Bifunctional protein

Acyl-CoA oxidase deficiency D-bifunctional protein deficiency Racemase deficiency Refsum s disease... 

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. 

Safiejko-Mroczka, B. and Bell, P. B. (1996) Bifunctional protein cross-linking reagents improve labeling of cytoskeletal proteins for qualitative and quantitative fluorescence microscopy. J. Histochem. Cytochem. 44,641-656. 

D-bifunctional protein deficiency [5], 2-methyl acyl-CoA racemase (AMACR) deficiency [3] and sterol carrier protein (SCP-x) deficiency [6], the disorders of etherphospholipid biosynthesis (dihydroxyacetone phosphate acyltransferase and alkyl- dihydroxyacetone phosphate synthase deficiency) [2], the disorders of phytanic acid alpha-oxidation (Refsum disease) [15], and the disorders of glyoxylate detoxification with hyperoxaluria type 1 as caused by alanine glyoxylate aminotransferase deficiency as a sole representative. 

Unfortunately, a minority of the patients with peroxisomal dysfunction cannot be diagnosed using plasma parameters. In the authors laboratory, patients have been seen with peroxisome biogenesis defects, D-bifunctional protein deficiency, and acyl-CoA oxidase deficiency in whom no abnormalities of plasma VLCFA, phytanic acid, pristanic acid or bile acids could be established. Hence, a strong clinical suspicion of peroxisomal disease should always be verified by fibroblast investigation, regardless of the outcome of plasma analyses. 

Conversion of dUMP to dTMP is catalyzed by thy-midylate synthase. A one-carbon unit at the hydroxymethyl (—CH2OH) oxidation level (see Fig. 18-17) is transferred from Af5,Af10-methylenetetrahydrofolate to dUMP, then reduced to a methyl group (Fig. 22-44). The reduction occurs at the expense of oxidation of tetrahydrofolate to dihydrofolate, which is unusual in tetrahydrofolate-requiring reactions. (The mechanism of this reaction is shown in Fig. 22-50.) The dihydrofolate is reduced to tetrahydrofolate by dihydrofolate reductase—a regeneration that is essential for the many processes that require tetrahydrofolate. In plants and at least one protist, thymidylate synthase and dihy-drofolate reductase reside on a single bifunctional protein. 

In protozoa thymidylate synthase and dihydrofolate reductase exist as a single bifunctional protein. 

Fructose-2,6-bisphosphate is a potent activator of the liver phosphofructokinase (PFK-1) and a potent inhibitor of liver fructose-1,6-bisphosphate phosphatase (FBPase-1). Fructose-2,6-bisphosphate is the product of a second phosphofructokinase (PFK-2) and is hydrolyzed to fructose-6-phosphate by FBPase-2. The activities of PKF-2 and FBPase-2 reside on a single, bifunctional protein in liver. The bifunctional protein is under glucagon control imposed via cAMP. 

A highly unusual feature of DHFR in Apicomplexa and Kinetoplastida is its association with thymidylate synthase in the same protein. DHFR activity is always located at the amino terminal portion, while the thymidylate synthase activity resides in the carboxyl terminal. The two enzyme functions do not appear to be interdependent eg, the DHFR portion of the P falciparum enzyme molecule was found to function normally in the absence of the thymidylate synthase portion. It is likely that since the protozoan parasites do not perform de novo synthesis of purine nucleotides, the primary function of the tetrahydrofolate produced by DHFR is to provide 5,10-methylenetetrahydrofolate only for the thymidylate synthase-catalyzed reaction. Physical association of the two enzymes may improve efficiency of TMP synthesis. If an effective means of disrupting the coordination between the two activities can be developed, this bifunctional protein may qualify as a target for antiparasitic therapy. 

Su, H.M., Moser, A.B., Moser, H.W., and Watkins, P.A., Peroxisomal straight-chain Acyl-CoA oxidase and D-bifunctional protein are essential for the retroconversion step in docosahexaenoic acid synthesis, J. Biol. Chem., 276, 38115, 2001. 

Betton, J.-M., Jacob, J. P., Hofnung, M., and Broome-Smith, J. K. (1997). Creating a bifunctional protein by insertion of /3-lactamase into the maltodextrin-binding protein. Nat. Biotechnology, 15, 1276-1279. 

El Alami, M., Messenguy, F., Scherens, B., and Dubois, E., 2003, Arg82p is a bifunctional protein whose inositol polyphosphate kinase activity is essential for nitrogen and PHO gene expression but not for Mcmlp chaperoning in yeast. Mol. Microbiol. 49 457 168. 

Phosphopantetheine undergoes adenylyl transfer from ATP to yield de-phospho-CoA, which is then phosphorylated at the 3 position of the ribose moiety to yield CoA. Phosphopantetheine adenylyltransferase and dephos-pho- CoA kinase activities occur in a single bifunctional enzyme, which is found in both cytosol and mitochondria. However, in addition to the bifunctional protein, human tissues also contain a separate dephospho-CoA kinase (Begley et al., 2001 Zhyvoloup et al., 2002). 

Toleman C, Paterson AJ, Whisenhunt TR, Kudlow JE. Characterization of the histone acetyltransferase (HAT) domain of a bifunctional protein with activable O-GIcNAcase and HAT activities. J. Biol. Chem. 2004 279 53665-53673. 

Figure 4 Posttranslational modifications in the biosynthesis of the class II lantibiotic lacticin 481. Both the dehydration and the cyclization events are catalyzed by the bifunctional protein LctM. The unmodified leader sequence is removed by the cysteine protease domain of LctT concomitant with transport of the mature lantibiotic outside the cell.

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