Retinoid phosphorylation

Retinol A. can be enzymically formed from retinoic acid. B. is transported from the intestine to the liver in chylomicrons. C. is the light-absorbing portion of rhodopsin. D. is phosphorylated and dephosphorylated during the visual cycle. E. mediates most of the actions of the retinoids. Correct answer = B. Retinyf esters are incorporated into chylomicrons. Retinoic acid cannot be reduced to retinol. Retinal, the aldehyde form of retinol, is the chromophore for rhodopsin. Retinal is photoisomerized during the visual cycle. Retinoic acid, not retinol, is the most important retinoid. 

The vitamin D receptor acts mainly as a heterodimer with the retinoid X receptor (RXR Section 2.3.2.1). Binding of calcitriol induces a conformational change in the receptor protein, permitting dimerization with occupied or unoccupied RXR, followed by phosphorylation to activate binding to the vitamin D response element on DNA (DeLuca and Zierold, 1998). Abnormally high concentrations of 9-cis-retinoic acid result in sequestration of RXR as the homodimers, meaning that it is unavailable to form heterodimers with the vitamin D receptor (or other receptors) excessive vitamin A can therefore antagonize the nuclear actions of vitamin D (Haussler et al., 1995 Rohde et al., 1999). 

In human breast and prostate cancer cell fines, retinoids have been shown to induce apoptosis via induction of p21/ WAF/cipl (Thompson et al., 1996 Li et al., 1996) and affect G1 cell cycle arrest through mitogen-activated protein kinase phosphorylation (Nakagawa et al., 2003). Zhang and Rosdahl (2005) demonstrated that expression of Idl protein decreased and that of pi6 protein increased in melanoma cell fines exposed to all-rntwr-RA, and suggested that these alterations may be involved in the observed apoptosis and cell cycle redistribution. 

Phosphorylation—the addition of phosphate groups to Ser/Thr and Tyr residues, as shown in receptor interacting protein 140 (RIP140) [4], orphan testicular receptor 2 (TR2) [18], retinoic acid receptor (RAR) [19], and retinoid X receptor (RXR) [19]. 

This Wittig reaction was useful not only for the economical synthesis of retinoids but also subsequently as an excellent general method for the synthesis of carotenoids (Kienzle, 1976). Using the Wittig reaction, Pommer et al. revolutionized polyene chemistry, providing it with a variety otherwise scarcely imaginable (Weedon, 1976). New modified reagents, such as phosphoryl-stabilized anions (Homer et al., 1959 Stilz and Pommer, 1961 Wadsworth, 1977), and modified reaction conditions, such as the use of oxiranes as bases (Buddms, 1974), substantially increased the spectrum of possible syntheses of retinoids and carotenoids. 

The carboxylic acids (332) and (333) are retinoids lacking a terminal ring system. The carbon skeletons of the two compounds were built in accordance with the (Ci8 + C2) method via Reformatsky reactions (Augustyn et al., 1971). The aldehyde (334) was synthesized using a PO-stabilized phosphoryl anion in conventional reaction steps (Crouch, 1982). 

To the extent that it is possible, we attempt to simplify the picture by discussing separately each of the cellular systems in which evidence exists for retinoid-mediated effects on protein kinases and protein phosphorylation. In studies of the biochemical effects of retinoids we are again faced with the central role occupied by their specific effects on neoplastic cells. The cellular systems employed for these studies have been either murine embryonal carcinoma cells (F9) or human promyelocytic leukemia cells (HL-60), each of which has been demonstrated to undergo terminal differentiation to nonneoplastic cell types following retinoid treatment (see Section IV,B,1 and 2), or murine melanoma cells in which retinoids have a marked antiproliferative effect (Section IV,B,3). 

Opsin is the apoprotein of rhodopsin that can result from exposure of the protein to hght (termed bleached opsin) or from lack of the availability of the 11-ds retinal (termed virgin opsin) (Figure 127.4). There is, however, a physiological difference at these two forms of opsin. Bleached opsin is induced by light exposure of rhodopsin and is phosphorylated by rhodopsin kinase. Bleached opsin was shown to have residual activity that reduces visual sensitivity. On the other hand, the characteristics of opsin that has not previously bound 11-c/s retinal, because it was not available due to a disruption in the retinoid metaboHsm " and prior to its developmental occurrence, or because it was unable to bind the Hgand and form rhodopsin, are different from those of the opsin resulting from the photoactivation... 

Ablonczy, Z., Crouch, RK., Goletz, R, Redmond, T.M., Knapp, D.R., Ma, J.-X., and Rohrer, B., 11-cis Retinal reduces constitutive opsin phosphorylation and improves quantum catch in retinoid deficient mouse rod photoreceptors, /. Biol Chem., 277, 40491, 2002. 

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