Katie B Wissbroecker, Anthony J Zmuda, Harsheeth Karumanchi, Thomas D Niehaus
{"title":"Biochemical and genomic evidence for converging metabolic routes of metformin and biguanide breakdown in environmental Pseudomonads.","authors":"Katie B Wissbroecker, Anthony J Zmuda, Harsheeth Karumanchi, Thomas D Niehaus","doi":"10.1016/j.jbc.2024.107935","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>-1</sup>) 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.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biological Chemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.jbc.2024.107935","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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.