A structure-based catalytic mechanism for the xanthine oxidase family of molybdenum enzymes
Open accessAbstract
The crystal structure of the xanthine oxidase-related molybdenum-iron protein aldehyde oxido-reductase from the sulfate reducing anaerobic Gram-negative bacterium Desulfovibrio gigas (Mop) was analyzed in its desulfo-, sulfo-, oxidized, reduced, and alcohol-bound forms at 1.8-A resolution. In the sulfo-form the molybdenum molybdopterin cytosine dinucleotide cofactor has a dithiolene-bound fac-[Mo, = O, = S, ---(OH2)] substructure. Bound inhibitory isopropanol in the inner compartment of the substrate binding tunnel is a model for the Michaelis complex of the reaction with aldehydes (H-C = O,-R). The reaction is proposed to proceed by transfer of the molybdenum-bound water molecule as OH- after proton transfer to Glu-869 to the carbonyl carbon of the substrate in concert with hydride transfer to the sulfido group to generate [MoIV, = O, -SH, ---(O-C = O, -R)). Dissociation of the carboxylic acid product may be facilitated by transient binding of Glu-869 to the molybdenum. The metal-bound water is replenished from a chain of internal water molecules. A second alcohol binding site in the spacious outer compartment may cause the strong substrate inhibition observed. This compartment is the putative binding site of large inhibitors of xanthine oxidase.
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Xanthine oxidase generates H2O2 as a byproduct during oxidation of hypoxanthine and xanthine to uric acid.
“It catalyzes the oxidation of the bases hypoxanthine and xanthine to uric acid, which is the end product of purine catabolism. H2O2 is generated as a byproduct during two oxidation steps of the enzymatic reaction, marking XO as a potential ROS source.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [139]
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Self-citation
- Authors
- Huber, R., Hof, P., Duarte, R. O., Moura, J. J., Moura, I., Liu, M. Y., LeGall, J., Hille, R., Archer, M., & Romão, M. J.
- Affiliations
- Max Planck Institute of Biochemistry (DE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1996-08-20
- Volume
- 93
- Issue
- 17
- Pages
- 8846-8851
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC38556
- OpenAlex
- W2057637394
- Cited by
- 242
- References
- 37
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 12 · 2013: 6 · 2012: 6
- FWCI
- 22.24
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
- Topics
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- xanthine oxidase, molybdenum enzymes, aldehyde oxidase, Desulfovibrio gigas, molybdenum-iron protein, molybdopterin, catalytic mechanism, hydride transfer, crystal structure
- MeSH terms
- Aldehyde Oxidoreductases, Bacterial Proteins, Cytosine Nucleotides, Desulfovibrio, Models, Molecular, Molybdenum, Oxidation-Reduction, Pterins, Xanthine Oxidase, Crystallography, X-Ray
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