1xdl

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Structure of human aldolase B associated with hereditary fructose intolerance (A149P), at 277K

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Hereditary fructose intolerance (HFI) is a potentially lethal inborn error, in metabolism caused by mutations in the aldolase B gene, which is, critical for gluconeogenesis and fructose metabolism. The most common, mutation, which accounts for 53% of HFI alleles identified worldwide, results in substitution of Pro for Ala at position 149. Structural and, functional investigations of human aldolase B with the A149P substitution, (AP-aldolase) have shown that the mutation leads to losses in thermal, stability, quaternary structure, and activity. X-ray crystallography is, used to reveal the structural basis of these perturbations. Crystals of, AP-aldolase are grown at two temperatures (4 degrees C and 18 degrees C), and the structure solved to 3.0 angstroms resolution, using the wild-type, structure as the phasing model. The structures reveal that the single, residue substitution, A149P, causes molecular disorder around the site of, mutation (residues 148-159), which is propagated to three adjacent, beta-strand and loop regions (residues 110-129, 189-199, 235-242)., Disorder in the 110-129-loop region, which comprises one subunit-subunit, interface, provides an explanation for the disrupted quaternary structure, and thermal instability. Greater structural perturbation, particularly at, a Glu189-Arg148 salt bridge in the active-site architecture, is observed, in the structure determined at 18 degrees C, which could explain the, temperature-dependent loss in activity. The disorder revealed in these, structures is far greater than that predicted by homology modeling and, underscores the difficulties in predicting perturbations of protein, structure and function by homology modeling alone. The AP-aldolase, structure reveals the molecular basis of a hereditary disease and, represents one of only a few structures known for mutant proteins at the, root of the thousands of other inherited disorders.

Disease

Known disease associated with this structure: Fructose intolerance OMIM:[229600]

About this Structure

1XDL is a Single protein structure of sequence from Homo sapiens with SO4 as ligand. Active as Fructose-bisphosphate aldolase, with EC number 4.1.2.13 Full crystallographic information is available from OCA.

Reference

Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance., Malay AD, Allen KN, Tolan DR, J Mol Biol. 2005 Mar 18;347(1):135-44. Epub 2005 Jan 20. PMID:15733923

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