Role of short-chain hydroxyacyl CoA dehydrogenases in SCHAD deficiency.
Short-chain hydroxyacyl CoA dehydrogenase deficiency is an ill-defined, severe pediatric disorder of mitochondrial fatty acid beta-oxidation of short-chain hydroxyacyl CoAs. To understand the relative contributions of the two known short-chain hydroxyacyl CoA dehydrogenases (HADH) tissue biopsies of six distinct family individuals were analyzed and kinetic parameters were compared. Steady-state kinetic constants for HADH 1 and HADH 2 suggest that type 1 is the major enzyme involved in mitochondrial beta-oxidation of short-chain hydroxyacyl-CoAs. Two patients are heterozygous carriers of a HADH 1 polymorphism, whereas no mutation is detected in the HADH 2 gene of all patients. The data suggest that protein interactions rather than HADH mutations are responsible for the disease phenotype. Pull-down experiments of recombinant HADH 1 and 2 with human mitochondrial extracts reveal two proteins interacting with HADH 1, one of which was identified as glutamate dehydrogenase. This association provides a possible link between fatty acid metabolism and the hyperinsulinism/hyperammonia syndrome.
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Charlotta
C
Filling
Brigitte
B
Keller
Daniel
D
Hirschberg
Hanns-Ulrich
HU
Marschall
Hans
H
Jörnvall
Michael J
MJ
Bennett
Udo
U
Oppermann
D004746:Enoyl-CoA Hydratase / Q000145:classification / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008930:Mitochondria, Liver / Q000201:enzymology; D011485:Protein Binding
C044121:short-chain beta-hydroxyacyl-CoA dehydrase; D004746:Enoyl-CoA Hydratase