Collagen Prolyl 4-Hydroxylase as a Therapeutic Target: Miniperspective
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
RETRACTED: Collagen Prolyl Hydroxylases Are Essential for Breast Cancer Metastasis
Gilkes, D. M., Chaturvedi, P., Bajpai, S., Wong, C. C., Wei, H., Pitcairn, S., Hubbi, M. E., Wirtz, D., & Semenza, G. L. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3963 · Cited by 296 · see citing works
RetractedMolecular Mechanisms of Stress-Responsive Changes in Collagen and Elastin Networks in Skin
Aziz, J., Shezali, H., Radzi, Z., Yahya, N. A., Abu Kassim, N. H., Czernuszka, J., & Rahman, M. T. (2016) · Skin Pharmacology and Physiology · doi:10.1159/000447017 · Cited by 7,323 · see citing works
Collagen Structure and Stability
Shoulders, M. D., & Raines, R. T. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.77.032207.120833 · Cited by 3,923 · see citing works
Self-citationCollagens—structure, function, and biosynthesis
Gelse, K. (2003) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2003.08.002 · Cited by 2,663 · see citing works
Collagens, modifying enzymes and their mutations in humans, flies and worms
Myllyharju, J. (2003) · Trends in Genetics · doi:10.1016/j.tig.2003.11.004 · Cited by 1,179 · see citing works
Chelation in Metal Intoxication
Flora, S. J. S., & Pachauri, V. (2010) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph7072745 · Cited by 1,023 · see citing works
Fe(II)/α-Ketoglutarate-Dependent Hydroxylases and Related Enzymes
Hausinger, R. P. (2004) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409230490440541 · Cited by 937 · see citing works
Therapy for Fibrotic Diseases: Nearing the Starting Line
Friedman, S. L., Sheppard, D., Duffield, J. S., & Violette, S. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3004700 · Cited by 655 · see citing works
Gorres, K. L., & Raines, R. T. (2010) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409231003627991 · Cited by 611 · see citing works
Self-citationSchweigert, N., Zehnder, A. J. B., & Eggen, R. I. L. (2001) · Environmental Microbiology · doi:10.1046/j.1462-2920.2001.00176.x · Cited by 596 · see citing works
Berg, R. A., & Prockop, D. J. (1973) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(73)90961-3 · Cited by 582 · see citing works
Stylianopoulos, T., Munn, L. L., & Jain, R. K. (2018) · Trends in cancer · doi:10.1016/j.trecan.2018.02.005 · Cited by 570 · see citing works
Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis
Myllyharju, J. (2003) · Matrix Biology · doi:10.1016/s0945-053x(03)00006-4 · Cited by 491 · see citing works
Conformational Stability of Collagen Relies on a Stereoelectronic Effect
Bretscher, L. E., Jenkins, C. L., Taylor, K. M., DeRider, M. L., & Raines, R. T. (2001) · Journal of the American Chemical Society · doi:10.1021/ja005542v · Cited by 463 · see citing works
Self-citationInhibition of 2-oxoglutarate dependent oxygenases
Rose, N. R., McDonough, M. A., King, O. N. F., Kawamura, A., & Schofield, C. J. (2011) · Chemical Society Reviews · doi:10.1039/c0cs00203h · Cited by 395 · see citing works
Prolyl 4-hydroxylases and their protein disulfide isomerase subunit
Kivirikko, K. I., & Myllyharju, J. (1998) · Matrix Biology · doi:10.1016/s0945-053x(98)90009-9 · Cited by 285 · see citing works
A stereochemical concept for the catalytic mechanism of prolylhydroxylase
Hanauske-Abel, H. M., & Günzler, V. (1982) · Journal of Theoretical Biology · doi:10.1016/0022-5193(82)90320-4 · Cited by 267 · see citing works
Myllyharju, J. (2008) · Annals of Medicine · doi:10.1080/07853890801986594 · Cited by 264 · see citing works
Mechanism of the Prolyl Hydroxylase Reaction: 2. Kinetic Analysis of the Reaction Sequence
MYLLYLÄ, R., TUDERMAN, L., & KIVIRIKKO, K. I. (1977) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1977.tb11889.x · Cited by 263 · see citing works
Myllylä, R., Majamaa, K., Günzler, V., Hanauske-Abel, H. M., & Kivirikko, K. I. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)91023-9 · Cited by 243 · see citing works
Narrative Review: Fibrotic Diseases: Cellular and Molecular Mechanisms and Novel Therapies
Rosenbloom, J., Castro, S. V., & Jimenez, S. A. (2010) · Annals of Internal Medicine · doi:10.7326/0003-4819-152-3-201002020-00007 · Cited by 225 · see citing works
Hydroxylation of Proline in Synthetic Polypeptides with Purified Protocollagen Hydroxylase
Kivirikko, K. I., & Prockop, D. J. (1967) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)95770-4 · Cited by 168 · see citing works
2-Oxoglutarate-Dependent Oxygenases
Hausinger, R. P., & Schofield, C. J. (2015) · Royal Society of Chemistry eBooks · doi:10.1039/9781782621959 · Cited by 167 · see citing works
The 2‐oxoglutarate binding site of prolyl 4‐hydroxylase
Majamaa, K., Hanauske-Abel, H. M., Günzler, V., & Kivirikko, K. I. (1984) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1984.tb07907.x · Cited by 137 · see citing works
Partial identity of the 2-oxoglutarate and ascorbate binding sites of prolyl 4-hydroxylase.
Majamaa, K., Günzler, V., Hanauske-Abel, H. M., Myllylä, R., & Kivirikko, K. I. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)57475-0 · Cited by 135 · see citing works
Esbona, K., Yi, Y., Saha, S., Yu, M., Doorn, R. R. V., Conklin, M. W., Graham, D., Wisinski, K. B., Ponik, S. M., Eliceiri, K. W., et al. (2018) · American Journal Of Pathology · doi:10.1016/j.ajpath.2017.10.025 · Cited by 125 · see citing works
Structural basis of homo- and heterotrimerization of collagen I
Sharma, U., Carrique, L., Goff, S. V., Mariano, N., Georges, R.-N., Delolme, F., Koivunen, P., Myllyharju, J., Moali, C., Aghajari, N., et al. (2017) · Nature Communications · doi:10.1038/ncomms14671 · Cited by 119 · see citing works
Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron
de Jong, L., Albracht, S. P. J., & Kemp, A. (1982) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/0167-4838(82)90162-5 · Cited by 111 · see citing works
Biosynthesis of collagen and its alterations in pathological states.
Kivirikko, K. I., & Risteli, L. (1976) · PubMed · Cited by 110 · see citing works
COPII-coated membranes function as transport carriers of intracellular procollagen I
Gorur, A., Yuan, L., Kenny, S. J., Baba, S., Xu, K., & Schekman, R. W. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201702135 · Cited by 99 · see citing works
Cunliffe, C. J., Franklin, T. J., Hales, N. J., & Hill, G. B. (1992) · Journal of Medicinal Chemistry · doi:10.1021/jm00092a016 · Cited by 94 · see citing works
Bland, K. I., Palin, W. E., von Fraunhofer, J. A., et al. (1984) · Annals of Surgery · doi:10.1097/00000658-198406000-00017 · Cited by 78 · see citing works
Determination of the chemical mechanism of glutamate dehydrogenase from pH studies
Rife, J. E., & Cleland, W. W. (1980) · Biochemistry · doi:10.1021/bi00552a008 · Cited by 76 · see citing works
Ueber die Hydrolyse des Caseins durch Salzsäure.
Fischer, E. (1901) · Hoppe-Seyler´s Zeitschrift für physiologische Chemie · doi:10.1515/bchm2.1901.33.1-2.151 · Cited by 76 · see citing works
Synthetic polypeptides as substrates and inhibitors of collagen proline hydroxylase
Hutton, J. J., Marglin, A., Witkop, B., et al. (1968) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(68)90514-6 · Cited by 75 · see citing works
Chaperoning osteogenesis: new protein-folding disease paradigms
Makareeva, E., Aviles, N. A., & Leikin, S. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.11.007 · Cited by 75 · see citing works
Majamaa, K., Turpeenniemi-Hujanen, T. M., Latipää, P. M., Günzler, V., Hanauske-Abel, H. M., Hassinen, I. E., & Kivirikko, K. I. (1985) · Biochemical Journal · doi:10.1042/bj2290127 · Cited by 74 · see citing works
The Kinetics of Pig Heart Triphosphopyridine Nucleotide-Isocitrate Dehydrogenase
Northrop, D. B., & Cleland, W. W. (1974) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)42720-8 · Cited by 71 · see citing works
[6] Recent developments in posttranslational modification: Intracellular processing
Kivirikko, K. I., & Myllylä, R. (1987) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(87)44175-x · Cited by 64 · see citing works
Prolyl hydroxylase, protein disulfide isomerase, and other structurally related proteins
Guzman, N. A. (1998) · M. Dekker eBooks · Cited by 62 · see citing works
Ueber eine neue Aminosäure aus Leim
Fischer, E. (1902) · Berichte der deutschen chemischen Gesellschaft · doi:10.1002/cber.19020350324 · Cited by 61 · see citing works
Prolyl 4-hydroxylase, a target enzyme for drug development
Hanauske-Abel, H. M. (1991) · Journal of Hepatology · doi:10.1016/0168-8278(91)90003-t · Cited by 60 · see citing works
Mapping and Exploring the Collagen-I Proteostasis Network
DiChiara, A. S., Taylor, R. J., Wong, M. Y., Doan, N., Rosario, A. M. D., & Shoulders, M. D. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b01083 · Cited by 59 · see citing works
Sheth, S. (2014) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000031 · Cited by 58 · see citing works
Sasaki, T., Holeyfield, K. C., & Uitto, J. (1987) · Journal of Clinical Investigation · doi:10.1172/jci113265 · Cited by 48 · see citing works
Zhou, J., Xu, G., Han, R., et al. (2016) · Catalysis Science & Technology · doi:10.1039/c6cy00922k · Cited by 47 · see citing works
Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells
Vasta, J. D., Andersen, K. A., Deck, K. M., Nizzi, C. P., Eisenstein, R. S., & Raines, R. T. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00749 · Cited by 41 · see citing works
Self-citationNovel inhibitors of prolyl 4-hydroxylase
Dowell, R. I., & Hadley, E. M. (1992) · Journal of Medicinal Chemistry · doi:10.1021/jm00083a001 · Cited by 40 · see citing works
Wang, J., Buss, J. L., Chen, G., Ponka, P., & Pantopoulos, K. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03389-6 · Cited by 40 · see citing works
Conformational Preferences of Substrates for Human Prolyl 4-Hydroxylase
Gorres, K. L., Edupuganti, R., Krow, G. R., & Raines, R. T. (2008) · Biochemistry · doi:10.1021/bi8009373 · Cited by 39 · see citing works
Self-citationAnantharajan, J., Koski, M. K., Kursula, P., Hieta, R., Bergmann, U., Myllyharju, J., & Wierenga, R. K. (2013) · Structure · doi:10.1016/j.str.2013.09.005 · Cited by 37 · see citing works
Hales, N. J., & Beattie, J. F. (1993) · Journal of Medicinal Chemistry · doi:10.1021/jm00076a014 · Cited by 35 · see citing works
Wu, M., Moon, H., Begley, T. P., Myllyharju, J., & Kivirikko, K. I. (1999) · Journal of the American Chemical Society · doi:10.1021/ja981193h · Cited by 35 · see citing works
Franklin, T. J., Morris, W. P., Edwards, P. N., et al. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3530333 · Cited by 35 · see citing works
Franklin, T. J., Morris, W. P., Edwards, P. N., et al. (2001) · Biochemical Journal · doi:10.1042/bj3530333 · Cited by 35 · see citing works
Syncatalytic inactivation of prolyl 4-hydroxylase by anthracyclines
Günzler, V., Hanauske-Abel, H. M., Myllylä, R., Kaska, D. D., Hanauske, A., & Kivirikko, K. I. (1988) · Biochemical Journal · doi:10.1042/bj2510365 · Cited by 34 · see citing works
Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center
Vasta, J. D., & Raines, R. T. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00251 · Cited by 32 · see citing works
Self-citationGünzler, V., Hanauske-Abel, H. M., Myllylä, R., Mohr, J., & Kivirikko, K. I. (1987) · Biochemical Journal · doi:10.1042/bj2420163 · Cited by 28 · see citing works
Günzler, V., Brocks, D. G., Henke, S., Myllylä, R., Geiger, R., & Kivirikko, K. I. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)77662-5 · Cited by 26 · see citing works
Can Collagen Metabolism Be Controlled
COHEN, I. K. (1985) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/00005373-198505000-00006 · Cited by 26 · see citing works
Koski, M. K., Anantharajan, J., Kursula, P., Dhavala, P., Murthy, A. V., Bergmann, U., Myllyharju, J., & Wierenga, R. K. (2017) · Biochemical Journal · doi:10.1042/bcj20161000 · Cited by 24 · see citing works
Approaches to the design of anti-fibrotic drugs
Franklin, T. J., Hales, N. J., Johnstone, D., et al. (1991) · Biochemical Society Transactions · doi:10.1042/bst0190812 · Cited by 22 · see citing works
Inhibition of collagen synthesis by α, α′-dipyridyl in human skin fibroblasts in culture
Switzer, B. R., & Summer, G. K. (1973) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02618433 · Cited by 21 · see citing works
Dowell, R., Hales, N., & Tucker, H. (1993) · European Journal of Medicinal Chemistry · doi:10.1016/0223-5234(93)90019-b · Cited by 21 · see citing works
Karvonen, K. E., Ala‐Kokko, L., Pihlajaniemi, T. A., Helaakoski, T., Henke, S., Günzler, V., Kivirikko, K. I., & Savolainen, E. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)38903-3 · Cited by 19 · see citing works
Direct and continuous assay for prolyl 4-hydroxylase
Gorres, K. L., & Raines, R. T. (2008) · Analytical Biochemistry · doi:10.1016/j.ab.2008.11.046 · Cited by 19 · see citing works
Self-citationWong, M. Y., Doan, N. D., DiChiara, A. S., Papa, L. J., Cheah, J. H., Soule, C. K., Watson, N., Hulleman, J. D., & Shoulders, M. D. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00378 · Cited by 19 · see citing works
Vasta, J. D., Choudhary, A., Jensen, K. H., et al. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00976 · Cited by 16 · see citing works
Self-citationSelective inhibition of prolyl 4-hydroxylases by bipyridinedicarboxylates
Vasta, J. D., & Raines, R. T. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2015.05.003 · Cited by 15 · see citing works
Self-citationBioavailable affinity label for collagen prolyl 4-hydroxylase
Vasta, J. D., Higgin, J. J., Kersteen, E. A., & Raines, R. T. (2013) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2013.04.057 · Cited by 7 · see citing works
Self-citationEffect of alpha alpha dipyridyl on collagen synthesis in healing wounds.
Tc, W., & Peacock, E. E. (1969) · PubMed · Cited by 6 · see citing works
Über die Hydrolyse des Caseïns durch Salzsäure
Fischer, E. (1906) · Springer eBooks · doi:10.1007/978-3-642-99499-9_45 · Cited by 3 · see citing works
Rapaka, R. S., Dw, U., Rk, R., et al. (1978) · PubMed · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The role of collagen in cancer: from bench to bedside
Xu, S., Xu, H., Wang, W., Li, S., Li, H., Li, T., Zhang, W., Yu, X., & Liu, L. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-2058-1 · Cited by 735 · see citing works
Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination
Doseděl, M., Jirkovský, E., Macáková, K., Krčmová, L., Javorská, L., Pourová, J., Mercolini, L., Remião, F., Nováková, L., Mladěnka, P., et al. (2021) · Nutrients · doi:10.3390/nu13020615 · Cited by 553 · see citing works
- 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
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-07-09
- Volume
- 61
- Issue
- 23
- Pages
- 10403-10411
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC6344319
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review