A Fe2+-dependent self-inhibited state influences the druggability of human collagen lysyl hydroxylase (LH/PLOD) enzymes
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Published:2022-08-25
Issue:
Volume:9
Page:
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ISSN:2296-889X
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Container-title:Frontiers in Molecular Biosciences
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language:
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Short-container-title:Front. Mol. Biosci.
Author:
Scietti Luigi,Moroni Elisabetta,Mattoteia Daiana,Fumagalli Marco,De Marco Matteo,Negro Lisa,Chiapparino Antonella,Serapian Stefano A.,De Giorgi Francesca,Faravelli Silvia,Colombo Giorgio,Forneris Federico
Abstract
Multifunctional human collagen lysyl hydroxylase (LH/PLOD) enzymes catalyze post-translational hydroxylation and subsequent glycosylation of collagens, enabling their maturation and supramolecular organization in the extracellular matrix (ECM). Recently, the overexpression of LH/PLODs in the tumor microenvironment results in abnormal accumulation of these collagen post-translational modifications, which has been correlated with increased metastatic progression of a wide variety of solid tumors. These observations make LH/PLODs excellent candidates for prospective treatment of aggressive cancers. The recent years have witnessed significant research efforts to facilitate drug discovery on LH/PLODs, including molecular structure characterizations and development of reliable high-throughput enzymatic assays. Using a combination of biochemistry and in silico studies, we characterized the dual role of Fe2+ as simultaneous cofactor and inhibitor of lysyl hydroxylase activity and studied the effect of a promiscuous Fe2+ chelating agent, 2,2’-bipyridil, broadly considered a lysyl hydroxylase inhibitor. We found that at low concentrations, 2,2’-bipyridil unexpectedly enhances the LH enzymatic activity by reducing the inhibitory effect of excess Fe2+. Together, our results show a fine balance between Fe2+-dependent enzymatic activity and Fe2+-induced self-inhibited states, highlighting exquisite differences between LH/PLODs and related Fe2+, 2-oxoglutarate dioxygenases and suggesting that conventional structure-based approaches may not be suited for successful inhibitor development. These insights address outstanding questions regarding druggability of LH/PLOD lysyl hydroxylase catalytic site and provide a solid ground for upcoming drug discovery and screening campaigns.
Funder
Giovanni Armenise-Harvard Foundation
Associazione Italiana per la Ricerca Sul Cancro
Mizutani Foundation for Glycoscience
Ministero Dell’Istruzione, dell’Università e Della Ricerca
European Commission
Publisher
Frontiers Media SA
Subject
Biochemistry, Genetics and Molecular Biology (miscellaneous),Molecular Biology,Biochemistry
Cited by
1 articles.
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