6WB4

Microbiome-derived Acarbose Kinase Mak1 Labeled with selenomethionine

Summary for 6WB4

• Entry DOI: 10.2210/pdb6wb4/pdb
• Related PRD ID: PRD_900007
• Descriptor: Acarbose Kinase Mak1, 4,6-dideoxy-4-{[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl]amino}-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ADENOSINE-5'-TRIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: carbohydrate kinase, acarbose, transferase, nucleotide binding, atp binding, metal ion binding, ribokinase activity, complex
• Biological source: uncultured bacterium
• Total number of polymer chains: 2
• Total formula weight: 71643.28

Authors

Jeffrey, P.D.,Balaich, J.N.,Estrella, M.A.,Donia, M.S. (deposition date: 2020-03-26, release date: 2021-04-21, Last modification date: 2024-10-30)

Primary citation

Balaich, J.,Estrella, M.,Wu, G.,Jeffrey, P.D.,Biswas, A.,Zhao, L.,Korennykh, A.,Donia, M.S.
The human microbiome encodes resistance to the antidiabetic drug acarbose.
Nature, 600:110-115, 2021

PubMed Abstract: The human microbiome encodes a large repertoire of biochemical enzymes and pathways, most of which remain uncharacterized. Here, using a metagenomics-based search strategy, we discovered that bacterial members of the human gut and oral microbiome encode enzymes that selectively phosphorylate a clinically used antidiabetic drug, acarbose, resulting in its inactivation. Acarbose is an inhibitor of both human and bacterial α-glucosidases, limiting the ability of the target organism to metabolize complex carbohydrates. Using biochemical assays, X-ray crystallography and metagenomic analyses, we show that microbiome-derived acarbose kinases are specific for acarbose, provide their harbouring organism with a protective advantage against the activity of acarbose, and are widespread in the microbiomes of western and non-western human populations. These results provide an example of widespread microbiome resistance to a non-antibiotic drug, and suggest that acarbose resistance has disseminated in the human microbiome as a defensive strategy against a potential endogenous producer of a closely related molecule.

PubMed: 34819672
DOI: 10.1038/s41586-021-04091-0

Experimental method

X-RAY DIFFRACTION (2.593 Å)