Biochemical and genomic evidence for converging metabolic routes of metformin and biguanide breakdown in environmental Pseudomonads.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Biological Chemistry Pub Date : 2024-10-28 DOI:10.1016/j.jbc.2024.107935
Katie B Wissbroecker, Anthony J Zmuda, Harsheeth Karumanchi, Thomas D Niehaus
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Abstract

Metformin is commonly used to lower blood glucose levels and is one of the most widely used pharmaceuticals worldwide. Typical doses are high (0.5-2.0 g day-1) and the majority travels through the digestive system unabsorbed and enters the wastewater system. Metformin isn't removed by standard wastewater treatments and eventually enters freshwater systems, where it can form N-chloro-derivatives that are toxic to fish and human cells. Thus, metformin is one of the most prevalent anthropogenic pollutants worldwide and there has been considerable interest in finding ways to remove it. We recently isolated Pseudomonads capable of growing on metformin as the sole nitrogen source. We identified candidate genes involved in metformin breakdown through genomic analyses informed by feeding studies. One candidate, a pair of genes that are located on ∼80kb extra-genomic plasmids, was shown to encode a heteromeric Ni-dependent hydrolase that converts metformin to guanylurea and dimethylamine. Metforminase activity of these gene products is now well established as our results confirm three recently published independent studies. Our isolated Pseudomonads also grow on biguanide, suggesting the existence of an additional breakdown enzyme. Another candidate gene located on the ∼80kb plasmids was shown to encode an aminohydrolase that converts biguanide to guanylurea. Biguanide may arise through successive N-demethylations of metformin or come from other sources. Our results suggest that the recent evolution of metforminase and biguanide hydrolase enzymes allow Pseudomonads to convert either metformin or biguanide to guanylurea, which can be assimilated by existing pathways.

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环境假单胞菌中二甲双胍和双胍分解代谢途径趋同的生化和基因组证据。
二甲双胍通常用于降低血糖水平,是全球使用最广泛的药物之一。二甲双胍的典型剂量较高(0.5-2.0 克/天-1),大部分会在未被吸收的情况下通过消化系统进入废水系统。二甲双胍不会被标准废水处理法去除,最终会进入淡水系统,在那里会形成对鱼类和人体细胞有毒的 N-氯衍生物。因此,二甲双胍是全球最普遍的人为污染物之一,人们对如何去除二甲双胍产生了浓厚的兴趣。我们最近分离出了能够以二甲双胍为唯一氮源生长的假单胞菌。我们通过喂养研究的基因组分析,确定了参与二甲双胍分解的候选基因。其中一个候选基因,即一对位于 ∼80kb 基因组外质粒上的基因,被证明编码一种异构的依赖 Ni- 的水解酶,可将二甲双胍转化为鸟苷脲和二甲胺。这些基因产物的二甲双胍酶活性现已得到证实,我们的研究结果证实了最近发表的三项独立研究。我们分离出的假单胞菌也能在双胍上生长,这表明还存在一种分解酶。位于 ∼80kb 质粒上的另一个候选基因被证明编码一种氨基水解酶,可将双胍转化为鸟苷酸。双胍可能是通过二甲双胍的连续 N-去甲基化产生的,也可能来自其他来源。我们的研究结果表明,二甲双胍酶和双胍水解酶的最新进化使假单胞菌能够将二甲双胍或双胍转化为鸟苷酸,而鸟苷酸可被现有途径同化。
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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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