Cts-Retinal

Figure 29-3. Chemical structures of important vitamin A species and the provitamin A carotenoid i-carotene. All-fra/w-fi-carolene (T) is the most important provitamin A carotenoid, which can be converted to all-fraws-retinal and then all-tram-retinol (If), which by definition is vitamin A. All-tram-retinol can be esterified with long-chain fatty acids to form retinyl ester (III), the storage form of vitaminA in the body.The active form of vitamin A in vision is 11-cts-retinal (TV).The transcriptionally active forms of vitaminA are all-tram-retinoic acid (V) and 9-cts-retinoic acid (VI). 13-cA-Retinoic acid (VII) has poor transcriptional regulatory activity but is used clinically as isotretinoin to treat skin diseases.

Hubbard " found in the retina an enzjnne, retinal isomerase, which changes all trans- to 11-CTS-retinal. In the dark, retinal isomerase converts all trans- or 11-m-retinal to a mixture of about 5% 11-as and 95% all trans. In the light, the rate of isomerization of all trans is in-... 

Describe the key enzymatic steps in the visual cycle converting bleached all-fra/ts-retinal back into light-sensitive 11-cts-retinal. 

Metarhodopsin II is then recycled back into rhodopsin by a multi-step sequence involving cleavage to all-frans-retinal and cis-trans isomerization back to ll-cts-retinal. 

Light-induced isomerization of 11-cts-retinal plays a central role in the conversion of visual signals, i.e., light, into nerve impulses known as the visual cascade (see below) (23). 

In the retina a protein called opsin combines with 11-cts-retinal to form a modified protein, rhodopsin. The ll-cis-retinal portion of rhodopsin is a prosthetic group (a nonprotein portion of a protein that is necessary for its action). 

FIGURE 40. Plot of the differences in chemical shift observed between rhodopsin and the ll-ct s-retinal PSB chloride salt (open squares), and between isorhodopsin and the 9-ds-retinal PSB chloride salt (closed squares), for retinal carbons along the polyene chain. Reprinted with permission from Reference 55. Copyright (1990) American Chemical Society... 

CT excitation energy. The amount of the blue-shift was qualitatively explained by the change in ES potential along the skeleton. This is a general feature seen in the retinal protein including PSB. 

In the NMR spectrum of the irradiated retinal, the C-1, C-5, and C-9 methyl peaks remained unchanged and we do not observe a splitting in the spectrum of the mixture. But on the other hand, we notice, besides the C-13 methyl peak at 7.70 t, a peak at 7.88 t with a doublet shape (J = 1 Hz.). The integrated spectrum shows that the peaks altogether correspond to three protons. The peak at 7.88 r corresponds to the C-13-methyl of the 13-ct s isomer of the retinal. An upheld shift of 0.18 ppm when we change from the trans to the cis derivative is in perfect agreement with many examples of this kind. 

Parisi MA, Doherty D, Eckert ML ct al. AHIl mutations cause both retinal dystrophy and renal cystic disease in joubert syndrome. J Med Genet 2006 43(4) 334-39. 

Kohner EM, Hamilton AM, Bulpitt CJ, Dollery CT. Streptokinase in the treatment of central retinal vein occlusion. Trans Ophthalmol Soc UK 1974 94 599-603. 

Photoisomerization of retinal from the all-trans to the 13-ct.v form leads to a cyclic photoreaction with intermediates, bR, K, L, M, N, and O, which are subsequently formed before recovery of the initial state, as schematically illustrated, with the absorption wavelength in the suffix (Fig. 5), together with their individual lifetimes.50 51 The first proton transfer in the photocycle of the all-trans, 15-anti isomer is from the retinal Schiff base to Asp 85 at the central part of the protein. Then, a proton is released from the proton release complex (PRC) consisting of Glu 204, 194 and a bound water molecule at the extracellular surface, as illustrated by arrow A. This is followed by reprotonation of... 

Certain cells of the retina are packed with rhodopsin, a large protein covalently bonded to 1 l-ci -retinal. The energies of photons of visible light have a range (165-293 kJ/mol) that includes the energy needed to break a C=C It bond (about 250 kJ/mol). Within a few millionths of a second after rhodopsin absorbs a photon, the 1 l-cw it bond breaks, the intact ct bond between C-11 and C-12 rotates, and the it bond re-forms to produce all-trans retinal. 

Several approaches for calculating excited states in protein environments were proposed to improve the ordinary QM/MM description. The effect of polarization was included as a classical force field [27], and the excitation energy calculated for bacteriorhodopsin (bR) was 0.34 eV less than that from a fixed-charge non-polarizable QM/MM method [27]. Later, a triple-layer QM1/QM2/MM approach was proposed, and DFT(PBEO) calculations were performed for the QM2 layer, which consisted of the amino acids 4 A from the retinal PSB [28]. The calculated excitation energy of bR was only 0.08 eV smaller than that obtained using the ordinary QM/MM method [28]. In another study, an empirical polarization model combined with the QM/MM calculation produced a red shift of 0.14-0.17 eV [29]. However, these pioneering studies neglected the CT effects between the retinal and the protein environments. 

Creech Kraft, J. Kimelman, D. Juchau, M.R. Xenopus Laevis A model system for the study of embryonic retinoid metabolism. I. Embryonic metabolism of 9-cts- and all-tmns-retinals and retinols and their corresponding acid forms. Drug Metab.Dispos., 1995, 23, 72—82... 

An 8-year-old girl presented with bilateral moderate conductive hearing loss, bilateral microtia, left external auditory canal stenosis, and right external auditory canal atresia, after prenatal isotretinoin exposure. Co-morbidities included developmental delay, ventricular septal defects, hypotonia, and retinal maldevelopment. The left EAC was sharply upsloping with a 2-mm-diameter meatus. A CT scan showed normal middle and inner ears bilaterally. Serial CT scans over 6 years showed progressive development of a left canal cholesteatoma. 

In the retinal cells of the eye, vitamin A (all-trans-retinol) is converted into the 11-ds-isomer, which is then oxidised to 11-cts-retinaldehde. In the dark the latter then combines with the protein opsin to form rhodopsin (visual purple), which is the photoreceptor for vision at low light intensities. When light falls on the retina, the czs-retinaldehyde molecule is converted back into the aW-trans form and is released from the opsin. This conversion results in the transmission of an impulse up the optic nerve. The all-frans-retinaldehyde is converted to all-trans-retinol, which re-enters the cycle, thus continually renewing the light sensitivity of the retina (Rg. 5.2). 

Urinary tract Bilateral flank pain and progressive oliguria developed over 3 weeks in a 47-year-old woman who took sulfadiazine for toxoplasmosis retinitis [183 ]. Only in a second CT scan (an nnenhanced helical scan with very low attennation for stones) was urolithiasis detected snlfonamide crystals were found in the urine. 

---