Discovery of a Ni2+-dependent heterohexameric metformin hydrolase

Tao Li, Zhi-Jing Xu, Shu-Ting Zhang, Jia Xu, Piaopiao Pan and Ning-Yi Zhou ()
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Tao Li: Shanghai Jiao Tong University
Zhi-Jing Xu: Shanghai Jiao Tong University
Shu-Ting Zhang: Shanghai Jiao Tong University
Jia Xu: Shanghai Jiao Tong University
Piaopiao Pan: Shanghai Jiao Tong University
Ning-Yi Zhou: Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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 Ni2+-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.

Date: 2024
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DOI: 10.1038/s41467-024-50409-7

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