Collagen Prolyl 4-Hydroxylase as a Therapeutic Target
Name
nihms-982603.pdf
Description
Accepted version
Size
711.44 KB
Format
Adobe PDF
Checksum (MD5)
71ddf5da824e462280ff33ad976c25b9
Author(s)
Vasta, James D.
Raines, Ronald T
Date Issued
July 9, 2018
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Citation
Vasta, James D. et al. "Collagen Prolyl 4-Hydroxylase as a Therapeutic Target." Journal of Medicinal Chemistry 61, 23 (December 13, 2018): 10403-10411 © 2018 American Chemical Society
Version
Author's final manuscript
Abstract
Collagen is the dominant protein of the extracellular matrix. Its distinguishing feature is a three-stranded helix of great tensile strength. (2S,4R)-4-Hydroxyproline residues are essential for the stability of this triple helix. These residues arise from the post-translational modification of (2S)-proline residues by collagen prolyl 4-hydroxylases (CP4Hs), which are members of the Fe(II)- and α-ketoglutarate (AKG)-dependent dioxygenase family. Here, we provide a framework for the inhibition of CP4Hs as the basis for treating fibrotic diseases and cancer metastasis. We begin with a summary of the structure and enzymatic reaction mechanism of CP4Hs. Then, we review the metal ions, metal chelators, mimetics of AKG and collagen strands, and natural products that are known to inhibit CP4Hs. Our focus is on inhibitors with potential utility in the clinic. We conclude with a prospectus for more effective inhibitors.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/acs.jmedchem.8b00822
