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Cited by 13Pharmaceutical and Antibiotic Environmental ImpactsEnzyme Structure and FunctionEnzyme Catalysis and Immobilization

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Discovery of a Ni2+-dependent heterohexameric metformin hydrolase

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Li, Tao, Xu, Zhi-Jing, Zhang, Shu-Ting, Xu, Jia, Pan, Piaopiao, Zhou, Ning-Yi·2024·Nature Communications
DOI 10.1038/s41467-024-50409-7PMC PMC11271267

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Abstract

The biguanide drug metformin is a first-line blood glucose-lowering medication for type 2 diabetes, leading to its presence in the global environment. However, little is known about the fate of metformin by microbial catabolism. Here, we characterize a Ni 2+ -dependent heterohexameric enzyme (MetCaCb) from the ureohydrolase superfamily, catalyzing the hydrolysis of metformin into guanylurea and dimethylamine. Either subunit alone is catalytically inactive, but together they work as an active enzyme highly specific for metformin. The crystal structure of the MetCaCb complex shows the coordination of the binuclear metal cluster only in MetCa, with MetCb as a protein binder of its active cognate. An in-silico search and functional assay discover a group of MetCaCb-like protein pairs exhibiting metformin hydrolase activity in the environment. Our findings not only establish the genetic and biochemical foundation for metformin catabolism but also provide additional insights into the adaption of the ancient enzymes toward newly occurred substrate.

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Metadata

Authors
Li, T., Xu, Z.-J., Zhang, S.-T., Xu, J., Pan, P., & Zhou, N.-Y.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
Zhou, Ning-Yi
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-07-20
Volume
15
Issue
1
Pages
6121-6121
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-50409-7
PMC
PMC11271267
OpenAlex
W4400842703
Cited by
13
References
2
Citations by year
2026: 4 · 2025: 5 · 2024: 4
FWCI
1.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (32230001)
Topics
  • Physical Sciences › Environmental Science › Pollution › Pharmaceutical and Antibiotic Environmental Impacts
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
Keywords
metformin, nickel-dependent enzymes, guanylurea, dimethylamine, type 2 diabetes drugs, environmental fate of pharmaceuticals, enzyme evolution, crystal structure
MeSH terms
Bacterial Proteins, Hydrolases, Hydrolysis, Metformin, Models, Molecular, Nickel, Substrate Specificity, Crystallography, X-Ray

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