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Cited by 733Enzyme Structure and FunctionGout, Hyperuricemia, Uric AcidBiochemical and Molecular Research

Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: Structure-based mechanism of conversion

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Enroth, Cristofer, Eger, Bryan T., Okamoto, Ken, Nishino, Tomoko, Nishino, Takeshi, Pai, Emil F.·2000·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.97.20.10723PMC PMC27090
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Abstract

Mammalian xanthine oxidoreductases, which catalyze the last two steps in the formation of urate, are synthesized as the dehydrogenase form xanthine dehydrogenase (XDH) but can be readily converted to the oxidase form xanthine oxidase (XO) by oxidation of sulfhydryl residues or by proteolysis. Here, we present the crystal structure of the dimeric ( M r , 290,000) bovine milk XDH at 2.1-Å resolution and XO at 2.5-Å resolution and describe the major changes that occur on the proteolytic transformation of XDH to the XO form. Each molecule is composed of an N-terminal 20-kDa domain containing two iron sulfur centers, a central 40-kDa flavin adenine dinucleotide domain, and a C-terminal 85-kDa molybdopterin-binding domain with the four redox centers aligned in an almost linear fashion. Cleavage of surface-exposed loops of XDH causes major structural rearrangement of another loop close to the flavin ring (Gln 423—Lys 433). This movement partially blocks access of the NAD substrate to the flavin adenine dinucleotide cofactor and changes the electrostatic environment of the active site, reflecting the switch of substrate specificity observed for the two forms of this enzyme.

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  • The N-terminal domain of XOR contains the two Fe/S clusters, a central domain contains the FAD cofactor and a NAD+/H binding site, and the C-terminal domain contains the molybdopterin cofactor and a purine binding site.

    “The N-terminal domain contains the two Fe/S clusters, a central domain contains the FAD cofactor, and a NAD+/H binding site and the C-terminal domain contains the molybdopterin cofactor and a purine binding site (268).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [268]

  • Comparison of crystal structures for XDH and XO indicates movement of a loop that partially blocks the NAD+ binding site and alters the electrostatics of the FAD environment.

    “The comparison of the crystal structures for XDH and XO indicates the movement of a loop that partially blocks the NAD+ binding site and alters the electrostatics of the FAD environment (268, 542).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [268]

  • XDH can be converted to XO by the oxidation of thiols.

    “XDH can be converted to XO by the oxidation of thiols (Fig. 19) (Enroth et al. 2000).”

    From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Enroth et al. 2000

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Authors
Enroth, C., Eger, B. T., Okamoto, K., Nishino, T., Nishino, T., & Pai, E. F.
Affiliations
University of Toronto (CA)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2000-09-26
Volume
97
Issue
20
Pages
10723-10728
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.97.20.10723
PMC
PMC27090
OpenAlex
W2136310944
Cited by
733
References
40
Citations by year
2026: 23 · 2025: 30 · 2024: 28 · 2023: 36 · 2022: 35 · 2021: 37 · 2020: 26 · 2019: 26 · 2018: 43 · 2017: 28 · 2016: 27 · 2015: 28 · 2014: 41 · 2013: 24 · 2012: 30
FWCI
20.86
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
xanthine dehydrogenase, xanthine oxidase, xanthine oxidoreductase, enzyme dimer structure, flavin adenine dinucleotide, molybdopterin, iron-sulfur clusters, substrate specificity, NAD+ binding
MeSH terms
Animals, Cattle, Milk, Molecular Sequence Data, Protein Conformation, Xanthine Dehydrogenase, Xanthine Oxidase, Dimerization, Static Electricity

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