Bifunctional enzyme, deficiency

Bifunctional protein deficiency. The enzyme defect involves the D-bifunctional protein. This enzyme contains two catalytic sites, one with enoyl-CoA hydratase activity, the other with 3-hydroxyacyl-CoA activity [13]. Defects may involve both catalytic sites or each separately. The severity of clinical manifestations varies from that of a very severe disorder that resembles Zellweger s syndrome clinically and pathologically, to somewhat milder forms. Table 41-6 shows that biochemical abnormalities involve straight chain, branched chain fatty acids and bile acids. Bifunctional deficiency is often misdiagnosed as Zellweger s syndrome. Approximately 15% of patients initially thought to have a PBD have D-bifunctional enzyme deficiency. Differential diagnosis is achieved by the biochemical studies listed in Table 41-7 and by mutation analysis. 

Wanders, R.J., van Roermund, C.W., Brul, S., Schutgens, R.B. Tager, J.M. (1992) J. Inherit Metab. Dis. 15, 385-388. Bifunctional enzyme deficiency identification of a new type of peroxisomal disorder in a patient with an impairment in peroxisomal beta-oxidation of unknown aetiology by means of complementation analysis. 

D-Bifunctional enzyme deficiency (D-BP deficiency) D bifunctional protein (DBP) Generalized 5q2 261515... 

Alkyl PAT, alkyl-dihydroxy phosphate synthase Bif, bifunctional enzyme DHAPAT, dihydroxyphosphate acyltransferase deficiency DHCA, dihydroxycholestanoic acid N, normal nd, not determined Ox, acyl-CoA oxidase Rac, 2-methylacyl-CoA racemase RCDP, rhizomelic chondrodysplasia punctata Ref, Refsum s disease THCA, trihydroxycholestanoic acid VLCFA, very-long-chain fatty acid. 

Saccharomyces cerevisiae (mutant resistant to 2-amino-4-methyl-5- -hy-droxyethylthiazole, an antimetabolite of 4-methyl-5-/l-hydroxyethylthia-zole, deficient in activity of both EC 2.5.1.3 and EC 2.7.1.50 [2] bifunctional enzyme with hydroxyethylthiazole kinase and thiamine-phosphate pyrophosphorylase activity [2]) [1, 2]... 

Orotidine 5 -phosphate decarboxylase (ODCase, E. C. 4.1.1.23) catalyzes the decarboxylation of orotidine 5 -phosphate (OMP) to form uridine 5 -phos-phate in the sixth and final step of pyrimidine biosynthesis (Fig. 1) [1]. The discovery of ODCase in 1954 followed the identification, three years earlier, of orotic acid as the metabolic precursor of nucleic acids [2, 3]. ODCase is a distinct, monofunctional polypeptide in bacteria and fungi, whereas in mammals it combines with orotate phosphoribosyltransferase (OPRTase) to form the bifunctional enzyme UMP synthase. Human deficiencies in either OPRTase or ODCase activity result in an autosomal recessive disorder called hereditary orotic aciduria [4]. The disease is characterized by depleted levels of pyrimidine nucleotides in the blood and by the appearance of crystalline... 

The second and third steps of peroxisomal P-oxidation are catalysed by two multifunctional enzymes D-bifunctional protein and L-bifunctional protein. Here we show that fibroblasts of a patient described as being deficient in the 3-hydroxyacyl-CoA dehydrogenase component of D-bifunctional protein and fibroblasts of a patient described as being deficient in L-bifunctional protein do not complement one another. Using a newly developed method to measure the activity of D-bifunctional protein in fibroblast homogenates, we found that the activity of the D-bifunctional protein was completely deficient in the patient with presumed L-bifunctional protein deficiency. 

Taken together, our results resolve the puzzling finding that cells from our patient 1 with a defect in the 3-hydroxyacyl-CoA dehydrogenase component of the D-biflmctional protein failed to show complementation with cells from the patient with presumed L-bifunctional protein deficiency which we have now found to be deficient in the D-specific enzyme. The finding that C26 0 is strongly increased in plasma from both... 

Fibroblast cell lines from patients with aldehyde oxidase 1 (AOxl) and D-bifunctional protein (DBF) deficiency accumulated metabolic intermediates between 18 3n-3 and 24 6n-3 similar to control cells when incubated with [l- C] 18 3n-3 (Table 2). However, the rate of 22 6n-3 synthesis was <10% of control in these cell lines, indicating that these 2 peroxisomal fatty acid P-oxidation enzymes are involved in the retrocon-version of 24 6n-3 to 22 6n-3. The involvement of AOxl in the synthesis of 22 6n-3 was also demonstrated in vivo by Infante et al. (21) who detected less radiolabeled 22 6n-3 synthesis in AOxl knockout mouse livers compared with control litter-mates after the intraperitoneal injection of [U- C]18 3n-3. 

Finally, patients have been reported with deficiency of the bifunctional shunt enzyme, BPG muta e/2,3-BPG phosphatase, and these patients have low concentrations of 2,3-BPG. 

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