Pyridine nucleotide-disulfide oxidoreductases

The Reactions Catalyzed—Chemical Similarities AND Cross-Reactivity 

Electron transfer between pyridine nucleotides and disulfide compounds is catalyzed by several fiavoproteins and three of these are well characterized. Lipoamide dehydrogenase functions in the oxidative decarboxylation of a-keto acids catalyzing the reoxidation of reduced lipoate by NAD+ (18, 19). Glutathione reductase catalyzes electron transfer between NADPH and glutathione ZO-22). Thioredoxin reductase catalyzes the reduction of thioredoxin by NADPH (5) thioredoxin is a protein of 12,000 molecular weight containing a single cystine residue which is the electron acceptor S3). 

It is not surprising that enzymes catalyzing such similar chemical reactions should bear striking similarity to one another both structurally and mechanistically. Lipoamide dehydrogenase (34-38), glutathione reductase (39), and thioredoxin reductase (SO, 31) contain, in addition to FAD, a reactive disulfide which is functional in catalysis. These fiavoproteins consist of two identical or near identical polypeptide chains, each with a reactive cystine residue, and two molecules of FAD (31-36). 

The specificity of these enzymes toward their disulfide substrates is quite remarkable There is virtually no cross-reactivity. Since it is quite difficult to separate glutathione reductase from thioredoxin reductase it 

The fluorescence of the tryptophan residues changes markedly upon reduction and reoxidation of the disulfide (48,40). 

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Xanthobacter sp. strain Py2 may be grown with propene or propene oxide. On the basis of amino acid sequences, the monooxygenase that produces the epoxide was related to those that catalyzes the monooxygenation of benzene and toluene (Zhou et al. 1999). The metabolism of the epoxide is initiated by nucleophilic reaction with coenzyme M followed by dehydrogenation (Eigure 7.13a). There are alternative reactions, both of which are dependent on a pyridine nucleotide-disulfide oxidoreductase (Swaving et al. 1996 Nocek et al. 2002) ... 

Mammalian thioredoxin reductases are a family of selenium-containing pyridine nucleotide-disulfide oxidoreductases. These enzymes catalyze NADPH-dependent reduction of the redox protein thioredoxin (Trx), which contains a redox-active disulfide and dithiol group and by itself may function as an efficient cytosolic antioxidant [77]. One of the functions of Trx/ thioredoxin reductase system is the NADPH-catalyzed reduction of protein disulfide [78] ... 

Figure 12.18. Output of Pfam search results. Pfam search is performed with amino acid sequence derived from lipoamide dehydrogenase (Schizosaccharomyces pombe). The table for the trusted matches from Pfam-A for pyr redox (pyridine nucleotide disulfide oxidoreductase) and pyr redox dim (pyridine nucleotide disulfide oxidoreductase, dimerization) domains and their alignments (partial) to HMMs ( ->) are shown. The trusted matches from Pfam-B, the potential matches (Thi4 for thiamine biosynthetic enzyme domain), and the bead-on-a-string sketches are not shown. Select the linked domain name to view the functional description of the domain. The HMM alignments are followed by an option button (Align to seed or Align to family) that enables the user to view/save the multiple alignment of each matched family.

TrxRs are homodimeric flavoproteins [80] that catalyze the NADPH-dependent reduction of thioredoxin (Trx), a ubiquitous 12 kDa protein that is the major protein disulfide reductase in cells [81], and belongs to the pyridine nucleotide-disulfide oxidoreductase family [82]. Each monomer includes an FAD prosthetic group, a NADPH binding site and an active site containing a redox-active selenol group. Electrons are transferred from NADPH via FAD to the active-site selenol of TrxR, which then reduces the substrate Trx [83]. The crystal structure of TrxR is shown in Fig. 13 [84],... 

The pyridine nucleotide-disulfide oxidoreductases, lipoamide dehydrogenase (4), glutathione reductase (5), and thioredoxin reductase (6-8) share so many properties in common that they will be compared and contrasted before being considered separately. As their group name implies, they catalyze the transfer of electrons between pyridine nucleotides and disulfides. In spite of their similarities they function in widely divergent metabolic roles. 

The gross structure of the pyridine nucleotide-disulfide oxidoreductases is the same, i.e., two polypeptide chains each containing a redox active... 

Amino Acid Analysis of Pyridine Nucleotide-Disulfide Oxidoreductases"... 

The specificity of glutathione reductase toward its disulfide substrate was emphasized in Section II,A, since there is virtually no reactivity with the substrates of the other pyridine nucleotide-disulfide oxidoreductases. Other authors have emphasized the lack of specificity of this enzyme since it can catalyze the reduction of a variety of mixed disulfides provided that glutathione or y-glutamylcysteine comprises one-half (IP5, 21%) Table IV summarizes these (39, 226-231). It is important to distin-... 

Swaving, J., J.A.M. de Bont, A. Westphal, and A. de Kok. 1996. A novel type of pyridine nucleotide-disulfide oxidoreductase is essential for NAD+- and NAD-PH-dependent degradation of epoxyalkanes by Xanthobacter strain Py2. /. Bacteriol. 178 6644-6646. 

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