystal structure of the EcNfsB-BBR complex showed that BBR binds into the active pocket at the dimer interface, and its large conjugated plane stacks above the plane of the FMN cofactor in a nearly parallel orientation. BBR is mainly stabilized by pi-stacking interactions with both neighboring aromatic residues and FMN. Structure-based mutagenesis studies further revealed that the highly conserved Phe70 and Phe199 are important residues for the conversion of BBR. The structure revealed that the C6 atom of BBR (which receives the hydride) is similar to 7.5 angstrom from the N5 atom of FMN (which donates the hydride), which is too distant for hydride transfer. Notably, several well ordered water molecules make hydrogen-bond/van der Waals contacts with the N1 atom of BBR in the active site, which probably donate protons in conjunction with electron transfer from FMN. The structure-function studies revealed the mechanism for the recognition and binding of BBR by bacterial NRs and may help to understand the conversion of BBR by the gut microbiota.
机译：细菌硝基还原酶(NRs) NfsB NfsA是守恒的homodimeric FMN-dependent黄素蛋白负责减少硝基芳香化合物基质。(BBR)是一种植物的异喹啉生物碱有一个很大的共轭环系统广泛应用于各种疾病的治疗。最近发现肠道微生物群可吸收的形式)由细菌的关系。BBR的转换的分子基础肠道微生物群仍不清楚。研究表明,NfsB从大肠杆菌(EcNfsB),而不是EcNfsA负责转换的BBR dhBBR尽管低反应速率。EcNfsB-BBR复杂表明BBR绑定到活性口袋的二聚体界面,和它的大共轭平面栈的平面之上近平行的FMN代数余子式取向。pi-stacking与邻近的交互芳香残留物和FMN。诱变的研究进一步揭示了高度保守的Phe70和Phe199是很重要的残留的BBR的转换。显示的C6原子BBR(接收氢化物)类似于7.5埃它们的原子FMN氢化(捐赠)太遥远了,氢化物转移。几个好下令水分子形成氢键或范德华接触N1BBR原子的活性位点,可能质子与电子捐款从FMN转移。识别和披露机制绑定的BBR细菌NRs和可能帮助理解BBR通过肠道的转换微生物群。

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