Structure of the Thermolabile Mutant Aldolase B, A149P: Molecular Basis of Hereditary Fructose Intolerance

Malay, Ali D.; Allen, Karen N.; Tolan, Dean R.

doi:10.1016/j.jmb.2005.01.008

Cited by 36 publications

(71 citation statements)

References 45 publications

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“…In addition, to evaluate metabolic effects of the novel ALDOB variants also in actual cells, we now start cloning ALDOB cDNA in a eukaryotic expression system. Models of natural variants based on crystal structural data may also shed light on mutationinduced structural-functional alterations [Santamaria et al, 2000;Rellos et al, 2000;Esposito et al, 2002;Esposito et al, 2004a;Malay et al, 2005]. Analysis of the ALDOB three-dimensional structures clearly indicates that both Arg46 and Tyr343 are exposed to the solvent, far from the tetramer interface ( Arg 304 in the correct position for substrate binding and catalysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion

et al. 2010

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Section: Resultsmentioning

confidence: 99%

Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion

et al. 2010

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“…Although previous studies had got some achievements in HFI, our knowledge about this disease is still limited. The structure of the common mutant A149P protein was not published until 2005 [17] and the frequency of HFI has not been determined with precision in any population [18]. These findings unveil the case report of ALDOB gene mutation for HFI in China and provide us an approach to investigate the incidence of HFI in Chinese population as our future work.…”

Section: Discussionmentioning

confidence: 98%

Clinical and genetic analysis for a Chinese family with hereditary fructose intolerance

Chi

Hong

Yang

et al. 2007

Endocr

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Hereditary fructose intolerance (HFI) is an inheritable disorder of fructose metabolism, inherited as an autosomal recessive disorder and caused by catalytic deficiency of aldolase B, which is critical for gluconeogenesis and fructose metabolism. The affected individuals develop severe hypoglycemia after taking foods containing fructose and cognate sugars. The exons 2-9 of the aldolase B (gene symbol ALDOB) gene from one Chinese HFI patient were amplified by the polymerase chain reaction (PCR), and direct sequence determination was applied to the amplified fragments. The mutation of a 4-bp (AACA) deletion (479_482 del) in exon 4 of ALDOB gene was identified in the patient, which had been reported to cause a frameshift at codon 118 and a truncated protein of 132 amino acids in the previous study. Then, the second case with the same homozygote deletion and eight cases with heterozygotes had been found through screening for the mutation c.479_482 del AACA in the whole family. This is the first report of HFI with the mutation c.479_482 del AACA in the ALDOB gene in a Chinese family.

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“…Certainly, there are no steric constraints to prevent this. In contrast, the dimeric aldolase B A149P variant (Malay et al, 2002) did form the tetramer in the crystalline state (Malay et al, 2005).…”

Section: Calculation Of the Buried Surface Areamentioning

confidence: 85%

Structure of a rabbit muscle fructose-1,6-bisphosphate aldolase A dimer variant

Sherawat

Tolan

Allen

2008

Acta Crystallogr D Biol Cryst

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Fructose‐1,6‐bisphosphate aldolase (aldolase) is an essential enzyme in glycolysis and gluconeogenesis. In addition to this primary function, aldolase is also known to bind to a variety of other proteins, a property that may allow it to perform `moonlighting' roles in the cell. Although monomeric and dimeric aldolases possess full catalytic activity, the enzyme occurs as an unusually stable tetramer, suggesting a possible link between the oligomeric state and these noncatalytic cellular roles. Here, the first high‐resolution X‐ray crystal structure of rabbit muscle D128V aldolase, a dimeric form of aldolase mimicking the clinically important D128G mutation in humans associated with hemolytic anemia, is presented. The structure of the dimer was determined to 1.7 Å resolution with the product DHAP bound in the active site. The turnover of substrate to produce the product ligand demonstrates the retention of catalytic activity by the dimeric aldolase. The D128V mutation causes aldolase to lose intermolecular contacts with the neighboring subunit at one of the two interfaces of the tetramer. The tertiary structure of the dimer does not significantly differ from the structure of half of the tetramer. Analytical ultracentrifugation confirms the occurrence of the enzyme as a dimer in solution. The highly stable structure of aldolase with an independent active site is consistent with a model in which aldolase has evolved as a multimeric scaffold to perform other noncatalytic functions.

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Structure of the Thermolabile Mutant Aldolase B, A149P: Molecular Basis of Hereditary Fructose Intolerance

Cited by 36 publications

References 45 publications

Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion

Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion

Clinical and genetic analysis for a Chinese family with hereditary fructose intolerance

Structure of a rabbit muscle fructose-1,6-bisphosphate aldolase A dimer variant

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