Catalysis of vitamin A aldehyde isomerization by primary and secondary amines

Lukton, David; Rando, Robert R.

doi:10.1021/ja00328a037

Cited by 15 publications

(16 citation statements)

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“…Acid Catalysis of Isomerization of7> in PC MLV. Since the isomerization of aromatic and aliphatic amine retinal Schiff bases is acid-base-catalyzed in organic solvents (Lukton & Rando, 1984a, 1984b, it is important to determine if the same holds true for the isomerization of 3 in PC MLV. An important question here is whether the expected low of the protonated form of 3 would render this a moot point.…”

Section: Resultsmentioning

confidence: 99%

“…All procedures were conducted under dim red light with samples kept on ice. All Schiff bases were preformed and checked for Schiff base formation as previously described (Lukton & Rando, 1984b). To a solution of Schiff base or 11-czí-retinal in heptane was added the appropriate lipid in chloroform as well as other reagents such as radical inhibitors, and the solvents were removed in vacuo to give a thin film.…”

Section: Methodsmentioning

confidence: 99%

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Mechanism of isomerization of 11-cis-retinal in lipid dispersions by aromatic amines

Fulton¹,

Rando²

1987

Biochemistry

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It has previously been shown that retinotoxic, primary aromatic amines catalyze the isomerization of 11-cis-retinal to its all-trans congener after Schiff base formation [Bernstein, P.S., Fulton, B.S., & Rando, R.R. (1986) Biochemistry 25, 3370-3377]. This process led to the short-circuiting of the visual cycle and the observed retinotoxicity when it occurred in vivo. The catalysis was also observed to occur in vitro in phosphatidylcholine-based vesicles but not in hydrocarbon solutions. The rate of isomerization of an aromatic amine Schiff base of 11-cis-retinal in the phospholipid vesicles was typically 10(3)-fold more rapid than in hydrocarbon solutions. In this article, the mechanistic basis of this apparently membrane-specific catalysis is described. It was found that the rate enhancement effect observed was independent of the lipid used. Moreover, a bilayer structure was not important because rate enhancements were also observed in micelles. The rapid isomerization rates observed in lipid dispersions appear not be free radical initiated because free radical quenching agents, such as alpha-tocopherol and beta-carotene, had little effect on the isomerization rates. It was further found that aliphatic amines, such as n-dodecylamine, could be substituted for the aromatic amines in phospholipid. Finally, and most importantly, it was found that the isomerization of the aromatic amine retinal Schiff bases in phospholipid vesicles was acid-catalyzed. It is concluded that the rate enhancements observed for the isomerization of 11-cis-retinal-aromatic amine Schiff bases in lipid dispersions over that in hydrocarbon solvents are due to the occurrence of acid-base catalysis in the former.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mechanism of isomerization of 11-cis-retinal in lipid dispersions by aromatic amines

Fulton¹,

Rando²

1987

Biochemistry

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“…However, since the conditions used in these latter syntheses have usually led to an approximately 3:1 mixture of E and Z isomers with respect to the newly formed double bond, we instead used conditions that had been reported to allow highly stereoselective preparation of ( E )-α-fluoro-α,β-unsaturated esters by condensation of fluorinated HWE reagents with either presynthesized aldehydes 12h or aldehydes obtained in situ by DIBALH reduction of the corresponding esters 12d. We envisaged that the stereochemically pure cis compounds so obtained would easily be isomerizable to their more stable trans isomers and would additionally provide cis -fluororetinoids of interest for research on the biological activities of this type of compounds (13- cis -retinal in relation to BR, , 11- cis -retinal for rhodopsin, and 9- cis -retinoic acid for research on retinoid receptors , ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Retinals Fluorinated at Odd-Numbered Side-Chain Positions and of the Corresponding Fluorobacteriorhodopsins

et al. 1997

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Conventional Horner-Wadsworth-Emmons and Wittig condensations were used to fluorinate the odd-numbered positions of the retinal side chain past C(7). The stereochemically labile cis-fluororetinals were easily converted into the most stable trans-fluororetinals, which were incubated with bacterio-opsin. Contrary to expectations, the fluorinated retinals provided artificial pigments with near normal absorption properties, showing that any electrostatic interactions between the fluorine atoms and protein groups were insufficient to prevent normal binding. The new artificial pigments had smaller opsin shifts than did native bacteriorhodopsin, which is interpreted as due either to greater electrostatic interaction between the protonated imine and its counterion, or to local interactions between the fluorine substituents and nearby polar protein groups.

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“…It is clear that the attack of X' produces a highly stabilized product [6] The importance of a phospholipid environment, which of course is found in the eye, deserves consideration. At 65TC in n-heptane, the thermal rate of isomerization of 11-cisretinal is 2.4 x 10-6sec', a t1/2 of 80 hr (9). At 37TC, the rate in n-heptane would be in the range of 10-7 sec'1, while in phosphatidylcholine-based liposomes it is 7.7 x 10-6 sec'1.…”

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confidence: 95%

“…Schiff-base formation with an aromatic amine in these liposomes further increases the isomerization rate 3-to 18-fold (Table 2). By contrast, Schiff-base formation with 11-cisretinal by aniline in n-heptane at 650C has almost no catalytic effect, changing the isomerization rate to just 2.8 x 10-6 sect (9). The importance of a phospholipid environment is further supported by the fact that aromatic amines are Proc.…”

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confidence: 99%

Short-circuiting the visual cycle with retinotoxic aromatic amines.

Bernstein¹,

Lichtman²,

Rando³

1986

Proc. Natl. Acad. Sci. U.S.A.

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The retinotoxic drug 1,5-di-(p-aminophenoxy)pentane inhibits the accumulation of all ll-cis-retinoids in the eye and can deplete preformed stores of them. It is shown here that these effects are not specific to 1,5-di-(p-aminophenoxy)pentane but are shared generally by primary aromatic amines containing a hydrophobic tail. Furthermore, certain clinically used drugs, such as the anti-inflammatory drug phenacetin, can be metabolized to produce these retinotoxic amines. It is likely that hydrophobic aromatic amines will in general be retinotoxic, and drugs based on these structures need to be reassessed in this light. It is proposed here that these amines function by catalyzing the isomerization of 11-cisretinal thermodynamically downhill to form its all-trans congener. This mechanism accounts for the lack of structural specificity observed with these compounds and is supported by experimental evidence presented here. Schiff bases formed between 11-cis-retinal and a relevant aromatic amine in phosphatidylcholine-based liposomes lead to the formation of the all-trans isomer, at rates =15 times faster than the rate of li-cis-retinal isomerization by itself in these liposomes and O24103 times faster than the rate of isomerization of this molecule in n-heptane. The rates of the amine-catalyzed isomerization are fast enough to account for their in vivo effect.The initial event in vertebrate vision involves the photochemical isomerization of the li-cis-retinal Schiff base chromophore ofrhodopsin to its all-trans congener (1, 2). Rhodopsin, activated in this fashion, catalyzes the exchange of GTP for GDP in a G protein, which in turn activates a phosphodiesterase specific for cGMP (3, 4). For vision to proceed, the all-trans-retinal released from rhodopsin must be converted back into ll-cis-retinal, a thermodynamically uphill process (5). The

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Catalysis of vitamin A aldehyde isomerization by primary and secondary amines

Cited by 15 publications

References 1 publication

Mechanism of isomerization of 11-cis-retinal in lipid dispersions by aromatic amines

Mechanism of isomerization of 11-cis-retinal in lipid dispersions by aromatic amines

Synthesis of Retinals Fluorinated at Odd-Numbered Side-Chain Positions and of the Corresponding Fluorobacteriorhodopsins

Short-circuiting the visual cycle with retinotoxic aromatic amines.

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