Studies on the chemical isomerization of vitamin D. V. Chemical isomerization course of vitamin D2 to isotachysterol-2 by acetyl chloride.
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Acetates↗
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Highly Enantioselective Isomerization of 4,7-Dihydro-1,3-dioxepins Catalyzed by Me-DuPHOS-Modified Dihalogenonickel Complexes and Determination of the Absolute Configuration of the Isomerization Products This work was supported by the Fonds der Chemische Industrie. We would like to thank Prof. Dr. H. Brunner, Universität Regensburg, for help in questions concerning analytical data. Me-DuPHOS=1,2-bis(2,5-dimethylphospholanyl)benzene.
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Journal Article↗
[A-b Isomerism of cyano-aquo-corrinoids. On the equilibrium condition of the isomerization reaction].
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Acetates↗
[On the coordination-isomerism ("a-b-isomerism") of cobyrinic acid].
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Chemical Phenomena↗
[On the coordination isomerism (a-b isomerism) of Co-alkyl corrinoids. Partial synthesis and some properties of Co-methyl-cobalamin a].
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Carbon Isotopes↗
Clinical implications of atrial isomerism.
Right atrial isomerism or left atrial isomerism is frequently diagnosed as situs ambiguous without further discrimination of the specific morbid anatomy. Thirty six cases of right atrial isomerism and seven cases of left atrial isomerism were collected from the records and pathological museum at the National Taiwan University Hospital. There was a necropsy report for 18 cases. In all patients one or more of the following conditions was met: (a) isomeric bronchial anatomy, (b) echocardiographic and angiocardiographic evidence of isomerism, and (c) surgical or necropsy evidence of abnormal atrial anatomy. An anomalous pulmonary venous connection was present in 55% of patients with right atrial isomerism; in left atrial isomerism one case (14%) had a partial anomalous pulmonary venous connection. Forty per cent of cases of anomalous pulmonary venous connection with right atrial isomerism had obstruction. Six (86%) of seven cases with left atrial isomerism had an ambiguous biventricular atrioventricular connection. In contrast, univentricular atrioventricular connection (26 of 36, 72%) was significantly more common in right atrial isomerism. A common atrioventricular valve was the most frequent mode of connection in both forms. Two discrete atrioventricular valves were significantly more common in left atrial isomerism. Atrioventricular valve regurgitation was detected in 14 cases. Double outlet right ventricle was the most common type of ventriculoarterial connection. The most commonly cited causes of death after either palliative or definitive operation were undetected anomalous pulmonary venous connection, pulmonary venous stricture, and uncorrected atrioventricular valve or aortic regurgitation complicated by abnormal coagulation. Although the prognosis is poor, successful operation depends on knowledge of the precise anatomical arrangement associated with atrial isomerism.
Abnormalities, Multiple↗
Local structural changes caused by peptidyl-prolyl cis/trans isomerization in the native state of proteins.
Peptidyl-prolyl cis/trans isomerization, observed in the native state of an increasing number of proteins, is of considerable biological significance. The first evidence for an asymmetric transmission along the polypeptide chain of the structural effects of prolyl isomerization is now derived from the statistics of the C(alpha)/C(alpha)-atom distance distributions in the crystal structures of 848 non-homologous proteins. More detailed information on how isomerization affects segments adjacent to proline is obtained from crystal structures of proteins, that are more than 95% homologous, and that exhibit two different states of isomerization at a particular prolyl bond. The resulting 64 cases, which represent 3.8% of the database used, form pairs of coordinates which were analyzed for the existence of isomer-specific intramolecular nonbonded C(alpha)/C(alpha)-atom distances around the critical proline, and for the positional preferences for particular amino acids in the isomeric sequence segment. The probability that a native protein exhibits both prolyl isomers in the crystalline state increases in particular with a Pro at the third position N-terminal to the isomeric bond (-3 position), and with Ser, Gly and Asp at the position preceding the isomeric bond (-1 position). Structural alignment of matched pairs of isomeric proteins generates three classes with respect to position-specific distribution of C(alpha)-atom displacements around an isomeric proline imide bond. In the majority of cases the distribution of these intermolecular isomer-specific C(alpha)-atom distances shows a symmetric behavior for the N-terminal and C-terminal segment flanking the proline residue, and the magnitude did not exceed 1.3+/-0.6 A including the C(alpha) atoms in proximity to the prolyl bond. However, in the remaining 12 protein pairs the structural changes are unidirectional relative to the isomerizing bond whereby the magnitude of the isomer-specific effect exceeds 3.0+/-2.0 A even at positions remote to proline. Interestingly, the magnitude of the intramolecular isomer-specific C(alpha) atom displacements reveals a lever-arm amplification of the isomerization-mediated structural changes in a protein backbone. The observed backbone effects provide a structural basis for isomer-specific reactions of proline-containing polypeptides, and thus may play a role in biological recognition and regulation.
Crystallography, X-Ray↗
Arrangement of the systemic and pulmonary venous components of the atrial chambers in hearts with isomeric atrial appendages.
BACKGROUND: The morphological definition of atrial chambers, and the determination of atrial laterality, are based on analysis of the structure of the atrial appendages. The systemic and pulmonary venous connections to the heart, nonetheless, are important in the management of patients having isomeric appendages. In this study, therefore, we analysed the morphology of the postero-superior walls of the atrial chambers so as to provide evidence concerning the morphogenetic background of those hearts, and to improve operative management. METHODS: We reviewed 15 autopsied specimens with isomeric right appendages, and 10 with isomeric left appendages, paying particular attention to the morphology of the systemic and pulmonary venous connections. The postero-superior walls of the atrial chambers can be made up of the atrial body, the systemic venous components, or the pulmonary venous component. We analysed the contributions made by each of these components. RESULTS: The postero-superior walls of the atrial chambers were markedly variable, but could be grouped into five patterns. Bilaterally well-developed systemic venous components and absence of the pulmonary venous component within the hypoplastic atrial body were present in 9 hearts with extracardiac pulmonary venous connections in the setting of right isomerism. Bilaterally well-developed systemic venous components, and a hypoplastic pulmonary venous component within the hypoplastic atrial body, were present in 5 hearts with intracardiac pulmonary venous connections in right isomerism. Bilaterally well-developed systemic venous components, and a hypoplastic pulmonary venous component within the sizable atrial body, were present in 1 heart with an intracardiac pulmonary venous connection in right isomerism. A well-developed pulmonary venous component within the atrial body, and hypoplasia of one systemic venous component, were present in 7 hearts with left isomerism. A well-developed pulmonary venous component within the atrial body, and hypoplasia of bilateral systemic venous components, were present in 3 hearts with left isomerism. CONCLUSIONS: The postero-superior walls of the atrial chambers in hearts with isomeric atrial appendages can be analysed on the basis of a compound structure made of bilateral systemic venous components, a central pulmonary venous component, and the body of the atrium. Hearts with isomeric right appendages have absence or hypoplasia of the pulmonary venous component, while hearts with isomeric left appendages have hypoplastic systemic venous components.
Autopsy↗
Reduction-reoxidation cycles contribute to catalysis of disulfide isomerization by protein-disulfide isomerase.
Protein-disulfide isomerase (PDI) catalyzes the formation and isomerization of disulfides during oxidative protein folding. This process can be error-prone in its early stages, and any incorrect disulfides that form must be rearranged to their native configuration. When the second cysteine (CGHC) in the PDI active site is mutated to Ser, the isomerase activity drops by 7-8-fold, and a covalent intermediate with the substrate accumulates. This led to the proposal that the second active site cysteine provides an escape mechanism, preventing PDI from becoming trapped with substrates that isomerize slowly (Walker, K. W., and Gilbert, H. F. (1997) J. Biol. Chem. 272, 8845-8848). Escape also reduces the substrate, and if it is invoked frequently, disulfide isomerization will involve cycles of reduction and reoxidation in preference to intramolecular isomerization of the PDI-bound substrate. Using a gel-shift assay that adds a polyethylene glycol-conjugated maleimide of 5 kDa for each sulfhydryl group, we find that PDI reduction and oxidation are kinetically competent and essential for isomerization. Oxidants inhibit isomerization and oxidize PDI when a redox buffer is not present to maintain the PDI redox state. Reductants also inhibit isomerization as they deplete oxidized PDI. These rapid cycles of PDI oxidation and reduction suggest that PDI catalyzes isomerization by trial and error, reducing disulfides and oxidizing them in a different configuration. Disulfide reduction-reoxidation may set up critical folding intermediates for intramolecular isomerization, or it may serve as the only isomerization mechanism. In the absence of a redox buffer, these steady-state reduction-oxidation cycles can balance the redox state of PDI and support effective catalysis of disulfide isomerization.
Binding Sites↗
Isomerism of the atrial appendages in the fetus.
Thirty hearts from fetuses with visceral heterotaxy were examined to determine the range of cardiac malformations. By examining the morphology of the atrial appendages, 20 hearts were identified as having left isomerism (67%) and 10 hearts right isomerism (33%). Fifteen of the hearts with left isomerism had biventricular atrioventricular connections and five had univentricular atrioventricular connections. All 10 hearts with right isomerism had biventricular atrioventricular connections. Flow to the pulmonary arteries was obstructed or occluded in 6 hearts with left isomerism (30%) and 7 hearts with right isomerism (70%). Obstruction to aortic flow was present in 4 hearts with left isomerism (20%). Anomalies of the systemic and pulmonary veins were common in both groups. The suprarenal portion of the inferior caval vein was interrupted in 11 hearts with left isomerism (55%) and 1 heart with right isomerism (10%). Atrioventricular septal defect was present in 13 hearts with left isomerism (65%) and 9 hearts with right isomerism (90%). The arrangement of the liver or stomach in each group was not consistent, nor was the status of the spleen. The constellations of cardiac malformations in both groups corresponded to those known in postnatal life and similar guidelines for their identification were applicable.
Aorta, Thoracic↗
Role of proline isomerization in folding of ribonuclease A at low temperatures.
In unfolded RNase A there is an interconversion between slow-folding and fast-folding forms (U(S) right harpoon over left harpoon U(F)) that is known to show properties characteristic of proline isomerization in model peptides. Here, we accept the evidence that U(S) molecules contain nonnative proline isomers and we ask about the isomerization of these proline residues during folding. The U(S) right harpoon over left harpoon U(F) reaction in unfolded RNase A is used both to provide data on the kinetics of proline isomerization in the unfolded protein and as the basis of an assay for measuring proline isomerization during folding.The tyrosine-detected folding kinetics at low temperatures have been compared to those of proline isomerization in unfolded RNase A. The comparison is based on the recent observation that the U(S) right harpoon over left harpoon U(F) kinetics are independent of guanidinium chloride concentration, so that they can be extrapolated to low guanidinium chloride concentrations, at which folding takes place. At 0 degrees C the tyrosine-detected folding reaction is 100-fold faster than the conversion of U(S) to U(F) in unfolded RNase A. Consequently, the folding reaction is not rate-limited by proline isomerization as it occurs in unfolded RNase A. An assay is given for proline isomerization during folding. The principle is that native RNase A yields U(F) on unfolding, whereas protein molecules that still contain nonnative proline isomers yield U(S). Unfolding takes place at 0 degrees C, at which proline isomerization is slow compared to unfolding. This assay yields two important results: (i) The kinetics of proline isomerization during folding are substantially faster than in unfolded RNase A-e.g., 40-fold at 0 degrees C. The mechanism of the rate enhancement is unknown. (ii) At low temperatures (0-10 degrees C), and also in the presence of (NH(4))(2)SO(4), the tyrosine-detected folding reaction occurs before proline isomerization and yields a folded intermediate I(N) that is able to bind the specific inhibitor 2'-CMP. The results demonstrate that a folding intermediate is spectrally detectable when folding occurs at low temperatures. They suggest that low temperatures provide suitable conditions for determining the kinetic pathway of folding by characterizing folding intermediates.
Ammonium Sulfate↗
Isomerization of trans-2,delta 5-dienoyl-CoA's to delta 3,delta 5-dienoyl-CoA's in the beta-oxidation of delta 5-unsaturated fatty acids.
The NADPH-dependent reduction pathway for the metabolism of delta 5-unsaturated fatty acids involves the isomerization of trans-2,delta 5-dienoyl-CoA, initially formed from the dehydrogenation of delta 5-enoyl-CoA, to isomeric delta 3,delta 5-dienoyl-CoA. The latter intermediates were then isomerized to trans-2,trans-4-dienoyl-CoA, which then follows the NADPH-dependent pathway mediated by 2,4-dienoyl-CoA reductase. The isomerization from trans-2,delta 5-dienoyl-CoA to delta 3,delta 5-dienoyl-CoA is catalyzed by delta 3,delta 2-enoyl-CoA isomerase. In this investigation, we identified the stereoisomers of delta 3,delta 5-dienoates that were formed in the reaction. Starting from trans-2,cis-5-decadienoyl-CoA, the isomerization produced cis-3,cis-5- and trans-3,cis-5-decadienoates. On the other hand, trans-2,trans-5-decadienoyl-CoA yielded cis-3,trans-5- and trans-3,trans-5-decadienoates. In addition to purified rat liver delta 3,delta 2-enoyl-CoA isomerase, acyl-CoA oxidase from Arthrobacter also catalyzed the isomerization from trans-2,cis-5-dienoyl-CoA. However, this acyl-CoA oxidase could not catalyze the similar isomerization of trans-2,trans-5-dienoyl-CoA. delta 3,delta 5-t-2,t-4-Dienoyl-CoA isomerase used cis-3,cis-5-, trans-3,cis-5-, and cis-3,trans-5-dienoyl-CoA's as substrates and converted them to trans-2,trans-4-dienoyl-CoA. In contrast, trans-3,trans-5-dienoyl-CoA was not a substrate for this isomerization. Extensive purification of acyl-CoA oxidase through column chromatography could not remove or diminish the isomerization activity associated with acyl-CoA oxidase. Acyl-CoA oxidases derived from Candida and rat liver also possess isomerization activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Acyl Coenzyme A↗
Proline isomerization in bovine pancreatic ribonuclease A. 2. Folding conditions.
The kinetics of cis-trans isomerization of individual X-Pro peptide groups is used to study the backbone dynamics of bovine pancreatic ribonuclease A (RNase A). We previously developed and validated a fluorescence method for monitoring the cis-trans isomerization of the Tyr92-Pro93 and Asn113-Pro114 peptide groups of RNase A under unfolding conditions [Juminaga, D., Wedemeyer, W. J., and Scheraga, H. A. (1998) Biochemistry 37, 11614-11620]. The essence of this method is to introduce a fluorescent residue (Tyr or Trp) in a position adjacent to the isomerizing proline (if one is not already present) and to eliminate the fluorescence of other such residues adjacent to prolines by mutating them to phenylalanine. Here, we extend this method to observe the cis-trans isomerization of these peptide groups under folding conditions using two site-directed mutants (Y92F and Y115F) of RNase A. Both isomerizations decelerate with increasing concentrations of GdnHCl, with nearly identical m values (1.11 and 1.19 M(-1), respectively) and extrapolated zero-GdnHCl time constants (42 and 32 s, respectively); by contrast, under unfolding conditions, the cis-trans isomerizations of both Pro93 and Pro114 are independent of GdnHCl concentration. Remarkably, the isomerization rates under folding conditions at GdnHCl concentrations above 1 M are significantly slower than those measured under unfolding conditions. The temperature dependence of the Pro114 isomerization under folding conditions is also unusual; whereas Pro93 exhibits an activation energy typical of proline isomerization (19.4 kcal/mol), Pro114 exhibits a sharply reduced activation energy of 5.7 kcal/mol. A structurally plausible model accounts for these results and, in particular, shows that folding conditions strongly accelerate the cis-trans isomerization of both peptide groups to their native cis conformation, suggesting the presence of flickering local structure in their beta-hairpins.
Animals↗
Stereoselective metabolism of 2-phenylpropionic acid in rat. I. In vitro studies on the stereoselective isomerization and glucuronidation of 2-phenylpropionic acid.
Optical isomerization of 2-phenylpropionic acid (hydratropic acid, HTA) was studied in the organs of male rat in vitro. (R)-(-)-HTA was not isomerized by rat liver homogenate even after the addition of CoA, ATP, and Mg2+ to the incubation mixture; however, it was isomerized slowly but significantly in liver slices. This suggests that some additional factor(s) are required for the optical isomerization of HTA in rat liver homogenate. Kidney slices showed about 3-fold higher isomerizing activity of (R)-(-)-HTA than liver slices. (S)-(+)-HTA was also slightly isomerized to (R)-(-)-HTA in kidney slices suggesting that the isomerization of HTA is stereoselective but not stereospecific. The liver and the kidney were considered to be the major organs for isomerization of HTA, since the isomerizing activity of the small intestine was low and other tissues examined were inactive. Change of the incubation medium of liver slices from Krebs-Ringer bicarbonate buffer to Krebs-Ringer buffer without bicarbonate, 0.25 M sucrose solution with 0.05 M Tris-HCl buffer (pH 7.4) or 0.9% NaCl solution with 0.05 M Tris-HCl buffer (pH 7.4) increased the isomerization rate of (R)-(-)-HTA to (S)-(+)-HTA, but decreased the glucuronide formation. During incubation of racemic HTA with liver slices, (S)-(+)-enantiomer percentage in HTA acyl glucuronide (HTA-G) increased with time, whereas that of the free HTA remained nearly constant. These results suggested the stereoselective hydrolysis of (R)-(-)-HTA-G in liver slices, which was confirmed by the results from incubation of HTA-G with rat liver preparations. Kidney homogenate also preferentially hydrolyzed (R)-(-)-HTA-G.
Animals↗
Escherichia coli fumarase A catalyzes the isomerization of enol and keto oxalacetic acid.
Fumarase A, a product of the fumA gene of Escherichia coli, has been found to catalyze the isomerization of enol to keto oxalacetic acid (OAA) in addition to catalyzing the fumarase reaction. The kcat/Km for the isomerization is almost identical to that for the fumarase reaction. The isomerization reaction apparently takes place at the same active site as the fumarase reaction since both reactions show a similar sensitivity to inactivation by O2, both reactions are strongly inhibited by 2-hydroxy-3-nitropropionate, and the isomerization reaction is inhibited by fumarate and malate. The isomerization requires the presence of a [4Fe-4S] or [3Fe-4S] cluster, perhaps for structural rather than catalytic reasons. Hydration of enol OAA to the gem diol has been ruled out as a possible mechanism of isomerization on the basis of the preservation of the oxygen on carbon 2 and the position of protonation on carbon 3. The isomerization is not stereospecific in the position of protonation at carbon 3 but appears to be stereoselective, with protonation preferentially occurring in the 3-pro-S position. Porcine fumarase, isopropyl malate isomerase, and dihydroxyacid dehydratase do not catalyze this isomerization. Fumarase A and aconitase, two enzymes with 4Fe-4S clusters that bind a linear 4-carbon dicarboxylic acid moiety in the trans conformation during their normal hydro-lyase reaction, do catalyze this isomerization.
Aconitate Hydratase↗
Isomerization of all-trans-9- and 13-desmethylretinol by retinal pigment epithelial cells.
Photoisomerization of 11-cis-retinal to all-trans-retinal triggers phototransduction in the retinal photoreceptor cells and causes ultimately the sensation of vision. 11-cis-Retinal is enzymatically regenerated through a complex set of reactions in adjacent retinal pigment epithelial cells (RPE). In this study using all-trans-9-desmethylretinol (lacking the C(19) methyl group) and all-trans-13-desmethylretinol (lacking the C(20) methyl group), we explored the effects of C(19) and C(20) methyl group removals on isomerization of these retinols in RPE microsomes. The C(19) methyl group may be involved in the substrate activation, whereas the C(20) methyl group causes steric hindrance with a proton in position C(10) of 11-cis-retinol; thus, removal of this group could accelerate isomerization. We found that all-trans-9-desmethylretinol and all-trans-13-desmethylretinol are isomerized to their corresponding 11-cis-alcohols, although with lower efficiencies than isomerization of all-trans-retinol to 11-cis-retinol. These findings make the mechanism of isomerization through the C(19) methyl group unlikely, because in the case of 9-desmethylretinol, the isomerization would have to progress by proton abstraction from electron-rich olefinic C(9). The differences between all-trans-retinol, all-trans-9-desmethylretinol, and all-trans-13-desmethylretinol appear to be a consequence of the enzymatic properties, and binding affinities of the isomerization system, rather than differences in the chemical or thermodynamic properties of these compounds. This observation is also supported by quantum chemical calculations. It appears that both methyl groups are not essential for the isomerization reaction and are not likely involved in formation of a transition stage during the isomerization process.
Alcohol Oxidoreductases↗
[3H]Pirenzepine and [3H]quinuclidinyl benzilate binding to brain muscarinic cholinergic receptors. Differences in measured receptor density are not explained by differences in receptor isomerization.
Muscarinic receptor densities were measured in membranes prepared from rat cerebral cortex using [3H]pirenzepine and [3H]quinuclidinyl benzilate. Isotherms of equilibrium binding data modeled to a single apparent binding site for both ligands. However, as has been reported previously, [3H]pirenzepine labeled only a small fraction of the binding sites that were labeled by [3H]quinuclidinyl benzilate. This observation has been used to support the hypothesis that subtypes of muscarinic receptors exist. Several investigators have previously suggested that antagonist binding to muscarinic receptors involves an isomerization of the receptor-antagonist complex, and it is only the isomerized form of the receptor that is identified by radioligand binding studies. To examine the possibility that the difference in the density of binding sites identified by [3H]pirenzepine and [3H]quinuclidinyl benzilate is due to differences in the degree of isomerization of the receptor associated with the binding of each ligand, the kinetics of the binding of [3H]pirenzepine and [3H]quinuclidinyl benzilate to membranes prepared from rat cerebral cortex were examined. The pseudo-first-order rate constant of association for both ligands showed a nonlinear (hyperbolic) dependence on ligand concentration. These results suggested that a rapidly equilibrating initial binding step was followed by a more slowly equilibrating isomerization of the initially formed ligand-receptor complex. The kinetic data were computer-modeled to obtain estimates of the equilibrium constants for both reaction steps. The equilibrium constants for the isomerization step were 0.1 and 0.004 for [3H]pirenzepine and [3H]quinuclidinyl benzilate, respectively. Our measurements, in agreement with others, suggested that only the fraction of receptors which isomerized were measurable using filtration binding assays. Although essentially all (99.6%) of the [3H]quinuclidinyl benzilate binding sites appeared to isomerize, only 90% of the [3H]pirenzepine binding sites isomerized, and thus only 90% were measured in our assay. It therefore appears that differences in receptor isomerization can partially, but not wholly, account for the differences between [3H]pirenzepine and [3H]quinuclidinyl benzilate binding in rat cerebral cortex.
Animals↗
Cardiac rhythm in atrial isomerism.
Standard electrocardiograms from 126 consecutive patients with atrial isomerism were reviewed. Of 67 patients with left isomerism, 49 had sinus rhythm, 8 nodal rhythm and 10 atrioventricular (AV) block. Fifty-eight of 59 patients with right isomerism had sinus rhythm. Complete AV block was significantly more frequent in association with AV septal defect in left isomerism (5 of 45 patients) than in right isomerism (0 of 47 patients, p = 0.049). The P-wave axis was superior in 49% of patients with left isomerism but did not correlate with abnormalities of systemic or pulmonary venous connection. A significant shift of P-wave axis (more than 90 degrees) was seen on a subsequent electrocardiogram in 14 of 44 patients (32%) with left isomerism and 2 of 16 (13%) with right isomerism. Ambulatory electrocardiographic monitoring in 17 patients (14 with left isomerism) showed that only 4 had sinus rhythm throughout 24 hours. Only 1 patient with complete AV block received a permanent pacemaker. Despite the high incidence of electrocardiographic abnormalities, significant arrhythmias appear to be rare. The arrhythmias apparently do not influence the natural history of this condition or affect the outcome of palliative or corrective surgery. The prognosis is determined mainly or solely by the associated anatomic abnormalities.
Arrhythmias, Cardiac↗