Peroxisomal d -hydroxyacyl-CoA dehydrogenase deficiency: Resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency

Peroxisomal d-hydroxyacyl-CoA dehydrogenase deficiency: Resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency

^*University of Amsterdam, Academic Medical Centre, Department of Clinical Chemistry, Laboratory of Genetic Metabolic Diseases, Amsterdam, The Netherlands; ^†Erasmus University, Sophia Children’s Hospital, Department of Paediatrics, Rotterdam, The Netherlands; ^‡GSF-Forzungszentrum, Institut für Säugetiergenetik, Neuherberg, D-85764 Oberschleissheim, Germany; ^§Institute of Child Health, University of London, London WC1N 1EH, United Kingdom; ^¶Southwest Missouri State University, Department of Chemistry, Springfield, MO 65804; and ^‖University of Amsterdam, Academic Medical Centre, Department of Paediatrics, Emma Children’s Hospital, Amsterdam, The Netherlands

Edited by Christian de Duve, International Institute of Cellular and Molecular, Brussels, Belgium, and approved December 2, 1997 (received for review September 3, 1997)

Abstract

Peroxisomes play an essential role in a number of different metabolic pathways, including the β-oxidation of a distinct set of fatty acids and fatty acid derivatives. The importance of the peroxisomal β-oxidation system in humans is made apparent by the existence of a group of inherited diseases in which peroxisomal β-oxidation is impaired. This includes X-linked adrenoleukodystrophy and other disorders with a defined defect. On the other hand, many patients have been described with a defect in peroxisomal β-oxidation of unknown etiology. Resolution of the defects in these patients requires the elucidation of the enzymatic organization of the peroxisomal β-oxidation system. Importantly, a new peroxisomal β-oxidation enzyme was recently described called d-bifunctional protein with enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activity primarily reacting with α-methyl fatty acids like pristanic acid and di- and trihydroxycholestanoic acid. In this patient we describe the first case of d-bifunctional protein deficiency as resolved by enzyme activity measurements and mutation analysis. The mutation found (Gly¹⁶Ser) is in the dehydrogenase coding part of the gene in an important loop of the Rossman fold forming the NAD⁺-binding site. The results show that the newly identified d-bifunctional protein plays an essential role in the peroxisomal β-oxidation pathway that cannot be compensated for by the l-specific bifunctional protein.

Footnotes

↵ ** To whom reprint requests and correspondence should be addressed at: University of Amsterdam, Academic Medical Centre, Department of Clinical Chemistry (Room F0-226), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: DHC, dihydroxycholestanoic acid; THC, trihydroxycholestanoic acid.