Discovery of a non-canonical prototype long-chain monoacylglycerol lipase through a structure-based endogenous reaction intermediate complex

Nikos Pinotsis, Anna Krüger, Nicolas Tomas, Spyros D. Chatziefthymiou, Claudia Litz, Simon Arnold Mortensen, Mamadou Daffé, Hedia Marrakchi, Garabed Antranikian and Matthias Wilmanns ()
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Nikos Pinotsis: European Molecular Biology Laboratory, Hamburg Unit
Anna Krüger: Hamburg University of Technology
Nicolas Tomas: Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier
Spyros D. Chatziefthymiou: European Molecular Biology Laboratory, Hamburg Unit
Claudia Litz: European Molecular Biology Laboratory, Hamburg Unit
Simon Arnold Mortensen: European Molecular Biology Laboratory, Hamburg Unit
Mamadou Daffé: Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier
Hedia Marrakchi: Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier
Garabed Antranikian: Hamburg University of Technology
Matthias Wilmanns: European Molecular Biology Laboratory, Hamburg Unit

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The identification and characterization of enzyme function is largely lacking behind the rapidly increasing availability of large numbers of sequences and associated high-resolution structures. This is often hampered by lack of knowledge on in vivo relevant substrates. Here, we present a case study of a high-resolution structure of an unusual orphan lipase in complex with an endogenous C18 monoacylglycerol ester reaction intermediate from the expression host, which is insoluble under aqueous conditions and thus not accessible for studies in solution. The data allowed its functional characterization as a prototypic long-chain monoacylglycerol lipase, which uses a minimal lid domain to position the substrate through a hydrophobic tunnel directly to the enzyme’s active site. Knowledge about the molecular details of the substrate binding site allowed us to modulate the enzymatic activity by adjusting protein/substrate interactions, demonstrating the potential of our findings for future biotechnology applications.

Date: 2023
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DOI: 10.1038/s41467-023-43354-4

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