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Titus, Gregory P.; Mueller, H.; Burgner, John W.; Córdoba, Santiago Rodrı́guez de; Peñalva, Miguel; Timm, David E.

doi:10.1038/76756

Cited by 137 publications

(19 citation statements)

References 30 publications

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“…Interestingly, most β-pleated sheets and interconnecting loops remained similar to the native protein, suggesting that the major impact of the exon 2 deletion is on the α-helical coils. In addition, the catalytic site constituted of the glutamic acid and the two histidines at amino acids 341, 335 and 371 [10], respectively, appeared unaltered but are likely to be encapsulated within the mutant tertiary structure, thus failing to allow access of homogentisic acid to the catalytic site. Overall, deletion of exon 2 from the HGD protein predicts a significant conformational change in protein structure and a resulting severe AKU phenotype caused by abnormal HGD enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

“…If such a protein were to be synthesized, its enzymatic activity is likely to be compromised, as evidenced by the accumulation of homogentisic acid in the proband [7]. Modeling of the mutant HGD protein with the 649 bp deletion resulted in an alternate structure that lacked from the native protein [10] two β-pleated sheets and an interconnecting loop, both encoded by the deleted exon 2. Furthermore, substitution of the eight α-helical coils with nine novel ones was characteristic of the predicted mutant HGD structure.…”

Section: Discussionmentioning

confidence: 99%

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First Report of a Deletion Encompassing an Entire Exon in the Homogentisate 1,2-Dioxygenase Gene Causing Alkaptonuria

et al. 2014

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Alkaptonuria is often diagnosed clinically with episodes of dark urine, biochemically by the accumulation of peripheral homogentisic acid and molecularly by the presence of mutations in the homogentisate 1,2-dioxygenase gene (HGD). Alkaptonuria is invariably associated with HGD mutations, which consist of single nucleotide variants and small insertions/deletions. Surprisingly, the presence of deletions beyond a few nucleotides among over 150 reported deleterious mutations has not been described, raising the suspicion that this gene might be protected against the detrimental mechanisms of gene rearrangements. The quest for an HGD mutation in a proband with AKU revealed with a SNP array five large regions of homozygosity (5–16 Mb), one of which includes the HGD gene. A homozygous deletion of 649 bp deletion that encompasses the 72 nucleotides of exon 2 and surrounding DNA sequences in flanking introns of the HGD gene was unveiled in a proband with AKU. The nature of this deletion suggests that this in-frame deletion could generate a protein without exon 2. Thus, we modeled the tertiary structure of the mutant protein structure to determine the effect of exon 2 deletion. While the two β-pleated sheets encoded by exon 2 were missing in the mutant structure, other β-pleated sheets are largely unaffected by the deletion. However, nine novel α-helical coils substituted the eight coils present in the native HGD crystal structure. Thus, this deletion results in a deleterious enzyme, which is consistent with the proband’s phenotype. Screening for mutations in the HGD gene, particularly in the Middle East, ought to include this exon 2 deletion in order to determine its frequency and uncover its origin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

First Report of a Deletion Encompassing an Entire Exon in the Homogentisate 1,2-Dioxygenase Gene Causing Alkaptonuria

et al. 2014

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“…Homogentisate is an isomer of HPCA, differing in having the two hydroxyl groups para to each other rather than ortho. HGD catalyzes the oxidative cleavage of the C–C bond to which the carboxylate and one hydroxyl group are connected, a transformation that can be related to alkaptonuria in humans [12, 48, 49]. As a consequence of the para positioning of the two hydroxyl groups, the substrate binds to the HGD iron center only with the hydroxyl group adjacent to the acetate substituent.…”

Section: Intermediates From Reactions Carried Out In Enzyme Crystalsmentioning

confidence: 99%

A two-electron-shell game: intermediates of the extradiol-cleaving catechol dioxygenases

2014

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Extradiol catechol ring-cleaving dioxygenases function by binding both the organic substrate and O2 at a divalent metal center in the active site. They have proven to be a particularly versatile group of enzymes with which to study the O2 activation process. Here, recent studies of homoprotocatechuate 2,3-dioxygenase (HPCD) are summarized with the objective of showing how Nature can utilize the enzyme structure and the properties of the metal and the substrate to select among many possible chemical paths to achieve both specificity and efficiency. Possible intermediates in the mechanism have been trapped by swapping active site metals, introducing active site amino acid substituted variants, and using substrates with different electron donating capacities. While each of these intermediates could form part of a viable reaction pathway, kinetic measurements significantly limit the likely candidates. Structural, kinetic, spectroscopic and computational analysis of the various intermediates shed light on how catalytic efficiency can be achieved.

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“…Generally, HGDO and GDO have strong overall structural similarity [100,107] as they share the bicupin fold. Yet HGDO, which has the active site located in the C-terminal cupin domain, employs the facial 2-His-1-carboxylate triad for catalysis [107], while GDO and SDO rely on the 3-His center.…”

Section: Atypically Coordinated Mononuclear Non-heme-fe(ii) Centersmentioning

confidence: 99%

“…Homogentisate mechanism as deduced from DFT calculations [99], which were calculated in the presence of putative catalytic outer shell residues His365 and His292 [107].…”

Section: Figmentioning

confidence: 99%

Structure and function of atypically coordinated enzymatic mononuclear non-heme-Fe(II) centers

Buongiorno

Straganz

2013

Coordination Chemistry Reviews

103

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Cited by 137 publications

References 30 publications

First Report of a Deletion Encompassing an Entire Exon in the Homogentisate 1,2-Dioxygenase Gene Causing Alkaptonuria

First Report of a Deletion Encompassing an Entire Exon in the Homogentisate 1,2-Dioxygenase Gene Causing Alkaptonuria

A two-electron-shell game: intermediates of the extradiol-cleaving catechol dioxygenases

Structure and function of atypically coordinated enzymatic mononuclear non-heme-Fe(II) centers

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