Crystal structure of human homogentisate dioxygenase

  title={Crystal structure of human homogentisate dioxygenase},
  author={Greg P. Titus and Heather A. Mueller and John W. Burgner and Santiago Rodrı́guez de C{\'o}rdoba and Miguel A. Pe{\~n}alva and David E. Timm},
  journal={Nature Structural Biology},
Homogentisate dioxygenase (HGO) cleaves the aromatic ring during the metabolic degradation of Phe and Tyr. HGO deficiency causes alkaptonuria (AKU), the first human disease shown to be inherited as a recessive Mendelian trait. Crystal structures of apo-HGO and HGO containing an iron ion have been determined at 1.9 and 2.3 Å resolution, respectively. The HGO protomer, which contains a 280-residue N-terminal domain and a 140-residue C-terminal domain, associates as a hexamer arranged as a dimer… 

Structure and mechanism of mouse cysteine dioxygenase.

  • J. McCoyL. Bailey G. Phillips
  • Chemistry, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2006
Metal analysis showed that the recombinant enzyme contained a mixture of iron, nickel, and zinc, with increased iron content associated with increased catalytic activity.

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The Ins and Outs of Ring-Cleaving Dioxygenases

The ability of extradiol dioxygenases to act on a variety of non-catecholic compounds is consistent with proposed differences in the breakdown of this iron-alkylperoxo intermediate in the two enzymes, involving alkenyl migration in extradiol enzymes and acyl Migration in intradiol enzymes.

Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database.

A HGD mutation database that is open for future submissions and available online provides a valuable tool for information exchange in AKU research and care fields and certainly presents a useful data source for genotype-phenotype correlations and also for future clinical trials.



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Structure and assembly of protocatechuate 3,4-dioxygenase

The X-ray structure determination of 3,4-PCD reveals the catalytic iron environment required for oxygenolytic cleavage of aromatic rings and also provides a novel holoenzyme assembly with cubic 23(T) symmetry and first examples of mixed β-barrel domains.

The molecular basis of alkaptonuria

The cloning of the human HGO gene is reported and it is established that it is the AKU gene, illustrating that HGO harbours missense mutations that cosegregate with the disease, and providing biochemical evidence that at least one of these missesense mutations is a loss–of–function mutation.

Evolutionary relationships among extradiol dioxygenases

Phylogenetic analyses indicate that the ancestral extradiol dioxygenase was a one-domain enzyme and that the two-domain enzymes arose from a single genetic duplication event.

Bovine liver homogentisicase: apoand reconstituted holoenzymes.

Bovine liver homogentisicase can exist in two forms which are interpreted as being apo-and holoenzymes, which are compared with respect to absorption spectrum, effects of reducing agents and pH on activity (or on reconstitution), stability, and molecular weight.

Murine Liver Homogentisate 1,2-Dioxygenase

HGO consists of a single type of subunit with no intermolecular disulfide bridges and requires Fe2+ as a cofactor, which emphazises that the enzyme is familiar with the class of extradiol dioxygenases.

Crystal structure of isopenicillin N synthase is the first from a new structural family of enzymes

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Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients.

Haplotype and mutational analysis of the HGO gene in 29 novel AKU chromosomes and characterization of five polymorphic sites in HGO provide insight into the origin and evolution of the various AKU alleles.

Structure of ribonuclease H phased at 2 A resolution by MAD analysis of the selenomethionyl protein.

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