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PubMed1980

Potential prophylactic antitumor activity of retinylidene 1,3-diketones.

Treatment of all-trans-retinal with a series of 1,3-diketones using Knoevenagel conditions gave the expected condensation products. These retinylidene 1,3-diketones were characterized and their biological activities in the hamster tracheal organ culture test measured. It was found that the cyclohexane- 1,3-dione derivatives are highly active in this in vitro assay, while other 1,3-diketones are less active. Retinylidenedimedone has been chosen for further evaluation.

Animals↗
PubMed2006

Molecular evolution of adrenoceptors and dopamine receptors: implications for the binding of catecholamines.

We derived homology models for all human catecholamine-binding GPCRs (CABRs; the alpha-1, alpha-2, and beta-adrenoceptors and the D1-type and D2-type dopamine receptor) using the bovine rhodopsin-11-cis-retinal X-ray structure. Interactions were predicted from the endogenous ligands norepinephrine or dopamine and from the binding site and were used to optimize receptor-ligand interactions. Similar binding modes in the complexes agree with a large "binding core" conserved across the CABRs, that is, D3.32, V(I)3.33, T3.37, S5.42, S(A/C)5.43, S5.46, F6.51, F6.52, and W6.48. Model structures and docking simulations suggest that extracellular loop 2 could provide a common attachment point for the ligands' beta-hydroxyl via a hydrogen bond donated by the main-chain NH group of residue xl2.52. The modeled CABRs and docking modes are in good agreement with published experimental studies. Complementarity between the ligand and the binding site suggests that the bovine rhodopsin structure is a suitable template for modeling agonist-bound CABRs.

Adrenergic Agonists↗
PubMed2000

A highly stereoselective synthesis of 11Z-retinal using tricarbonyliron complex.

A stereoselective synthesis of 11Z-retinal 2, which is the chromophore of visual pigment (rhodopsin), was accomplished from the beta-ionylideneacetaldehyde-tricarbonyliron complex 3. The Peterson reaction of 3 using ethyl trimethylsilylacetate smoothly proceeded to afford predominantly the Z-ester 6. Transformation of the Z-ester 6 to the methyl ketone 19, followed by the Emmons-Horner reaction of 19 with C2-cyanophosphonate, produced ethyl 11Z, 13E-retinonitrile-tricarbonyliron complex 21 as the only product. Decomplexation of 21 with CuCl2 and subsequent DIBAL reduction gave 11Z-retinal 2 in excellent yield. Mechanistic consideration of Z-selectivity in the Peterson reaction of the aldehyde-tricarbonyliron complex is also discussed.

Ferric Compounds↗
PubMed2005

Calculating absorption shifts for retinal proteins: computational challenges.

Rhodopsins can modulate the optical properties of their chromophores over a wide range of wavelengths. The mechanism for this spectral tuning is based on the response of the retinal chromophore to external stress and the interaction with the charged, polar, and polarizable amino acids of the protein environment and is connected to its large change in dipole moment upon excitation, its large electronic polarizability, and its structural flexibility. In this work, we investigate the accuracy of computational approaches for modeling changes in absorption energies with respect to changes in geometry and applied external electric fields. We illustrate the high sensitivity of absorption energies on the ground-state structure of retinal, which varies significantly with the computational method used for geometry optimization. The response to external fields, in particular to point charges which model the protein environment in combined quantum mechanical/molecular mechanical (QM/MM) applications, is a crucial feature, which is not properly represented by previously used methods, such as time-dependent density functional theory (TDDFT), complete active space self-consistent field (CASSCF), and Hartree-Fock (HF) or semiempirical configuration interaction singles (CIS). This is discussed in detail for bacteriorhodopsin (bR), a protein which blue-shifts retinal gas-phase excitation energy by about 0.5 eV. As a result of this study, we propose a procedure which combines structure optimization or molecular dynamics simulation using DFT methods with a semiempirical or ab initio multireference configuration interaction treatment of the excitation energies. Using a conventional QM/MM point charge representation of the protein environment, we obtain an absorption energy for bR of 2.34 eV. This result is already close to the experimental value of 2.18 eV, even without considering the effects of protein polarization, differential dispersion, and conformational sampling.

Absorption↗
PubMed2005

Tuning of retinal twisting in bacteriorhodopsin controls the directionality of the early photocycle steps.

Productive proton pumping by bacteriorhodopsin requires that, after the all-trans to 13-cis photoisomerization of the retinal chromophore, the photocycle proceeds with proton transfer and not with thermal back-isomerization. The question of how the protein controls these events in the active site is addressed here using quantum mechanical/molecular mechanical reaction-path calculations. The results indicate that, while retinal twisting significantly contributes to lowering the barrier for the thermal cis-trans back-isomerization, the rate-limiting barrier for this isomerization is still 5-6 kcal/mol larger than that for the first proton-transfer step. In this way, the retinal twisting is finely tuned so as to store energy to drive the subsequent photocycle while preventing wasteful back-isomerization.

Bacteriorhodopsins↗
PubMed2006

Exploring the molecular mechanism for color distinction in humans.

We examine here the role of the red, green, and blue human opsin structures in modulating the absorption properties of 11-cis-retinal bonded to the protein via a protonated Schiff base (PSB). We built the three-dimensional structures of the human red, green, and blue opsins using homology modeling techniques with the crystal structure of bovine rhodopsin as the template. We then used quantum mechanics (QM) combined with molecular mechanics (MM) (denoted as QM/MM) techniques in conjunction with molecular dynamics to determine how the room temperature molecular structures of the three human color opsin proteins modulate the absorption frequency of the same bound 11-cis-retinal chromophore to account for the differences in the observed absorption spectra. We find that the conformational twisting of the 11-cis-retinal PSB plays an important role in the green to blue opsin shift, whereas the dipolar side chains in the binding pocket play a surprising role of red-shifting the blue opsin with respect to the green opsin, as a fine adjustment to the opsin shift. The dipolar side chains play a large role in the opsin shift from red to green.

Amino Acid Sequence↗
PubMed2006

Solvent effects on the low-lying excited states of a model of retinal.

The low-lying excited states of a solution in alcohol of a five-double-bond model of the rhodopsin protein chromophore, the protonated 11-cis-retinal Schiff base (PSB11), are studied theoretically. We combine a multireference perturbational treatment in the description of the solute molecule with molecular dynamics calculations in the description of the solvent. The geometry, charge distribution, and electronic spectra are strongly influenced by the solvent. The solvent shift values show a marked dependence on the use of relaxed geometries in solution and on the nature of the states involved in the excitation process. The dynamic correlation has a strong effect on the order of the excited states. In solution, the first two excited states almost become degenerate.

Alcohols↗
PubMed2007

The role of the beta-ionone ring in the photochemical reaction of rhodopsin.

Time-dependent density functional theory (TDDFT) calculations on the photoabsorption process of the 11-cis retinal protonated Schiff base (PSB) chromophore show that the Franck-Condon relaxation of the first excited state of the chromophore involves a torsional twist motion of the beta-ionone ring relative to the conjugated retinyl chain. For the ground state, the beta-ionone ring and the retinyl chain of the free retinal PSB chromophore form a -40 degrees dihedral angle as compared to -94 degrees for the first excited state. The double bonds of the retinal are shorter for the fully optimized structure of the excited state than for the ground state suggesting a higher cis-trans isomerization barrier for the excited state than for the ground state. According to the present TDDFT calculations, the excitation of the retinal PSB chromophore does not primarily lead to a reaction along the cis-trans torsional coordinate at the C11-C12 bond. The activation of the isomerization center seems to occur at a later stage of the photo reaction. The results obtained at the TDDFT level are supported by second-order Møller-Plesset (MP2) and approximate singles and doubles-coupled cluster (CC2) calculations on retinal chromophore models; the MP2 and CC2 calculations yield for them qualitatively the same ground state and excited-state structures as obtained in the density functional theory and TDDFT calculations.

Bacteriorhodopsins↗
PubMed1999

Enantioselective binding of an 11-cis-locked cyclopropyl retinal. The conformation of retinal in bovine rhodopsin.

[formula: see text] The conformation of the retinal chromophore in rhodopsin is central for understanding the visual transduction process. The absolute twist around the 12-s bond of the chromophore in rhodopsin has been determined by studies with 11-cis-locked 11,12-cyclopropylretinal analogues (11S,12R)-2 and (11R,12S)-3, enantioselectively synthesized with the aid of an enzyme. The finding that enantiomer 2 binds to opsin while the other 3 does not defines the absolute sense of twist around the 12-s bond.

Animals↗
PubMed2001

Free radical lipid peroxidation inhibits enzymatic conversion of beta-carotene into vitamin A.

Free radical oxidation of arachidonic acid with soybean lipoxygenase was accompanied by inhibition of retinal synthesis from beta-carotene catalyzed by enzyme preparation from rabbit intestinal mucosa. Lipoxygenase inhibitor salicylhydroxamic acid and antioxidants suppressing free radical reactions (ethyl gallate, alpha-tocopherol, astaxanthine, and quercetin) promoted conversion of beta-carotene into retinal catalyzed by beta-carotene-15,15'-dioxygenase. These results indicate that lipoperoxides and/or products of their homolysis attenuate enzymatic conversion of beta-carotene and confirm the important role of natural antioxidants in the maintenance of stable vitamin A content in mammals.

Animals↗
PubMedDate not supplied

[A convenient synthesis of retinal derivatives with a modified trimethylcyclohexene ring].

A method of simultaneous one-stage synthesis of three retinal derivatives (5,6-dioxo-5,6-seco-, 5,6-dihydro-5,6-epoxy-, and 4-oxoretinal) was proposed, with the yield of the first derivative being approximately 50%. These compounds are useful tools for studying the antitumor activity of retinoids, the reconstituted bacteriorhodopsin analogues with changed parameters of photocycle, and the reactivity of retinal derivatives in the processes of oxidation by molecular oxygen. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol. 28, no. 6; see also http://www.maik.ru.

Cyclohexanes↗
PubMed1998

Differential rhodopsin regeneration in photoreceptor membranes is correlated with variations in membrane properties.

Rhodopsin, the major transmembrane protein in both the plasma membrane and the disk membranes of photoreceptor rod outer segments (ROS) forms the apo-protein opsin upon the absorption of light. In vivo the regeneration of rhodopsin is necessary for subsequent receptor activation and for adaptation, in vitro this regeneration can be followed after the addition of 11-cis retinal. In this study we investigated the ability of bleached rhodopsin to regenerate in the compositionally different membrane environments found in photoreceptor rod cells. When 11-cis retinal was added to bleached ROS plasma membrane preparations, rhodopsin did not regenerate within the same time course or to the same extent as bleached rhodopsin in disk membranes. Over 80% of the rhodopsin in newly formed disks regenerated within 90 minutes while only 40% regenerated in older disks. Since disk membrane cholesterol content increases as disks are displaced from the base to the apical tip of the outer segment, we looked at the affect of membrane cholesterol content on the regeneration process. Enrichment or depletion of disk membrane cholesterol did not alter the % rhodopsin that regenerated. Bulk membrane properties measured with a sterol analog, cholestatrienol and a fatty acid analog, cis parinaric acid, showed a more ordered, less "fluid", lipid environment within plasma membrane relative to the disks. Collectively these results show that the same membrane receptor, rhodopsin, functions differently as monitored by regeneration in the different lipid environments within photoreceptor rod cells. These differences may be due to the bulk properties of the various membranes.

Animals↗
PubMed2000

Low cleavage activity of 15,15'dioxygenase to convert beta-carotene to retinal in cattle compared with goats, is associated with the yellow pigmentation of adipose tissue.

Two experiments (one with twelve heifers and the other with 14 goats) were designed to evaluate the effect of increasing dietary beta-carotene concentration on the activity of the cleaving enzyme 15,15' beta-carotene dioxygenase and the concentration of beta-carotene and retinol in selected tissues. The experiments lasted 120 days. During the first 90 days animals were offered a beta-carotene unsupplemented diet. In the following 30 days, they were distributed to one of three treatments: 0, 5.5 or 352 mg of beta-carotene/kg of dry matter intake. All animals were slaughtered at the end. In heifers the concentration of beta-carotene in plasma, reflected the level of beta-carotene fed. Goats had detectable levels of beta-carotene only on day 10 of supplementation. In the liver, beta-carotene concentrations were highest with the 352 dose in both species. Heifers had the highest concentration of beta-carotene in the adipose tissue. In bovines, no interaction between beta-carotene treatment and intestinal sampling site was found (P > 0.2) for the activity of 15,15 dioxygenase. Across beta-carotene levels, results of the enzyme assay were: 0.19, 0.32 and 0.45 nmol retinal/(mg S-9 protein/h) (P < 0.01) for 0, 5.5 and 352 mg beta-carotene.kg dry matter intake -1.d-1, respectively; across intestinal sampling sites results of the enzyme assay were 0.45, 0.43 and 0.08 nmol retinal/(mg S-9 protein/h) (P < 0.01) for duodenum, jejunum and ileum, respectively. Caprine data showed an interaction between beta-carotene treatment and intestinal sampling site (P < 0.05) for the activity of 15,15 dioxygenase. The results for treatment 0 were: 1.4, 1.4 and 0; for treatment 5.5: 1.41, 1.42 and 0.13; and for treatment 352: 1.46, 1.99 and 0.48 nmol retinal/mg S-9 protein/h for duodenum, jejunum and ileum, respectively. The lower levels of duodenal and jejunal 15,15'dioxygenase activity in cattle compared with goats, may explain the greater pigmentation of adipose tissue in the former ruminant specie.

Adipose Tissue↗
PubMed2003

Differential expression of heparin-binding EGF-like growth factor (HB-EGF) mRNA in normal human keratinocytes induced by a variety of natural and synthetic retinoids.

It was recently revealed that epidermal growth following topical treatment with all-trans retinoic acid (atRA) was at least partly induced by heparin-binding epidermal growth factor-like growth factor (HB-EGF) released from suprabasal keratinocytes. Since proliferation of keratinocytes appears to be one of the critical roles of atRA in depigmentation treatment and promotion of wound healing, HB-EGF is considered suitable for assessing the therapeutic value of topical retinoids. In this study, HB-EGF mRNA expression in normal human keratinocytes after atRA treatment was examined, and the effects of a variety of natural and synthetic retinoids were compared. The results of reverse transcription polymerase chain reaction (RT-PCR) suggested that induction of differentiation increased HB-EGF mRNA expression in cultured keratinocytes. Real-time PCR analyses revealed that HB-EGF mRNA expression was elevated dose-dependently with atRA, peaking at 12 h. This elevation was more prominent in confluent keratinocytes than in subconfluent cells, suggesting that differentiated keratinocytes are more subject to stimulation of HB-EGF expression by atRA than proliferating keratinocytes. HB-EGF mRNA was upregulated in differentiation-induced keratinocytes by all retinoids used in this study at 1 micromol/l, and marked upregulation was seen when treated with three isotypes of retinoic acid (atRA, and 9-cis and 13-cis retinoic acid). RARalpha-selective agonists (Am80, Am580, ER-38925, and TAC-101) and a panagonist of RARs (Re80) caused relatively low elevation of HB-EGF transcripts, as did all-trans retinol (Rol) and all-trans retinal (Ral). Although another panagonist (Ch55) showed the highest elevation of HB-EGF mRNA, it was relatively cytotoxic at the concentration employed. Ral and Rol were found to upregulate HB-EGF when used at 100 micromol/l to 1 mmol/l, to a similar extent of atRA at 1-10 micromol/l. The capacity of retinoids to upregulate HB-EGF may be an important index for investigation and development of an ideal synthetic retinoid, which has maximum benefits and minimum side-effects

Cells, Cultured↗