Theoretical Study of the Photoisomerization Mechanism of All-Trans-Retinyl Acetate.
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ABSTRACT:
SUBMITTER: Kochman MA
PROVIDER: S-EPMC8488936 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeMice lacking retinal pigment epithelium-specific 65-kDa protein (RPE65) develop retinopathy and blindness resembling Leber congenital amaurosis. Effects of 9-cis-retinyl acetate (9-cis-R-Ac) on visual function and retinopathy progression were tested in Rpe65(-/-) mice.MethodsYoung C57Bl/6 mice were given 9-cis-R-Ac in each of four different oil-based vehicle solutions by gastric gavage to identify the vehicle most suitable for drug delivery by measuring retinoid levels in plasma. Then doses of 9-cis-R-Ac ranging from 1 to 100 mg/kg were administered to 5- to 12-week-old Rpe65(-/-) mice by different treatment regimens, including single doses and either intermittent or daily doses for various periods up to 8 weeks. Retinoid effects on visual function were evaluated by electroretinography, retinoid analyses, histologic methods, and vision-dependent behavioral testing.ResultsSoybean oil vehicle provided the highest 9-cis-R-Ac metabolite levels in plasma. Single doses of 9-cis-R-Ac (6.25-50 mg/kg) provided significant dose-dependent improvement in electroretinographic responses. Well-tolerated daily doses (1-12.5 mg/kg) for 2 weeks induced remarkable improvement of retinal function. Significant dose-dependent improvement of electroretinographic responses was observed 6 days after administration of 9-cis-R-Ac daily for 3 days at 1 to 12.5 mg/kg. Mice given either daily or intermittent 9-cis-R-Ac treatment at 1 and 4 mg/kg and evaluated 8 weeks later displayed dose-dependent improvement of retinal function and morphology, whereas retinal function deteriorated in control animals. Treated mice also performed better than control animals in vision-dependent behavioral tests.ConclusionsTreatment with 9-cis-R-Ac improves visual function and preserves retinal morphology in Rpe65(-/-) mice.
| S-EPMC2764364 | biostudies-literature
Project description:Long-term effects of treatment with 9-cis-retinyl acetate (9-cis-R-Ac), an artificial retinoid prodrug, were tested on changes in rod and cone visual functions in mice.The acetyl ester of the functional geometric chromophore 9-cis-retinal was delivered by oral gavage to C57BL/6 female mice. In initial experiments, 10-month-old mice were used for the single treatment with 9-cis-R-Ac or the control vehicle. In long-term experiments, 4-month-old mice were treated with 9-cis-R-Ac monthly for 6 and 10 months. Photoreceptor status was evaluated by various electroretinographic (ERG) techniques, retinoid analyses, and retinal morphology. Opsin, the predicted target of oxidized 9-cis-R-Ac, was purified and its chromophore was characterized.Age-related changes observed in vehicle-treated mice at 10 months of age, compared with those in 4-month-old mice, included a progressive decline in ERG responses, such as a decreased rate of dark adaptation and a lowered rhodopsin/opsin ratio. Administration of 9-cis-R-Ac increased the rhodopsin regeneration ratio, and improved ERG responses and dark adaptation. Compared with vehicle-treated control animals, 10- and 14-month-old mice treated monthly with 9-cis-R-Ac for 6 or 10 months exhibited improved dark adaptation. In 14-month-old mice treated monthly, changes in the expression of retina-specific genes in the eye were detected by mRNA expression profiling, but no significant effects in gene expression were detected in the liver and kidney.Deteriorating photoreceptor function documented in mice at 10 and 14 versus 4 months of age was improved significantly by long-term, monthly administration of 9-cis-R-Ac. These findings suggest a potential therapeutic approach to prevent age-related retinal dysfunction.
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Project description:Ruthenium nitrosyl complexes are fascinating versatile photoactive molecules that can either undergo NO linkage photoisomerization or NO photorelease. The photochromic response of three ruthenium mononitrosyl complexes, trans-[RuCl(NO)(py)₄]2+, trans-[RuBr(NO)(py)₄]2+, and trans-(Cl,Cl)[RuCl₂(NO)(tpy)]⁺, has been investigated using density functional theory and time-dependent density functional theory. The N to O photoisomerization pathways and absorption properties of the various stable and metastable species have been computed, providing a simple rationalization of the photoconversion trend in this series of complexes. The dramatic decrease of the N to O photoisomerization efficiency going from the first to the last complex is mainly attributed to an increase of the photoproduct absorption at the irradiation wavelength, rather than a change in the photoisomerization pathways.
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Project description:Ab initio methods are used to characterize the ground and first excited state of the chromophore in the rhodopsin family of proteins: retinal protonated Schiff base. Retinal protonated Schiff base has five double bonds capable of undergoing isomerization. Upon absorption of light, the chromophore isomerizes and the character of the photoproducts (e.g., 13-cis and 11-cis) depends on the environment, protein vs. solution. Our ab initio calculations show that, in the absence of any specific interactions with the environment (e.g., discrete ordered charges in a protein), energetic considerations cannot explain the observed bond selectivity. We instead attribute the origin of bond selectivity to the shape (topography) of the potential energy surfaces in the vicinity of points of true degeneracy (conical intersections) between the ground and first excited electronic states. This provides a molecular example where a competition between two distinct but nearly isoenergetic photochemical reaction pathways is resolved by a topographical difference between two conical intersections.
| S-EPMC122268 | biostudies-literature
Project description:This research was based on the quantum chemical calculations of a set of valid photoswitches of azobenzene compounds, with the aim of describing their thermal isomerization. The influences of familiar fluorine substitution and additional electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) on the para-position were also systematically studied. The results show that the presence of fluorine in different ortho-positions has a distinct effect on the molecular orbital distribution of the E isomer, which realizes the purpose of splitting the n → π* transition between the E and Z isomers. On this basis, further para-substitution can allow tunability on the order of the energy level to the molecular orbitals through their influence on the conjugation pattern of the compound. It is the modification of the substituent on these positions that allows the photoisomerization to proceed under visible wavelength light surroundings. The thermal Z → E isomerization mechanism has also been analyzed, and a detailed comparison of these compounds has been made with respect to the thermal half-life τ 1/2, and the rate constants k Z-E . The results reveal that isomerization is thought to be a process of globally structural change, during which the effect of the substituents is determined by the extent of their influence on the conjugated system.
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Project description:BACKGROUND:Better methods are needed for determining vitamin A absorption efficiency in humans to support development of dietary recommendations and to improve the accuracy of predictions of vitamin A status. OBJECTIVES:We developed and evaluated a method for estimating vitamin A absorption efficiency based on compartmental modeling of theoretical data on postprandial plasma retinyl ester (RE) kinetics. METHODS:We generated data on plasma RE and retinol kinetics (30 min to 8 h or 56 d, respectively) after oral administration of labeled vitamin A for 12 theoretical adults with a range of values assigned for vitamin A absorption (55-90%); we modeled all data to obtain best-fit values for absorption and other parameters using Simulation, Analysis, and Modeling software. We then modeled RE data only (16 or 10 samples), with or without added random error, and compared assigned to predicted absorption values. We also compared assigned values to areas under RE response curves (RE AUCs). RESULTS:We confirmed that a unique value for vitamin A absorption cannot be identified by modeling plasma retinol tracer kinetics. However, when RE data were modeled, predicted vitamin A absorptions were within 1% of assigned values using data without error and within 12% when 5% error was included. When the sample number was reduced, predictions were still within 13% for 10 of the 12 subjects and within 23% overall. Assigned values for absorption were not correlated with RE AUC (P = 0.21). CONCLUSIONS:We describe a feasible and accurate method for determining vitamin A absorption efficiency that is based on compartmental modeling of plasma RE kinetic data collected for 8 h after a test meal. This approach can be used in a clinical setting after fasting subjects consume a fat-containing breakfast meal with a known amount of vitamin A or a stable isotope label.
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Project description:Theoretical investigations are performed on mechanism and kinetics of the reaction of halogen peroxy radical ClOO with NO radical. The electronic structure information for both of the singlet and triplet potential energy surfaces (PESs) is obtained at the MP2/6-311 + G(2df) level of theory, and the single-point energies are refined by the CCSD(T)/6-311 + G(2df) level. The rate constants for various product channels of the reaction in the pressure range of 1-7600 Torr are predicted. The main results are as follows: On the singlet surface, the addition-elimination mechanism is the most important. First, the N atom of the NO radical can attack the O atom of the ClOO radical to form an energy-riched intermediate IM1 ClOONOtp (21.3 kcal/mol) barrierlessly, then IM1 could isomerizes to IM2 ClOONOcp (22.1 kcal/mol) via a low energy barrier. Both IM1 and IM2 can dissociate to the primary product P? ClNO + ¹O? and the secondary product P? ClO + NO?. On the triplet surface, the direct Cl-abstraction reaction is the most feasible pathway. The Cl-abstraction can take place via a van der Waals complex, ³IM1 ONClOO (4.1 kcal/mol), then it fragments readily to give P?' ClNO + ³O? with a small barrier. The kinetic calculations show that at low temperatures, the singlet bimolecular product P? is the primary product, while at high temperatures, the triplet product P?' becomes the primary one; only at high pressures and low temperatures, the unimolecular products IM1 and IM2 can be found with quite small yields. At experimentally measured temperature 213 K, ClNO is the primary product in the whole pressure range, which is consistent with the previous experiment. The present study may be useful for further experimental studies for the title reaction.
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Project description:Due to the recently uncovered health benefits and anti-HIV activities of dicaffeoylquinic acids (diCQAs), understanding their structures and functions is of great interest for drug discovery efforts. DiCQAs are analytically challenging to identify and quantify since they commonly exist as a diverse mixture of positional and geometric (cis/trans) isomers. In this work, we utilized ion mobility spectrometry coupled with mass spectrometry to separate the various isomers before and after UV irradiation. The experimental collision cross sections were then compared with theoretical structures to differentiate and identify the diCQA isomers. Our analyses found that naturally the diCQAs existed predominantly as trans/trans isomers, but after 3 h of UV irradiation, cis/cis, cis/trans, trans/cis, and trans/trans isomers were all present in the mixture. This is the first report of successful differentiation of cis/trans diCQA isomers individually, which shows the great promise of IMS coupled with theoretical calculations for determining the structure and activity relationships of different isomers in drug discovery studies.
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Project description:Density functional theory calculations are used to investigate the detailed reaction mechanism of benzoylformate decarboxylase, a thiamin diphosphate (ThDP)-dependent enzyme that catalyzes the nonoxidative decarboxylation of benzoylformate yielding benzaldehyde and carbon dioxide. A large model of the active site is constructed on the basis of the X-ray structure, and it is used to characterize the involved intermediates and transition states and evaluate their energies. There is generally good agreement between the calculations and available experimental data. The roles of the various active site residues are discussed and the results are compared to mutagenesis experiments. Importantly, the calculations identify off-cycle intermediate species of the ThDP cofactor that can have implications on the kinetics of the reaction.
| S-EPMC6028569 | biostudies-literature
Project description:1. retro-Retinyl acetate was shown to exert its biological activity by conversion into vitamin A. 2. When administered orally, retro-retinyl acetate was hydrolysed to retro-retinol in the intestine, isomerized to retinol and esterified before being transported to the liver for storage. 3. Administration of the compound at as high a dose as 4.0mg./day for 4 days led to the accumulation of both vitamin A and retro-vitamin A in the liver. The amount of retro-vitamin A in liver gradually decreased until it was almost completely converted into vitamin A in 18 days. 4. Intraperitoneal administration of the compound led to the accumulation of both vitamin A and retro-vitamin A in liver and other tissues. No vitamin A was detected in any tissue of rats receiving retro-retinyl acetate intraperitoneally after enterectomy. 5. The small intestine is the major site of conversion of retro-vitamin A into vitamin A. The conversion could also be demonstrated by everted intestinal sacs. 6. The biological potency of retro-retinyl acetate determined by the rat-growth assay was 20.5% that of all-trans-retinyl acetate, when given orally.
| S-EPMC1270440 | biostudies-other