The global anaerobic metabolism regulator fnr is necessary for the degradation of food dyes and drugs by Escherichia coli.
The global anaerobic metabolism regulator fnr is necessary for the degradation of food dyes and drugs by Escherichia coli.
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微生物组是肠道药物代谢的一个未被充分认识的贡献者，对药物疗效和毒性具有广泛的影响。虽然在确定肠道细菌基因和相关酶方面取得了相当大的进展，但环境因素在塑造其活性方面的作用仍然知之甚少。在这里，我们专注于肠道细菌还原偶氮键（R-N = N-R '），发现在不同的化学品在食品和药物。令人惊讶的是，大肠杆菌中的典型azoR基因被证明是偶氮键还原的。相反，偶氮还原酶活性由富马酸和硝酸盐还原（fnr）调节剂控制，与胃肠道内缺氧条件的要求一致。配对的转录组学和蛋白质组学分析的fnr调节子显示，除了改变多种还原酶的表达，FNR是必要的L-半胱氨酸代谢为硫化氢，使偶氮键的降解。此外，我们发现FNR通过小的非编码调节RNA fnrS间接调节这一过程。总之，这些结果显示了肠道细菌如何感知和响应其肠道环境，以使饮食和药物化合物中发现的化学基团代谢。这项工作具有广泛的相关性，因为在食品和药物中含有偶氮键的染料无处不在。我们报告说，偶氮染料可以降解人类肠道细菌通过酶和非酶机制，甚至从一个单一的肠道细菌物种。此外，我们还揭示了环境因素、氧和L-半胱氨酸控制E.由于偶氮染料对细菌转录和代谢的影响，大肠杆菌可以降解偶氮染料。这些结果开辟了通过操纵宿主饮食来操纵肠道微生物组的偶氮还原酶活性的新机会，表明偶氮还原酶的潜力可能在患有胃肠道疾病的患者中改变，并强调了研究细菌酶在其天然细胞和生态环境中用于药物代谢的重要性。
The microbiome is an underappreciated contributor to intestinal drug metabolism with broad implications for drug efficacy and toxicity. While considerable progress has been made toward identifying the gut bacterial genes and enzymes involved, the role of environmental factors in shaping their activity remains poorly understood. Here, we focus on the gut bacterial reduction of azo bonds (R-N = N-R’), found in diverse chemicals in both food and drugs. Surprisingly, the canonical azoR gene in Escherichia coli was dispensable for azo bond reduction. Instead, azoreductase activity was controlled by the fumarate and nitrate reduction (fnr) regulator, consistent with a requirement for the anoxic conditions found within the gastrointestinal tract. Paired transcriptomic and proteomic analysis of the fnr regulon revealed that in addition to altering the expression of multiple reductases, FNR is necessary for the metabolism of L-Cysteine to hydrogen sulfide, enabling the degradation of azo bonds. Furthermore, we found that FNR indirectly regulates this process through the small noncoding regulatory RNA fnrS. Taken together, these results show how gut bacteria sense and respond to their intestinal environment to enable the metabolism of chemical groups found in both dietary and pharmaceutical compounds. This work has broad relevance due to the ubiquity of dyes containing azo bonds in food and drugs. We report that azo dyes can be degraded by human gut bacteria through both enzymatic and nonenzymatic mechanisms, even from a single gut bacterial species. Furthermore, we revealed that environmental factors, oxygen, and L-Cysteine control the ability of E. coli to degrade azo dyes due to their impacts on bacterial transcription and metabolism. These results open up new opportunities to manipulate the azoreductase activity of the gut microbiome through the manipulation of host diet, suggest that azoreductase potential may be altered in patients suffering from gastrointestinal disease, and highlight the importance of studying bacterial enzymes for drug metabolism in their natural cellular and ecological context.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1007/698_2009_50
发表时间：
2010-01-01
期刊：
BIODEGRADATION OF AZO DYES
影响因子：
--
作者：
Bardi, Laura;Marzona, Mario
通讯作者：
Marzona, Mario
影响因子：
3.2
作者：
Blake, T;Barnard, A;Green, J
通讯作者：
Green, J
影响因子：
3.6
作者：
Durand, Sylvain;Storz, Gisela
通讯作者：
Storz, Gisela
影响因子：
1.6
作者：
Chen, HZ;Wang, RF;Cerniglia, CE
通讯作者：
Cerniglia, CE