The DOI matches its Crossref record; 335 of the 335 references it cites were found in a registry or an index.
Fe(II)/α-Ketoglutarate-Dependent Hydroxylases and Related Enzymes
Abstract
FeII/alpha-ketoglutarate (alphaKG)-dependent hydroxylases catalyze an amazing diversity of reactions that result in protein side-chain modifications, repair of alkylated DNA/RNA, biosynthesis of antibiotics and plant products, metabolism related to lipids, and biodegradation of a variety of compounds. These enzymes possess a beta-strand "jellyroll" structural fold that contains three metal-binding ligands found in a His1-X-Asp/Glu-Xn-His2 motif. The cosubstrate, alphaKG, chelates FeII using its C-2 keto group (binding opposite the Asp/Glu residue) and C-1 carboxylate (coordinating opposite either His1 or His2). Oxidative decomposition of alphaKG forms CO2 plus succinate and leads to the generation of an FeIV-oxo or other activated oxygen species that hydroxylate the primary substrate. The reactive oxygen species displays alternate reactivity in related enzymes that catalyze desaturations, ring expansions, or ring closures. Other enzymes resemble the FeII/alphaKG-dependent hydroxylases in terms of protein structure or chemical mechanism but do not utilize alphaKG as a substrate. This review describes the reactions catalyzed by this superfamily of enzymes, highlights key active site features revealed by structural studies, and summarizes results from spectroscopic and other approaches that provide insights into the chemical mechanisms.
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“Given that more than forty αKGDDs exist112, it is possible that other αKGDDs could contribute to the anticancer mechanisms of ascorbate.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [112]
In the citing paper
“Given that more than forty αKGDDs exist112, it is possible that other αKGDDs could contribute to the anticancer mechanisms of ascorbate.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [112]
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Cites
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HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
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“A prolyl 4-hydroxylase plays a key role in targeting HIFα for degradation on the basis of evidence indicating that Pro 564 of HIFα is hydroxylated in an oxygen-, Fe(II)-, and αKG-dependent reaction (Ivan et al., 2001; Jaakkola et al., 2001).”
BackgroundEpstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333
A conserved family of prolyl-4-hydroxylases that modify HIF
Bruick, R. K., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1066373 · Cited by 2,549
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Geometric and Electronic Structure/Function Correlations in Non-Heme Iron Enzymes
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Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
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Cited by
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Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012) · Genes & Development · doi:10.1101/gad.191056.112 · Cited by 1,188
“The DNA amount used for dot blot analysis was determined by methylene blue staining (Supplemental Fig.”
BackgroundInfluentialWhat a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570
2-Oxoglutarate-Dependent Oxygenases
Islam, M. S., Leissing, T. M., Chowdhury, R., Hopkinson, R. J., & Schofield, C. J. (2018) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044724 · Cited by 472
Targeting cancer vulnerabilities with high-dose vitamin C
Ngo, B., Van Riper, J. M., Cantley, L. C., & Yun, J. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0135-7 · Cited by 423
Chemical mechanisms of histone lysine and arginine modifications
Smith, B. C., & Denu, J. M. (2009) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2008.06.005 · Cited by 390
Metadata
- Authors
- Hausinger, R. P.
- Affiliations
- Michigan State University (US)
- Corresponding author
- Hausinger, Robert P.
- ORCID
- Hausinger, Robert P.
- Venue
- Critical Reviews in Biochemistry and Molecular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-01
- Volume
- 39
- Issue
- 1
- Pages
- 21-68
- ISSN
- 0045-6411 (ISSN-L)
- 1040-9238
- 1549-7798
- OpenAlex
- W2128586767
- Cited by
- 937
- References
- 335
- Citations by year
- 2026: 37 · 2025: 27 · 2024: 42 · 2023: 34 · 2022: 41 · 2021: 56 · 2020: 45 · 2019: 44 · 2018: 43 · 2017: 44 · 2016: 44 · 2015: 67 · 2014: 60 · 2013: 48 · 2012: 48
- FWCI
- 25.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Critical Reviews in Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM063584, R01GM063584)
- Topics
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- alpha-ketoglutarate, reactive oxygen species, DNA repair, alkylated DNA, antibiotic biosynthesis, lipid metabolism, biodegradation, desaturation, ring expansion, cyclization, active site structure, enzyme mechanism
- MeSH terms
- Ferrous Compounds, Mixed Function Oxygenases, Ketoglutaric Acids, Protein Conformation, Molecular Structure
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