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PubMed2002

Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3.

Influence of vitamin A (retinol) on growth depends on its sequential oxidation to retinal and then to retinoic acid (RA), producing a ligand for RA receptors essential in development of specific tissues. Genetic studies have revealed that aldehyde dehydrogenases function as tissue-specific catalysts for oxidation of retinal to RA. However, enzymes catalyzing the first step of RA synthesis, oxidation of retinol to retinal, remain unclear because none of the present candidate enzymes have expression patterns that fully overlap with those of aldehyde dehydrogenases during development. Here, we provide genetic evidence that alcohol dehydrogenase (ADH) performs this function by demonstrating a role for Adh3, a ubiquitously expressed form. Adh3 null mutant mice exhibit reduced RA generation in vivo, growth deficiency that can be rescued by retinol supplementation, and completely penetrant postnatal lethality during vitamin A deficiency. ADH3 was also shown to have in vitro retinol oxidation activity. Unlike the second step, the first step of RA synthesis is not tissue-restricted because it is catalyzed by ADH3, a ubiquitous enzyme having an ancient origin.

Alcohol Dehydrogenase↗
PubMed2002

(1)H and (13)C MAS NMR evidence for pronounced ligand-protein interactions involving the ionone ring of the retinylidene chromophore in rhodopsin.

Rhodopsin is a member of the superfamily of G-protein-coupled receptors. This seven alpha-helix transmembrane protein is the visual pigment of the vertebrate rod photoreceptor cells that mediate dim light vision. In the active binding site of this protein the ligand or chromophore, 11-cis-retinal, is covalently bound via a protonated Schiff base to lysine residue 296. Here we present the complete (1)H and (13)C assignments of the 11-cis-retinylidene chromophore in its ligand-binding site determined with ultra high field magic angle spinning NMR. Native bovine opsin was regenerated with 99% enriched uniformly (13)C-labeled 11-cis-retinal. From the labeled pigment, (13)C carbon chemical shifts could be obtained by using two-dimensional radio frequency-driven dipolar recoupling in a solid-state magic angle spinning homonuclear correlation experiment. The (1)H chemical shifts were assigned by two-dimensional heteronuclear ((1)H-(13)C) dipolar correlation spectroscopy with phase-modulated Lee-Goldburg homonuclear (1)H decoupling applied during the t(1) period. The data indicate nonbonding interactions between the protons of the methyl groups of the retinylidene ionone ring and the protein. These nonbonding interactions are attributed to nearby aromatic acid residues Phe-208, Phe-212, and Trp-265 that are in close contact with, respectively, H-16/H-17 and H-18. Furthermore, binding of the chromophore involves a chiral selection of the ring conformation, resulting in equatorial and axial positions for CH(3)-16 and CH(3)-17.

Animals↗
PubMed2002

All-trans-retinal shuts down rod cyclic nucleotide-gated ion channels: a novel role for photoreceptor retinoids in the response to bright light?

In retinal rods, light-induced isomerization of 11-cis-retinal to all-trans-retinal within rhodopsin triggers an enzyme cascade that lowers the concentration of cGMP. Consequently, cyclic nucleotide-gated (CNG) ion channels close, generating the first electrical response to light. After isomerization, all-trans-retinal dissociates from rhodopsin. We now show that all-trans-retinal directly and markedly inhibits cloned rod CNG channels in excised patches. 11-cis-retinal and all-trans-retinol also inhibited the channels, but at somewhat higher concentrations. Single-channel analysis suggests that all-trans-retinal reduces average open probability of rod CNG channels by inactivating channels for seconds at a time. At physiological cGMP levels, all-trans-retinal inhibited in the nanomolar range. Our results suggest that all-trans-retinal may be a potent regulator of the channel in rods during the response to bright light, when there is a large surge in the concentration of all-trans-retinal.

Animals↗
PubMed2001

The relaxation dynamics of the excited electronic states of retinal in bacteriorhodopsin by two-pump-probe femtosecond studies.

We present the results of two-pump and probe femtosecond experiments designed to follow the relaxation dynamics of the lowest excited state (S(1)) populated by different modes. In the first mode, a direct (S(0) --> S(1)) radiative excitation of the ground state is used. In the second mode, an indirect excitation is used where the S(1) state is populated by the use of two femtosecond laser pulses with different colors and delay times between them. The first pulse excites the S(0) --> S(1) transition whereas the second pulse excites the S(1) --> S(n) transition. The nonradiative relaxation from the S(n) state populates the lowest excited state. Our results suggest that the S(1) state relaxes faster when populated nonradiatively from the S(n) state than when pumped directly by the S(0) --> S(1) excitation. Additionally, the S(n) --> S(1) nonradiative relaxation time is found to change by varying the delay time between the two pump pulses. The observed dependence of the lowest excited state population as well as its dependence on the delay between the two pump pulses are found to fit a kinetic model in which the S(n) state populates a different surface (called S'(1)) than the one being directly excited (S(1)). The possible involvement of the A(g) type states, the J intermediate, and the conical intersection leading to the S(0) or to the isomerization product (K intermediate) are discussed in the framework of the proposed model.

Bacteriorhodopsins↗
PubMed2000

Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness.

Mutations in the retinal pigment epithelium gene encoding RPE65 are a cause of the incurable early-onset recessive human retinal degenerations known as Leber congenital amaurosis. Rpe65-deficient mice, a model of Leber congenital amaurosis, have no rod photopigment and severely impaired rod physiology. We analyzed retinoid flow in this model and then intervened by using oral 9-cis-retinal, attempting to bypass the biochemical block caused by the genetic abnormality. Within 48 h, there was formation of rod photopigment and dramatic improvement in rod physiology, thus demonstrating that mechanism-based pharmacological intervention has the potential to restore vision in otherwise incurable genetic retinal degenerations.

Administration, Oral↗
PubMed2001

X-ray structure of sensory rhodopsin II at 2.1-A resolution.

Sensory rhodopsins (SRs) belong to a subfamily of heptahelical transmembrane proteins containing a retinal chromophore. These photoreceptors mediate the cascade of vision in animal eyes and phototaxis in archaebacteria and unicellular flagellated algae. Signal transduction by these photoreceptors occurs by means of transducer proteins. The two archaebacterial sensory rhodopsins SRI and SRII are coupled to the membrane-bound HtrI and HtrII transducer proteins. Activation of these proteins initiates phosphorylation cascades that modulate the flagellar motors, resulting in either attractant (SRI) or repellent (SRII) phototaxis. In addition, transducer-free SRI and SRII were shown to operate as proton pumps, analogous to bacteriorhodopsin. Here, we present the x-ray structure of SRII from Natronobacterium pharaonis (pSRII) at 2.1-A resolution, revealing a unique molecular architecture of the retinal-binding pocket. In particular, the structure of pSRII exhibits a largely unbent conformation of the retinal (as compared with bacteriorhodopsin and halorhodopsin), a hydroxyl group of Thr-204 in the vicinity of the Schiff base, and an outward orientation of the guanidinium group of Arg-72. Furthermore, the structure reveals a putative chloride ion that is coupled to the Schiff base by means of a hydrogen-bond network and a unique, positively charged surface patch for a probable interaction with HtrII. The high-resolution structure of pSRII provides a structural basis to elucidate the mechanisms of phototransduction and color tuning.

Animals↗
PubMed2001

Preservation of light signaling to the suprachiasmatic nucleus in vitamin A-deficient mice.

To investigate the role of retinal-based pigments (opsins) in circadian photoreception in mice, animals mutated in plasma retinol binding protein were placed on a vitamin A-free diet and tested for photic induction of gene expression in the suprachiasmatic nucleus. After 10 months on the vitamin A-free diet, the majority of mice contained no detectable retinal in their eyes. These mice demonstrated fully intact photic signaling to the suprachiasmatic nucleus as measured by acute mPer mRNA induction in the suprachiasmatic nucleus in response to bright or dim light. The data suggest that a non-opsin pigment is the primary circadian photoreceptor in the mouse.

Animals↗
PubMed2003

Isorhodopsin rather than rhodopsin mediates rod function in RPE65 knock-out mice.

The chromophore of visual pigments is 11-cis-retinal and, thus, in its absence, opsin is not photosensitive and no visual function exists. However, in the RPE65 knockout (Rpe65-/-) mouse, where synthesis of 11-cis-retinal does not occur, a minimal visual response from rod photoreceptors is obtained. We have examined if an alternative pathway exists for cis-retinoid generation in the absence of RPE65. Cyclic-light-reared, 2-month-old Rpe65-/- mice were placed in complete darkness. No exogenous retinoids were administered. After 4 weeks, enhanced a- and b-wave amplitudes were obtained, increasing >10-fold for the a-wave and >3-fold for the b-wave as compared with cyclic-light-reared Rpe65-/- mice. Visual-pigment levels increased to approximately 10 pmol per retina, compared with no measurable pigment for cyclic-light-reared Rpe65-/- mice. The lambdamax of the isolated pigment was 487 nm, characteristic for isorhodopsin. Retinoid extractions confirmed the presence of 9-cis-retinal and the absence of 11-cis-retinal. Once the Rpe65-/- mice were returned to cyclic light, within 48 h the electroretinogram function returned to levels found in Rpe65-/- mice maintained in cyclic light. This dark-mediated pathway is also operational in older animals, because 13-month-old Rpe65-/- mice kept in prolonged darkness (12 weeks) had increased isorhodopsin levels and electroretinogram a- and b-wave amplitudes. These studies demonstrate that a pathway exists in the eye for the generation of 9-cis-retinal that is independent of RPE65 and light.

Animals↗
PubMed1975

Isorhodopsin II: artificial photosensitive pigment formed from 9,13-dicis retinal.

We have found that in addition to the 11-cis and 9-cis isomers of retinal which are known to couple with the visual pigment apoprotein opsin to form pigments, a third isomer 9,13-dicis retinal also will form a pigment. That this isomer is indeed bound to opsin has been shown unequivocally by removing the chromophore without isomerization and subsequent identification by high-speed liquid chromatography. Using similar techniques, we have shown that the product of bleaching by light of all three pigments in Trition X-100 is the all-trans isomer. This specificity in the product of bleaching, as with many other properties of visual pigments, is not shared by the free chromophore. Of particular interest is that when 9,13-dicis retinal is combined with opsin to form a pigment, a single photon can isomerize it about two double bonds, to the all-trans isomer.

Binding Sites↗
PubMed1976

Retinal has a highly dipolar vertically excited singlet state: implications for vision.

We have measured the effect of an intense electric field on the absorption spectrum of solutions of all-trans retinal, its unprotonated Schiff base with n-butylamine, and the Cl- salt of this protonated Schiff base. The field-induced change in extinction coefficient as a function of wavelength was analyzed to determine the ground-state dipole moment (mug), the change in dipole moment on excitation (deltamu), and the direction of mug and deltamu). These experiments have shown that all three species become highly dipolar upon excitation to the first allowed excited singlet state (deltamu = 15.6, 9.9, 12D, respectively). The ground-state and excited-state dipole moments are nearly parallel to the long axis of these molecules. Excitation is accompanied by a shift of negative charge toward the carbonyl or Schiff base terminus, making the ionone end of these molecules positively charged. The large excited state dipole moment of all-trans retinal indicates that the vertically excited state, which is of 1Bu parentage (C2h), has become significantly mixed with even-parity states. On the basis of previous theoretical calculations, this mixing is expected to facilitate isomerization in the singlet manifold. We have also found that 11-cis retinal has a large deltamu (12.7 +/- 1.4 D) on excitation. In the visual pigments, the interaction of the excited-state dipole moment of retinal with a suitably located charged group could control the position of the absorption maximum. Also, the large shift in charge density upon excitation of retinal may lead to new electrostatic interactions between the chromophore and the protein that would act as a driving force for the initial conformational changes in visual excitation.

Chemical Phenomena↗
PubMed1977

Time-resolved resonance Raman spectroscopy of bacteriorhodopsin on the millisecond timescale.

A simple technique is described that uses a continuous wave laser with electromechanical modulation to obtain time-resolved Raman spectra of transient species on the millisecond timescale. The time behavior of the vibrational bands of the intermediates involved in the proton pumping of bacteriorhodopsin is determined. From these results, along with resonance enhancement and power dependence studies, the bands that appear in the continuous wave Raman spectrum of bacteriorhodopsin can be assigned to three intermediates in the photochemical cycle of bacteriorhodopsin, bR570, bL550, and bM412. The Raman spectra of bR570 and bM412 are compared with published spectra of model Schiff bases of all-trans and 13-cis retinal.

Bacteriorhodopsins↗
PubMed1978

The molecular mechanism of excitation in visual transduction and bacteriorhodopsin.

An electronic theory of excitation is proposed and described in terms of a three-dimensional excited/ground-state energy surface which elucidates the photochemical and excited-state dynamics of rhodopsins. In this theory the primary action of light is to produce significant electron redistribution in the retinal, thereby generating new interactions that vibrationally excite and perturb the ground-state protein conformation. Thus, light energy causes charge redistribution in the retinal and induces transient charge-density assisted bond rearrangements (such as proton translocation) in the protein structure which is stabilized by subsequent retinal structural alteration. In this theory the isoprenoid chain of the retinal is considered a structurally pliable molecular entity that can generate charge redistributions and can be subsequently achieve intermediate conformations or various isomeric states to minimize the energy of the new protein structure generated by light. Thus, the 11-cis to all trans isomerization of the retinylidene chromophore is not considered a primary mechanism of excitation. An alternate biological role for this molecular process (which is eventually completed in all photoreceptors but not in bacterial rhodopsins) is to provide the irreversibility needed for effective quantum detection on the time scale of a neural response. Finally, it will be demonstrated that this mechanism, which readily accounts for the photophysical and photochemical data, can also be restated in terms of the Monod, Wyman, and Changeux terminology suggesting that aggregates of these pigments may function allosterically.

Bacteriorhodopsins↗
PubMed1978

Charge stabilization mechanism in the visual and purple membrane pigments.

The effects of charged groups of rhodopsin and bacteriorhodopsin on the potential energy surface of their chromophore are examined, taking into account the protein dielectric effect. It is found that the barriers for twisting double bonds of an isolated chromophore can be drastically reduced when the chromophore interacts with the protein charges. New types of local minima are found in the ground-state potential surface of the protein-chromophore complex. These minima correspond to "charge-stabilized intermediates" which are formed when a shift of the chromophore positive charge to the ring is stabilized by the ionization of a properly placed acidic group of the protein and by partial alternation of the bond lengths of the chromophore. It is suggested that the absorption of light by rhodopsin and bacteriorhodopsin may be used not only for isomerization about double bonds, but also for trapping such charge-stabilized intermediates. Thus, for example, it is concluded that prelumirhodopsin might be still in the cis configuration. Both the mechanism of the proton pump system of the purple membrane and the dark reaction of the visual and purple membrane pigments are considered. The connection between the finding of the present work and the mechanism of storage of light energy in photobiology is indicated.

Bacteriorhodopsins↗
PubMed1980

Wavelength regulation in rhodopsin: effects of dipoles and amino acid side chains.

The effects of dipoles and aromatic amino acid side-chain models on the absorption and optical activity of the rhodopsin chromophore were calculated by using perturbation theory, and the results were compared with those of a Pariser-Parr-Pople calculation for the unperturbed system. The interaction was assumed to result from purely electrostatic interactions. It was concluded that the side chains of phenylalanine and tryptophan should have no important effects. However, the charge separation in tyrosine is sufficient to cause substantial electrostatic perturbation; in fact, the effect of tyrosine is large enough to approximately many of the spectral properties of rhodopsin quantitatively. This is encouraging because the use of aromatic amino acid side-chain analogs probably provides a better physical model than the use of isolated full charges, except in the case of the counterion to the protonated Schiff base.

Chemical Phenomena↗
PubMed1980

Anaerobic growth of halobacteria.

An energy-transducing pathway in halobacteria is described. Arginine mediates substrate level phosphorylation and allows the cells to grow anaerobically. Bacteriorhodopsin plus light can function as an alternative energy source under these conditions, provided the cells contain the pigment when transferred to the anaerobic environment. Therefore the selection of mutants functionally defective in ATP synthase or bacteriorhodopsin becomes possible.

Adenosine Triphosphate↗
PubMed1980

Location of the chromophore in bacteriorhodopsin.

We present a location for the retinylidene chromophore in dark-adapted bacteriorhodopsin based on the differences in neutron scattering between purple membrane preparations reconstituted with retinal and with deuterated retinal. The Fourier difference density map contains more peaks than expected, and additional arguments are introduced to exclude artificial peaks, caused by the reconstitution techniques or the limited resolution of the diffraction data. The membrane preparation used is necessarily dark-adapted and therefore contains 13-cis- and all-trans-retinal isomers in roughly equal amounts. However, we find only a single position for both isomers. Presumably, the difference in conformation caused by isomerization around the C13-C14 double bond is minimized by rotation around other bonds. The retinal is located between alpha-helical segments of the protein and its nearest neighbor (intratrimer) distance is 26 A; the next-nearest neighbor (intertrimer) distance is 38 A.

Apoproteins↗
PubMed1981

Resonance Raman study of the primary photochemistry of bacteriorhodopsin.

Resonance Raman multicomponent spectra of the light-adapted form of bacteriorhodopsin, bRLA568, and its first photoproduct, K628, have been obtained at liquid nitrogen temperatures. The spectra of both bRLA568 and K628 could be obtained with the known sample compositions under our irradiating conditions and computer subtraction techniques. In agreement with previous results, we find that both bRLA568 and K628 contain chromophores linked to the apoprotein by protonated Schiff bases of retinal. Neither pigment form, suspended in H2O or 2H2O, compares closely to the spectral features of all-trans and 13-cis protonated and deuterated model chromophores, respectively. The data are consistent with other results, suggesting that a chromophore isomerization takes place in the bRLA568-to-K628 phototransition. However, the exact structure of the in situ chromophore would appear not to involve simple trans-to-13-cis structures found in solution.

Apoproteins↗