Cited by 82Collagen: Extraction and CharacterizationProtease and Inhibitor MechanismsMetal-Catalyzed Oxygenation Mechanisms

Collagen Prolyl 4-Hydroxylase as a Therapeutic Target: Miniperspective

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Vasta, James D., Raines, Ronald T.·2018·Journal of Medicinal Chemistry

Abstract

Collagen is the dominant protein of the extracellular matrix. Its distinguishing feature is a three-stranded helix of great tensile strength. (2 S,4 R)-4-Hydroxyproline residues are essential for the stability of this triple helix. These residues arise from the post-translational modification of (2 S)-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.

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Crossref · 10.1021/acs.jmedchem.8b00822

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Authors
Vasta, J. D., & Raines, R. T.
Affiliations
  • University of Wisconsin–Madison (US)
  • Massachusetts Institute of Technology (US)
Corresponding author
Raines, Ronald T.
Venue
Journal of Medicinal Chemistry
Published
2018-07-09
Volume
61
Issue
23
Pages
10403-10411
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
OpenAlex
W2869462691
Cited by
82
References
73
Citations by year
2026: 11 · 2025: 16 · 2024: 8 · 2023: 10 · 2022: 9 · 2021: 13 · 2020: 8 · 2019: 5 · 2018: 2
FWCI
0.46
Type
journal article
Language
en
Open access
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders
  • University of Wisconsin-Madison
  • National Institutes of Health (AR044276)
  • National Institute of General Medical Sciences (T32GM007215)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR044276)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Collagen: Extraction and Characterization
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Keywords
collagen prolyl 4-hydroxylase, 4-hydroxyproline, collagen triple helix, extracellular matrix, fibrotic diseases, metastasis, Fe(II)/α-ketoglutarate-dependent dioxygenase, enzyme inhibition, metal chelators, natural products, enzyme structure and mechanism
MeSH terms
Animals, Collagen, Humans, Molecular Targeted Therapy, Prolyl-Hydroxylase Inhibitors, Prolyl Hydroxylases

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