Molecular basis of d-bifunctional protein deficiency
Section snippets
d-Bifunctional protein/17β-hydroxysteroid dehydrogenase type 4/multifunctional protein 2
The d-bifunctional protein (d-BP) was first discovered in the pig as 17β-hydroxysteroid dehydrogenase type 4 (HSD4) (Adamski et al., 1992) due to its ability to oxidize 17β-estradiol and Δ5-androstene-3β/17β-diol at position 17 of the steroid backbone. The rat 17β-HSD4 ortholog was described as a protein that is induced by the peroxisome proliferation activator clofibrate (Corton et al., 1996). cDNAs of the enzyme were also cloned from man (Adamski et al., 1995), mouse (Normand et al., 1995),
Synonyms
Due to its multifunctionality and its discovery in connection with different metabolic pathways several names are in use for this enzyme: bifunctional protein (BP) or d-bifunctional protein (d-BP), multifunctional protein 2 (MFP-2) or multifunctional enzyme 2 (MFE-2), 17β-hydroxysteroid dehydrogenase type 4 (17β-HSD4), d-3-hydroxyacyl-CoA dehydratase/d-3-hydroxyacyl-CoA dehydrogenase, 2-enoyl-CoA hydratase-2/(R)-3-hydroxyacyl-CoA dehydrogenase (reviewed in de Launoit and Adamski (1999)).
d-Bifunctional protein deficiency
d-Bifunctional protein deficiency belongs to the large group of peroxisomal disorders that are inherited in man. These disorders are subdivided into two categories: (1) peroxisome biogenesis or assembly disorders in which peroxisomes are not formed, and (2) the defect or deficiency of single peroxisomal proteins. Four phenotypes are associated with the assembly disorders: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic
Point mutation G16S
The first explanation of the d-BP deficiency was given by van Grunsven et al. (1998). A patient with a homozygous point mutation in the SDR domain was reported. The base exchange 46G → A led to the expression of a full length protein with the amino acid exchange G16S in the cofactor binding region (Table 3 and Fig. 3). In the patient elevated plasma levels of VLCFA, pristanic acid and bile acid intermediates were found. Peroxisomes were present in the patient's fibroblasts although in reduced
Call for mutants
The authors would like to maintain a comprehensive data base on d-BP mutants. Should we have missed any observation we would greatly appreciate a notification about that.
Acknowledgements
The work was supported by a grant of the Deutsche Forschungsgemeinschaft to JA.
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