4.6 Article

A Fe2+-dependent self-inhibited state influences the druggability of human collagen lysyl hydroxylase (LH/PLOD) enzymes

期刊

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fmolb.2022.876352

关键词

collagen; lysyl hydroxylase (LH); Fe2+/2-oxoglutarate-dependent dioxygenases; structure-based drug design; molecular dynamics simulations; cancer metastasis; 2-2'-bipyridyl

资金

  1. Italian Association for Cancer Research (AIRC)
  2. Mizutani Foundation for Glycoscience [CDA2013]
  3. Fondazione Giovanni Armenise-Harvard [20075, 200039]
  4. Italian Ministry of Education, University and Research (MIUR): Dipartimenti di Eccellenza Program [9/2020]
  5. Marie Curie Individual Fellowship (MSCA-IF) from the European Union
  6. Regione Lombardia [3776/2020]
  7. [745934]

向作者/读者索取更多资源

Overexpression of LH/PLOD enzymes in the tumor microenvironment leads to abnormal accumulation of collagen post-translational modifications, which is correlated with increased metastatic progression of solid tumors. The chelating agent 2,2'-bipyridil unexpectedly enhances the enzymatic activity of LH by reducing the inhibitory effect of excess Fe2+. This finding provides new insights for drug discovery targeting LH/PLOD.
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.

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