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Human Molecular Genetics, 2000, Vol. 9, No. 15 2341-2350
© 2000 Oxford University Press

Structural and functional analysis of mutations in alkaptonuria

José M. Rodríguez1,+, David E. Timm+,2, Gregory P. Titus2, D. Beltrán-Valero de Bernabé1,3, O. Criado1, Heather A. Mueller2, S. Rodríguez de Córdoba1,3 and M.A. Peñalva1,§

1Centro de Investigaciones Biológicas CSIC, Velázquez 144, Madrid 28006, Spain, 2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA and 3Unidad de Patología Molecular, Fundación Jiménez Díaz, Madrid, Spain

Alkaptonuria (AKU), the prototypic inborn error of metabolism, was the first human disease to be interpreted as a Mendelian trait by Garrod and Bateson at the beginning of last century. AKU results from impaired function of homogentisate dioxygenase (HGO), an enzyme required for the catabolism of phenylalanine and tyrosine. With the novel 7 AKU and 22 fungal mutations reported here, a total of 84 mutations impairing this enzyme have been found in the HGO gene from humans and model organisms. Forty-three of these mutations result in single amino acid substitutions. This mutational information is analysed here in the context of the HGO structure and function using kinetic assays performed using purified AKU mutant enzymes and the crystal structure of human HGO. HGO is a topologically complex structure which assembles as a functional hexamer arranged as a dimer of trimers. We show how the intricate pattern of intra- and inter-subunit interactions and the extensive surfaces required for subunit folding and association of this oligomeric enzyme can be inactivated at multiple levels by single-residue substitutions. This explains, in part, the predominance of missense mutations (67%) in AKU.

+ These authors contributed equally to this work

§ To whom correspondence should be addressed. Tel: +34 91 5644562 ext. 4358; Fax: +34 91 5627518; Email: penalva@cib.csic.es


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