Retinal oxidation

Naturally occurring pigments in the macula limit retinal oxidative damage by absorbing incoming blue... 

Cyanopsin. Fish pigment of vision from 3-dehydro-retinal (oxidized vitamin A2) and opsin of the retinal uvula. The replacement of retinal by 3-dehydroretinal leads to a red-shifted absorption of visual pigment and is considered as an adaptation to the changed spectral distribution of incident light underwater. 

Bhat PV, Poissant L, Lacroix A (1988) Properties of retinal-oxidizing enzyme activity in rat kidney. Biochim Biophys Acta 967 211-217... 

Work at Rhc ne-Poulenc has involved a different approach to retinal and is based on the paHadium-cataly2ed rearrangement of the mixed carbonate (41) to the aHenyl enal (42). Isomerization of the aHene (42) to the polyene (43) completes the constmction of the carbon framework. Acid-catalyzed isomerization yields retinal (5). A decided advantage of this route is that no by-products such as triphenylphosphine oxide or sodium phenylsulfinate are formed. However, significant yield improvements would be necessary for this process to compete with the current commercial syntheses (25—27) (Fig. 9). 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

In nature, vitamin A aldehyde is produced by the oxidative cleavage of P-carotene by 15,15 - P-carotene dioxygenase. Alternatively, retinal is produced by oxidative cleavage of P-carotene to P-apo-S -carotenal followed by cleavage at the 15,15 -double bond to vitamin A aldehyde (47). Carotenoid biosynthesis and fermentation have been extensively studied both ia academic as well as ia iadustrial laboratories. On the commercial side, the focus of these iavestigations has been to iacrease fermentation titers by both classical and recombinant means. 

The retinol that is delivered to the retinas of the eyes in this manner is accumulated by rod and cone cells. In the rods (which are the better characterized of the two cell types), retinol is oxidized by a specific retinol dehydrogenase to become 2iW-trans retinal and then converted to 11-eis retinal by reti-... 

FIGURE 18.36 The incorporation of retinal into the light-sensitive protein rhodopsin involves several steps. All- ram-retinol is oxidized by retinol dehydrogenase and then iso-merized to ll-cis-retinal, which forms a Schiff base linkage with opsin to form light-sensitive rhodopsin. 

Conjugation is crucial not only for the colors we see in organic molecules but also for the light-sensitive molecules on which our visual system is based. The key substance for vision is dietary /3-carotene, which is converted to vitamin A by enzymes in the liver, oxidized to an aldehyde called 11-frans-retinal, and then isomerized by a change in geometry of the C11-C12 double bond to produce 11-cis-retinal. 

Bleaching is reversed in the dark and the red-purple color of rhodopsin returns. This is thought to occur by the reduction of all-Pms-retinal to vitamin Ai (retinal), which diffuses from the rod into the pigment epithelium, where it is converted enzymatically to the 1 l-c isomer of vitamin At. The enzymatic isomerization is followed by diffusion back into the rod, oxidation to 11 -rfr-retinal, and combination with opsin to form rhodopsin. This process is shown schematically in Figure 12.5.[Pg.289]

The oxidation of P-carotene with potassium permanganate was described in a dichloromethane/ water reaction mixture (Rodriguez and Rodriguez-Amaya 2007). After 12 h, 20% of the carotenoid was still present. The products of the reaction were identified as apocarotenals (apo-8 - to apo-15-carotenal = retinal), semi-P-carotenone, monoepoxides, and hydroxy-p-carotene-5,8-epoxide. 

Adhikari, S., Kapoor, S., Chattopadhyay, S., and Mukheijee, T. 2000. Pulse radiolytic oxidation of P-carotene with halogenated alkylperoxyl radicals in a quaternary microemulsion Formation of retinal. Biophys. Chem. 88 111-117. 

Moreover, carotenoids may quench electronically excited states and scavenge free radicals formed in the retina, and therefore protect biomolecules from oxidative damage. Due to the low energy level of the first excited triplet state ( Car), carotenoids (Car) can act as efficient acceptors of triplet state energy from photosensitizers (S) (Equation 15.1), such as all-tra .s-retinal, the photosensitizers of lipofuscin (Rozanowska et al., 1998), or singlet oxygen C02) (Equation 15.2) (Cantrell et al., 2003) ... 

Interestingly, carotenoids more abundant in the blood plasma than zeaxanthin, such as lycopene, P-carotene, and P-cryptoxanthin, do not accumulate in the retina. RPE cells express p,p-carotene 15,15 -monooxygenase (BCO), formerly known as P-carotene 15,l5 -dioxygcnase, an enzyme that catalyzes the oxidative cleavage of P-carotene into two molecules of all-trans-retinal (Aleman et al., 2001 Bhatti et al., 2003 Chichili et al., 2005 Leuenberger et al., 2001 Lindqvist and Andersson, 2002). Therefore it may be suggested that p -carotene transported into RPE-cells is efficiently cleaved into retinal molecules. BCO cleaves also P-cryptoxanthin (Lindqvist and Andersson, 2002), and its absence in the retina may also be explained by its efficient cleavage to retinoids. However, lycopene, often the most abundant carotenoid in human plasma, cannot serve as a substrate for BCO, and yet it is not detectable in the neural retina (Khachik et al., 2002). 

It has been shown in many studies that protective effects of carotenoids can be observed only at small carotenoid concentrations, whereas at high concentrations carotenoids exert pro-oxidant effects via propagation of free radical damage (Chucair et al., 2007 Lowe et al., 1999 Palozza, 1998, 2001 Young and Lowe, 2001). For example, supplementation of rat retinal photoreceptors with small concentrations of lutein and zeaxanthin reduces apoptosis in photoreceptors, preserves mitochondrial potential, and prevents cytochrome c release from mitochondria subjected to oxidative stress induced by paraquat or hydrogen peroxide (Chucair et al., 2007). However, this protective effect has been observed only at low concentrations of xanthophylls, of 0.14 and 0.17 pM for lutein and zeaxanthin, respectively. Higher concentrations of carotenoids have led to deleterious effects (Chucair et al., 2007). 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

Chen, M, Forrester, JV, and Xu, H, 2007. Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp Eye Res 84, 635-645. 

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