Amino Acids

, Volume 41, Issue 1, pp 91–102

Thiol dioxygenases: unique families of cupin proteins

  • Martha H. Stipanuk
  • Chad R. Simmons
  • P. Andrew Karplus
  • John E. DominyJr.
Review Article

DOI: 10.1007/s00726-010-0518-2

Cite this article as:
Stipanuk, M.H., Simmons, C.R., Andrew Karplus, P. et al. Amino Acids (2011) 41: 91. doi:10.1007/s00726-010-0518-2


Proteins in the cupin superfamily have a wide range of biological functions in archaea, bacteria and eukaryotes. Although proteins in the cupin superfamily show very low overall sequence similarity, they all contain two short but partially conserved cupin sequence motifs separated by a less conserved intermotif region that varies both in length and amino acid sequence. Furthermore, these proteins all share a common architecture described as a six-stranded β-barrel core, and this canonical cupin or “jelly roll” β-barrel is formed with cupin motif 1, the intermotif region, and cupin motif 2 each forming two of the core six β-strands in the folded protein structure. The recently obtained crystal structures of cysteine dioxygenase (CDO), with contains conserved cupin motifs, show that it has the predicted canonical cupin β-barrel fold. Although there had been no reports of CDO activity in prokaryotes, we identified a number of bacterial cupin proteins of unknown function that share low similarity with mammalian CDO and that conserve many residues in the active-site pocket of CDO. Putative bacterial CDOs predicted to have CDO activity were shown to have similar substrate specificity and kinetic parameters as eukaryotic CDOs. Information gleaned from crystal structures of mammalian CDO along with sequence information for homologs shown to have CDO activity facilitated the identification of a CDO family fingerprint motif. One key feature of the CDO fingerprint motif is that the canonical metal-binding glutamate residue in cupin motif 1 is replaced by a cysteine (in mammalian CDOs) or by a glycine (bacterial CDOs). The recent report that some putative bacterial CDO homologs are actually 3-mercaptopropionate dioxygenases suggests that the CDO family may include proteins with specificities for other thiol substrates. A paralog of CDO in mammals was also identified and shown to be the other mammalian thiol dioxygenase, cysteamine dioxygenase (ADO). A tentative fingerprint motif for ADOs, or DUF1637 family members, is proposed. In ADOs, the conserved glutamate residue in cupin motif 1 is replaced by either glycine or valine. Both ADOs and CDOs appear to represent unique clades within the cupin superfamily.


Cysteamine dioxygenase Cysteine dioxygenase Cupin proteins Domain of unknown function 1637 (DUF1637) Iron-dependent enzymes Thiols 



Cysteamine dioxygenase, or 2-aminoethanethiol dioxygenase


Cysteine dioxygenase

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Martha H. Stipanuk
    • 1
  • Chad R. Simmons
    • 1
    • 4
  • P. Andrew Karplus
    • 2
  • John E. DominyJr.
    • 1
    • 3
  1. 1.Division of Nutritional SciencesCornell UniversityIthacaUSA
  2. 2.Department of Biochemistry and BiophysicsOregon State UniversityCorvallisUSA
  3. 3.Department of Cancer Biology, Dana Farber Cancer InstituteHarvard Medical SchoolBostonUSA
  4. 4.Center for Single Molecule Biophysics, The Biodesign InstituteArizona State UniversityTempeUSA

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