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PubMed1990

Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase.

1. Isolated rat liver and heart mitochondria incubated in 150 mM-KSCN or sucrose medium in the presence of respiratory-chain inhibitors showed a large increase in swelling when exposed to 250 microM-Ca2+. Swelling was inhibited by bongkrekic acid and cyclosporin A in both media and by ADP in KSCN medium; the effect of ADP was reversed by carboxyatractyloside. These results demonstrate that this is a suitable technique with which to study the opening of the Ca2(+)-induced non-specific pore of the mitochondrial inner membrane and implicate the adenine nucleotide carrier in this process. 2. Titration of the rate of swelling with increasing concentrations of cyclosporin showed the number of cyclosporin-binding sites (+/- S.E.M.) in liver and heart mitochondria to be respectively 113.7 +/- 5.0 (n = 9) and 124.3 +/- 11.2 (n = 10) pmol/mg of protein, with a Ki of about 5 nM. 3. Liver and heart mitochondrial-matrix fractions were prepared free of membrane and cytosolic contamination and shown to contain cyclosporin-sensitive peptidyl-prolyl cis-trans isomerase (cyclophilin) activity. Titration of isomerase activity with cyclosporin gave values (+/- S.E.M.) of 110.6 +/- 10.1 (n = 5) and 165.4 +/- 15.0 (n = 3) pmol of enzyme/mg of liver and heart mitochondrial protein respectively, with a Ki of 2.5 nM. The similarity of these results to those from the swelling experiments suggest that the isomerase may be involved in the Ca2(+)-induced swelling. 4. The rapid light-scattering change induced in energized heart mitochondria exposed to submicromolar Ca2+ [Halestrap (1987) Biochem. J. 244, 159-164] was inhibited by ADP and bongkrekic acid, the former effect being reversed by carboxyatractyloside. These results suggest an interaction of Ca2+ with the adenine nucleotide carrier when the 'c' conformation. 5. A model is proposed in which mitochondrial peptidyl-prolyl cis-trans isomerase interacts with the adenine nucleotide carrier in the presence of Ca2+ to cause non-specific pore opening. The model also explains the involvement of the adenine nucleotide translocase in the PPi-mediated cyclosporin-insensitive increase in K+ permeability described in the preceding paper [Davidson & Halestrap (1990) Biochem. J. 268, 147-152]. 6. The physiological and pathological implications of the model are discussed in relation to reperfusion injury and cyclosporin toxicity.

Adenosine Diphosphate↗
PubMed1977

Relationship between the soluble glutathione-dependent delta 5-3-ketosteroid isomerase and the glutathione S-transferases of the liver.

Soluble, glutathione-stimulated delta 5-3-ketosteroid isomerase (EC 5.3.3.A) activity of human and rat liver resides in very basic proteins with molecular weights of about 45,000 which are present in high concentrations in these tissues. Physiochemical and immunological evidence is presented for the identity of the proteins responsible for this enzymatic activity with the glutathione S-transferases (RX:glutathione R-transferase, EC 2.5.1.18) that conjugate glutathione with a variety of electrophilic compounds. In the rat, the steroid isomerase is associated principally with the major transferase (B), which is also known as ligandin, and has the versatility to bind various hydrophobic compounds such as bilirubin, corticosteroids, and metabolites of a number of carcinogens. Other rat liver-glutathione S-transferase species are far less active in the steroid isomerization reaction. The delta 5-3-ketosteroid isomerase activity of human liver is more uniformly distributed among the five glutathione S-transferases that have been described. Steroid isomerization differs fundamentally from other reactions promoted by glutathione S-transferases in that glutathione is not consumed in the reaction. However, because the transferase enzymes promote nucleophilic attack by glutathione on a variety of largely foreign organic substrates, a similar mechanism may be involved in the isomerase reaction. Delta 5-3-ketosteroids are among the few known naturally occurring substrates for these enzymes.

Animals↗
PubMed1995

A 30-amino acid truncation of the microsomal triglyceride transfer protein large subunit disrupts its interaction with protein disulfide-isomerase and causes abetalipoproteinemia.

The microsomal triglyceride transfer protein (MTP) is a heterodimer composed of the multifunctional enzyme, protein disulfide-isomerase, and a unique large, 97 kDa, subunit. It is found as a soluble protein within the lumen of the endoplasmic reticulum of liver and intestine and is required for the assembly of very low density lipoproteins and chylomicrons. Mutations in MTP which result in an absence of MTP function have been shown to cause abetalipoproteinemia. Here, the gene encoding the MTP 97-kDa subunit of an abetalipoproteinemic subject, which we have previously demonstrated lacks MTP activity and protein (Wetterau, J. R., Aggerbeck, L. P., Bouma, M.-E., Eisenberg, C., Munck, A., Hermier, M., Schmitz, J., Gay, G., Rader, D. J., and Gregg, R. E. (1992) Science 258, 999-1001), was isolated and sequenced. A nonsense mutation, which predicts the truncation of the protein by 30 amino acids, was identified. To investigate if this apparently subtle change in MTP could explain the observed absence of MTP, protein disulfide-isomerase was co-expressed with either the normal or mutant MTP 97-kDa subunit in Sf9 insect cells using a baculovirus expression system. Although there were high levels of expression of both the normal and mutant forms of the MTP 97-kDa subunit, only the normal subunit was able to form a stable, soluble complex with protein disulfide-isomerase. These results indicate that the carboxyl-terminal 30 amino acids of the MTP 97-kDa subunit plays an important role in its interaction with protein disulfide-isomerase.

Abetalipoproteinemia↗
PubMed1998

Molecular characterization of Saccharomyces cerevisiae Delta3, Delta2-enoyl-CoA isomerase.

We report here the identification of the Saccharomyces cerevisiae peroxisomal Delta3,Delta2-enoyl-CoA isomerase, an enzyme that is essential for the beta-oxidation of unsaturated fatty acids. The yeast gene YLR284C was identified in an in silico screen for genes that contain an oleate response element, a transcription factor-binding site common to most fatty acid-induced genes. Growth on oleic acid resulted in a significant increase in YLR284C mRNA, demonstrating that it is indeed an oleate-induced gene. The deduced product of YLR284C contains a type 1 peroxisomal targeting signal-like sequence at its C terminus and localizes to the peroxisome in a PEX8-dependent manner. Removal of YLR284C from the S. cerevisiae genome eliminated growth on oleic acid, but had no effect on peroxisome biogenesis, indicating a role for YLR284C in fatty acid metabolism. Cells lacking YLR284C had no detectable Delta3,Delta2-enoyl-CoA isomerase activity, and a bacterially expressed form of this protein catalyzed the isomerization of 3-cis-octenoyl-CoA to 2-trans-octenoyl-CoA with a specific activity of 16 units/mg. We conclude that YLR284C encodes the yeast peroxisomal Delta3,Delta2-enoyl-CoA isomerase and propose a new name, ECI1, to reflect its enoyl-CoA isomerase activity.

Amino Acid Sequence↗
PubMed1983

Protein disulphide-isomerase activity in various cells synthesizing collagen.

A high correlation was found between the activities of protein disulphide isomerase and prolyl 4-hydroxylase when assayed in cells synthesizing various collagen types or the same type at markedly different rates. The highest activities of both enzymes were found in freshly isolated chick-embryo tendon and cartilage cells, intermediate activities in confluent cultures of human skin and lung fibroblasts and mouse 3T6 fibroblasts, and the lowest values in three human sarcoma cell lines, the difference in protein disulphide isomerase activity between the freshly isolated tendon cells and confluent simian-virus-40-transformed human lung fibroblasts being about 25-fold. All these differences are in good agreement with differences reported between the various cells in their rates of collagen synthesis. A great similarity was also found between the changes in the two enzyme activities measured per cell during the growth of 3T6 fibroblast cultures from the early logarithmic phase to the stationary phase. No correlation was found between protein disulphide isomerase activity and the type of collagen synthesized. The data suggest that protein disulphide isomerase may be involved in the formation of intra-chain and inter-chain disulphide bonds in procollagens, but there is no collagen type-related variation in this enzyme activity of a magnitude that would explain the marked differences in the rates of formation of inter-chain disulphide bonds between the various collagen types.

Adult↗
PubMed1996

Messenger RNA encoding thiol protein disulphide isomerase in amnion, chorion and placenta in human term and preterm labour.

OBJECTIVE: To investigate levels of messenger RNA (mRNA) encoding thiol protein disulphide isomerase, in human amnion, chorion and placenta during pregnancy and in relation to term and preterm labour. DESIGN: Amnion, chorion and placenta from 33 women delivered between 24 and 41 weeks of gestation were used in the study. SETTING: Reproductive Molecular Research Group, Department of Obstetrics and Gynaecology, University of Cambridge Clinical School, Rosie Maternity Hospital, Cambridge. RESULTS: Women who were delivered spontaneously before 30 weeks of gestation had higher levels of mRNA encoding thiol protein disulphide isomerase in placenta and chorion than those who were delivered spontaneously after this time (placenta (P < 0.01, chorion P < 0.01) and compared with those who were delivered by elective caesarean section before 30 weeks of gestation (placenta (P < 0.01, chorion P < 0.05). In the group in whom spontaneous labour occurred, at all gestations studied, there were increased levels of mRNA encoding thiol protein disulphide isomerase in the placenta (P < 0.001) and chorion (P < 0.001) compared with the amnion. CONCLUSION: Changes in the steady state level of mRNA encoding thiol protein disulphide isomerase may play a role in the onset of preterm labour before 30 weeks of gestation.

Adolescent↗
PubMed1996

Open reading frame 176 in the photosynthesis gene cluster of Rhodobacter capsulatus encodes idi, a gene for isopentenyl diphosphate isomerase.

Isopentenyl diphosphate (IPP) isomerase catalyzes an essential activation step in the isoprenoid biosynthetic pathway. A database search based on probes from the highly conserved regions in three eukaryotic IPP isomerases revealed substantial similarity with ORF176 in the photosynthesis gene cluster in Rhodobacter capsulatus. The open reading frame was cloned into an Escherichia coli expression vector. The encoded 20-kDa protein, which was purified in two steps by ion exchange and hydrophobic interaction chromatography, catalyzed the interconversion of IPP and dimethylallyl diphosphate. Thus, the photosynthesis gene cluster encodes all of the enzymes required to incorporate IPP into the ultimate carotenoid and bacteriochlorophyll metabolites in R. capsulatus. More recent searches uncovered additional putative open reading frames for IPP isomerase in seed-bearing plants (Oryza sativa, Arabidopsis thaliana, and Clarkia breweri), a worm (Caenorhabditis elegans), and another eubacterium (Escherichia coli). The R. capsulatus enzyme is the smallest of the IPP isomerases to be identified thus far and may consist mostly of a fundamental catalytic core for the enzyme.

Amino Acid Sequence↗
PubMed1992

Protein disulfide isomerase activity is released by activated platelets.

The release of protein disulfide isomerase by activated platelets was hypothesized on the basis of reported intermolecular and intramolecular thiol-disulfide exchange and disulfide reduction involving released thrombospondin in the supernatant solution of activated platelets (Danishefsky, Alexander, Detwiler: Biochemistry, 23:4984, 1984; Speziale, Detwiler: J Biol Chem, 265:17859, 1990; Speziale, Detwiler: Arch Biochem Biophys 286:546, 1991). Protein disulfide isomerase activity, measured by catalysis of the renaturation of ribonuclease inactivated by randomization of disulfide bonds, was detected in the supernatant solution after platelet activation. The activity was inhibited by peptides known to inhibit protein disulfide isomerase; the peptides also inhibited formation of disulfide-linked thrombospondin-thrombin complexes. The reaction catalyzed by the supernatant solution showed a pH dependence distinct from that of the uncatalyzed reaction. The activity was excluded by a 50-Kd dialysis membrane, and it was eluted in the void volume of a gel-filtration column, indicating that it was associated with a macromolecule. The activity was not removed by centrifugation at 100,000 g for 150 minutes indicating that it was not associated with membrane microvesicles. Possible functions for the release of protein disulfide isomerase by activated platelets are discussed.

Blood Platelets↗
PubMed1991

Cyclosporin A slows collagen triple-helix formation in vivo: indirect evidence for a physiologic role of peptidyl-prolyl cis-trans-isomerase.

Peptidyl-prolyl cis-trans-isomerase accelerates otherwise slow, rate-limiting isomerization steps during folding of proteins in vitro, but is not yet securely identified with any specific physiologic role. Peptidyl-prolyl cis-trans-isomerase and the cyclosporin A (CsA)-binding protein cyclophilin are identical, and peptidyl-prolyl cis-trans-isomerase activity is inhibited by the immunosuppressive drug CsA in vitro. To establish a possible physiologic role of peptidyl-prolyl cis-trans-isomerase, we have studied the folding of procollagen I in suspended chick embryo tendon fibroblasts. Folding of procollagen I is slowed by CsA: the time needed for 50% of the molecules to reach a completely helical confirmation is 8.5 min in the absence and 13.5 min in the presence of 5 microM CsA; and the calculated products, k x K, of the rate constant (k) and the equilibrium constant (K) of peptidyl-prolyl cis-trans isomerization are 2.10 and 1.30 s-1, respectively. In contrast, folding of purified collagen III in vitro is unaffected by CsA. In cultured human fibroblasts, CsA caused posttranslational overmodification (hydroxylation of lysine 32.1 versus 22.1%) and increased intracellular degradation (18.7 versus 12.5%), and hence decreased production (10.2 versus 13.2% of total protein synthesis) of collagens I and III, indicating that procollagen folding is slowed by CsA also in human fibroblasts. We conclude that peptidyl-prolyl cis-transisomerase (and hence cyclophilin) accelerates protein folding in living cells. Furthermore, the CsA-induced changes in collagen metabolism are reminiscent of those observed in several variants of osteogenesis imperfecta caused by structural abnormalities in the pro-collagen chains which impair helix formation.

Amino Acid Isomerases↗
PubMed1987

Interchain disulfide bond formation in types I and II procollagen. Evidence for a protein disulfide isomerase catalyzing bond formation.

The assembly of reduced pro-alpha chains of type I and type II procollagen into the native triple-helical molecule was examined in vitro in the presence and absence of pure protein disulfide isomerase. The data clearly indicates that protein disulfide isomerase is able to accelerate the formation of native interchain disulfide bonds in these procollagens. It takes about 6 min after disulfide bonding before triple-helical molecules exist, while the time required to produce triple-helical type I procollagen in the presence of protein disulfide isomerase is 9.4 min and that for type II procollagen 17.2 min. These values agree with those obtained for type I and II procollagen in vivo suggesting that protein disulfide isomerase is also an enzyme catalyzing interchain disulfide bond formation in procollagen in vivo. The formation of native disulfide bonds can proceed without any enzyme catalysis but then requires the presence of reduced and oxidized glutathione. Bonding is rather slow in such a case, however, resulting in a delay in the formation of the triple helix.

Animals↗
PubMed1983

Affinity alkylation of bacterial delta 5-3-ketosteroid isomerase. Identification of the amino acid modified by steroidal 17 beta-oxiranes.

The two steroidal 17 beta-oxiranes, spiro-17 beta-oxiranyl-delta 4-androsten-3-one (4 beta) and spiro-17 beta-oxiranylestra-1,3,5(10),6,8-pentaene-3-ol (5 beta) are active site-directed irreversible inhibitors of bacterial delta 5-3-ketosteroid isomerase. For each inhibitor, a stoichiometry of one molecule of steroid to one enzyme subunit was found. The inhibited enzyme was denatured and subjected to digestion by trypsin. The tryptic maps show two distinct steroid-bound peptides for both 4 beta- and 5 beta-inhibited isomerase. In each case, the two modified peptides are derived from residues 14 to 45 of the isomerase. Each of the steroid-bound peptides of the 4 beta-inhibited enzyme was subjected to further proteolytic digestion and the site of steroid attachment was found to be Asp-38 in each of the inactivation products. These results are interpreted to indicate that "backwards binding" is an important feature of the binding of steroids to delta 5-3-ketosteroid isomerase.

Amino Acids↗
PubMed1980

Homologies in the NH2-terminal amino acid sequences of gamma-carboxymuconolactone decarboxylases and muconolactone isomerases.

gamma-Carboxymuconolactone decarobxylase (EC 4.1.1.44) and muconolactone isomerase (EC 5.3.3.4) mediate chemically analogous reactions in bacteria. The enzymes are inducible, and different metabolites trigger the respective syntheses of the decarboxylases in Acinetobacter calcoaceticus and Pseudomonas putida. The decarobxylases share similar oligomeric structures in which identical subunits of about 13,300 daltons appear to be self-associated into hexamers. Identical residues are found in 18 of the first 36 positions of the enzymes' NH2-terminal amino acid sequences. Thus, genetic rearrangements appear to have placed homologous structural genes for the decarboxylases under different transcriptional control in the two bacterial species. The NH2-terminal amino acid sequences of the decarboxylases and muconolactone isomerases are similar, suggesting that a common ancestral protein gave rise to the enzymes with different (albeit analogous) activities. In addition, the NH2-terminal amino acid sequences of the decarboxylases appear to have been conserved at a second region within the primary structure of the muconolactone isomerases. As has been observed with the two enol-lactone hydrolases (EC 3.1.3.24) of Acinetobacter, the structural genes for the decarboxylases and the isomerases appear to have diverged widely as they were co-selected within a single cell line, In part the divergence appears to have been achieved by mutations in which fragments of DNA within structural genes are replaced with fragments of DNA derived from a co-evolving sequence.

Acinetobacter↗
PubMed1998

Determination of the amino acid requirements for a protein hinge in triosephosphate isomerase.

We have determined the sequence requirements for a protein hinge in triosephosphate isomerase. The codons encoding the hinge at the C-terminus of the active-site lid of triosephosphate isomerase were replaced with a genetic library of all possible 8,000 amino acid combinations. The most active of these 8,000 mutants were selected using in vivo complementation of a triosephosphate isomerase deficient strain of E. coli, DF502. Approximately 3% of the mutants complement DF502 with an activity that is above 70% of wild-type activity. The sequences of these hinge mutants reveal that the solutions to the hinge flexibility problem are varied. Moreover, these preferences are sequence dependent; that is, certain pairs occur frequently. They fall into six families of similar sequences. In addition to the hinge sequences expected on the basis of phylogenetic analysis, we selected three new families of 3-amino-acid hinges: X(A/S)(L/K/M), X(aromatic/beta-branched)(L/K), and XP(S/N). The absence of these hinge families in the more than 60 known species of triosephosphate isomerase suggests that during evolution, not all of sequence space is sampled, perhaps because there is no neutral mutation pathway to access the other families.

Amino Acid Sequence↗
PubMed1993

Biosynthesis of vicinal dihydroxy fatty acids in the red alga Gracilariopsis lemaneiformis: identification of a sodium-dependent 12-lipoxygenase and a hydroperoxide isomerase.

Biosynthesis of the vicinal diol fatty acid (12R,13S)-dihydroxy-(5Z,8Z,10E,14Z)-eicosatetrae noic acid from arachidonic acid was studied in preparations of the red alga Gracilariopsis lemaneiformis. The transformation consisted of initial 12-lipoxygenase-catalyzed oxygenation of arachidonic acid into (12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraeno ic acid followed by hydroperoxide isomerase-catalyzed conversion of the hydroperoxide into (12R,13S)-dihydroxyeicosatetraenoic acid. Short time incubations and trapping experiments with glutathione peroxidase revealed that (12S)-hydroperoxyeicosatetraenoic acid existed as a free intermediate in the overall conversion. The 12-lipoxygenase was mainly present in the soluble fraction of homogenate of G. lemaneiformis. Further, gel filtration experiments showed that the soluble 12-lipoxygenase was a protein having a molecular weight of 84,000-89,000. The enzymatic activity of 12-lipoxygenase isolated by gel filtration was weak; however, addition of 0.8-1 M sodium chloride to such desalted enzyme increased the activity 20-fold. Experiments with different salts revealed that sodium ion was specifically responsible for the stimulatory effect. Hydroperoxide isomerase was about equally distributed between the high speed supernatant and particulate fractions. Gel filtration of hydroperoxide isomerase present in the soluble fraction showed two peaks of activity corresponding to proteins having molecular weights of 220,000 or greater, and 40,000-45,000. The stereochemical course of the biosynthesis of vicinal diol fatty acids was determined using stereospecifically deuterated 6,9,12-octadecatrienoic acids. The 12-lipoxygenase-catalyzed reaction consisted of antarafacial hydrogen removal and oxygen insertion, whereas the hydroperoxide isomerase catalyzed an intramolecular oxygenation which occurred with retention of the configuration of the carbon atom hydroxylated.

Arachidonate 12-Lipoxygenase↗
PubMed1995

A thermolabile triosephosphate isomerase from the psychrophile Vibrio sp. strain ANT-300.

We report the isolation of a gene encoding triosephosphate isomerase (TIM; EC 5.3.1.1) from Vibrio sp. strain ANT-300, a psychrophilic marine eubacterium that grows optimally at 7 degrees C. The deduced primary sequence of this isomerase is 50% identical to Escherichia coli TIM and 37% identical to the isomerase of the psychrotroph Moraxella sp. TA137. Transformation with this gene allowed growth of a TIM-deficient E. coli strain on selective media, but only at temperatures below 30 degrees C. The temperature dependence of this complementation is likely to result from an intrinsic thermolability of the isomerase. Indeed, the TIM activity present in ANT-300 lysates is markedly heat-sensitive, with a half-life of inactivation of 520 s at 25 degrees C.

Amino Acid Sequence↗
PubMed1994

The ontogeny of dopachrome isomerase isozyme patterns in the tobacco hornworm Manduca sexta.

Melanogenesis in animals is initiated by tyrosinase and augmented by recently discovered dopachrome isomerase. Mushroom tyrosinase embedded 5% polyacrylamide gels are used to specifically stain for dopachrome isomerase activity after electrophoretic separation. Using this new procedure, the ontogenic changes in dopachrome isomerase are demonstrated for the first time in any organism. While there is no isozyme variation within the same stage of development, there are profound variations in isozyme patterns during the developmental stages from egg to adult, indicating differential expression and/or processing of dopachrome isomerase genes to match the metabolic needs at these stages.

Animals↗
PubMed1994

Identification of a novel tandemly repeated sequence present in an intron of the glucose phosphate isomerase (GPI) gene in mouse and man.

Glucose phosphate isomerase (GPI, glucose 6-phosphate ketol-isomerase, EC 5.3.1.9) is a housekeeping gene expressed in all tissues and organisms that utilize glycolysis and gluconeogenesis. Deficiency in humans leads to a rare form of nonspherocytic hemolytic anemia. We have isolated a 3.2-kb mouse cDNA containing glucose phosphate isomerase coding sequence and a 2.1-kb intronic sequence and a large proportion of the human gene (approaching 55 kb) in four phage lambda recombinants. A 4-kb intronic fragment from the human gene showing homology to the mouse intronic sequence has been isolated and sequenced. The fragment contains approximately 1.5 kb of sequence that is composed of 30 repeat units of a novel 50-bp tandemly repeated units. The mouse intronic sequence contains 18 similar units. The human consensus sequence differs from the mouse consensus sequence at only 7 positions out of 50 (positions 16, 26, 27, 42, 43, 47, and 48). A probe containing the repeat element detects polymorphisms, specific to glucose phosphate isomerase, in human DNA. The repeat element does not appear to be present at any other loci in human DNA. The conservation of this intronic repeat element extends to pig and Chinese hamster.

Animals↗
PubMed1992

Efficient production of thermostable Thermus thermophilus xylose isomerase in Escherichia coli and Bacillus brevis.

The xylose (glucose) isomerase from the thermophile Thermus thermophilus seems to have potential for the development of new isomerization processes using high temperatures and slightly acidic pH. The isomerase has an optimum temperature at 95 degrees C, and is also very stable at high temperatures. The optimum pH is around 7.0, close to where by-product formation is minimal. Since Thermus produces only a little of this useful isomerase, the production of the cloned gene in Escherichia coli and Bacillus brevis were compared. Especially B. brevis was able to produce the isomerase efficiently, more than 1 g/l, in spite of the high G + C content (67%) of the Thermus gene, and the presence of codons not frequently used in E. coli or B. brevis.

Aldose-Ketose Isomerases↗