Carotenoid cyclization

FIGURE 5.3.3A Carotenoid cyclization. Enzyme abbreviations and enzyme activities are... 

Some details of the stereochemistry of carotenoid cyclization have been elucidated. In the C40 series labelling with stable isotopes (deuterium) has been used for the first time in studies of carotenoid biosynthesis. A Flavobacterium species in the presence of nicotine accumulated the acyclic precursor lycopene (175). When the cells were washed free from the inhibitor and suspended in H20 cyclization of the lycopene proceeded, initiated by High-resolution n.m.r. 

Howes CD (1974) Nicotine inhibition of carotenoid cyclization in Cucurbita ficifolia cotyledons. Phytochemistry 13 1469-1471... 

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

Abscisin II may be viewed as a monocyclic analog of these two anomalous sesquiterpenes. Alternatively, it may be one of a larger group of miscellaneous compounds which do not necessarily possess exactly 10 or 15 carbon atoms but may be looked upon formally (and perhaps actually) as degradation products of the carotenoids. This view is favored by the fact that the carotenoids are the only class of plant products in which cyclization of the type found in abscisin II is very common. Other examples of these compounds in-... 

Subsequent cyclizations, dehydrogenations, oxidations, etc., lead to the individual naturally occurring carotenoids, but little is known about the biochemistry of the many interesting final structural modifications that give rise to the hundreds of diverse natural carotenoids. The carotenoids are isoprenoid compounds and are biosynthesised by a branch of the great isoprenoid pathway from the basic C5-terpenoid precursor, isopentenyl diphosphate (IPP). The entire biosynthesis takes place in the chloroplasts (in green tissues) or chromoplasts (in yellow to red tissues). 

Although trans to cis isomerization per se is not expected to cause major changes in color, it is the first step for intramolecular cyclization to form cyclic volatile compounds under conditions of high temperature. The oxidation of carotenoid is also required for subsequent reorganization... 

Carotenoids are a group of more than 750 naturally occurring molecules (Britton et al. 2004) of which about 50 occur in the normal human food chain. Of these, only 24 have, so far, been detected in human plasma and tissues (Khachik et al. 1995), with only six molecules being abundant in normal human plasma (for chemical formulas see Figure 13.1). Carotenoids are subdivided into two main classes the carotenes, cyclized (e.g., P-carotene) or uncyclized (e.g., lycopene) hydrocarbons, and the xanthophylls, which have hydroxyl groups (e.g., lutein and zeaxanthin), keto-groups (e.g., canthaxanthin), or both (e.g., astaxanthin) as functional groups. 

The elimination of arenes is not limited to the radical cations of the carotenoids. Just as the neutral compounds themselves also tend to undergo (thermal) cyclization followed by arene loss, the protonated analogues, e.g. ion 82 generated by Cl or fast atom bombardment (FAB) mass spectrometry are prone to eliminate one or even two arene molecules as well (Scheme 26)270. 

Biosynthesis and Metabolism.—Pathways and Reactions. Two reviews of carotenoid biosynthesis discuss, respectively, the early steps and the later reactions." The former paper deals with the mechanism of formation of phytoene and the series of desaturation reactions by which phytoene is converted into lycopene, and also describes in detail the biosynthesis of bacterial C30 carotenoids. The second paper" presents details of the mechanism and stereochemistry of cyclization and the other reactions that involve the carotenoid C-1 —C-2 double bond and the later modifications, especially the introduction of oxygen functions. 

The incorporation of " C-labelled neurosporene (138), lycopene, and y-carotene (141) into /3-carotene by cell extracts of Phycomyces blakesleeanus mutants has been demonstrated.Addition of unlabelled lycopene or /3-zeacarotene (140) caused approximately equal reduction of the incorpsration of [ C]neurosporene into /3-carotene, indicating that the alternative routes of Scheme 3 are of equivalent importance. The absolute configuration of C-6 of natural /3,y-carotene (55) is opposite to that of all C40 carotenoids with an e-ring end-group. " Opposite foldings of the aliphatic precursor are therefore required for cyclization to produce the y- and e-end-groups. 

Inhibitors have been used to investigate the biosynthesis of 1,2-dihydroneuro-sporene [l,2,7,8-tetrahydro-i/, i/f-carotene (143)] and related 1,2-dihydro-carotenoids in Rhodopseudomonas viridis, and possible alternative sequences are presented.The C-1,2 hydrogenation reaction is inhibited by CPTA [2-(4-chlorophenylthio)triethylammonium chloride], a compound known to inhibit cyclization and C-1,2-hydration in other systems, thus indicating possible similarity of the reactions involved. 

The cyclization inhibitor nicotine prevents formation of the C50 carotenoid bacterioruberin [2,2 -bis-(3-hydroxy-3-methylbutyl)-3,4,3, 4 -tetradehydro-... 

Some bacteria synthesize C50 carotenoids such as decaprenoxanthin (Fig. 22-5), the extra carbon atoms at each end being donated from additional prenyl groups, apparently at the stage of cyclization of lycopene.134 Thus, a carbocation derived by elimination of pyrophosphate from dimethylallyl-PP could replace the H+ shown in the first step of Eq. 22-11. The foregoing descriptions deal with only a few of the many known structural modifications of carotenoids.2 135 136... 

The carotenes and carotenoids are very important accessory pigments (Fig. 23-22). The major component in most green plants is (3-carotene. Green sulfur bacteria contain y-carotene in which one end of the molecule has not undergone cyclization and resembles lycopene (Fig. 22-5). Chloroplasts also contain a large variety of oxygenated carotenoids (xanthophylls). Of these, neoxanthin, violaxanthin... 

FIGURE 63.1 Starting with mevalonate, carotenoids are biosynthesized by a special branch of the terpenoid pathway. The first C-40 hydrocarbon unit formed is phytoene, a carotenoid with three conjugated double bonds, which then is enzymatically desaturated to successively yield (3-carotene, neurosporene, and lycopene. Other carotenoids such as (3-carotene and oxocarotenoids are produced from lycopene following cyclization and hydroxylation reactions. Thus, lycopene is a central molecule in the biosynthesis pathway of carotenoids. 

FIGURE 63.2 Essentially all carotenoids, which are widespread in nature, possess certain common chemical features — a polyisoprenoid structure, a long conjugated chain of double bonds in the central portion of the molecule, and near symmetry around the central double bond. This basic structure can be modified in a variety of ways, most prominently by cyclization of the end groups and by the introduction of oxygen functions, to yield a large family of > 600 compounds, exclusive of cis/trans isomers. 

At present, there is no doubt about the biosynthesis of ABA by the carotenoid pathway via the MEP pathway in plants. If ABA is biosynthesized by the direct pathway, the first cyclized intermediate will be ionylide-neethanol, having a hydroxyl group at C-l derived from farnesol however, ionylideneethanol has not been found in plants, so the direct pathway is not involved in ABA biosynthesis. The mevalonic acid pathway may also be excluded because almost no 13C label was incorporated into the carbons, which would be labeled in the mevalonic acid pathway in a feeding experiment with [l-13C]-D-glucose.640... 

New Structures and Stereochemistry.—New Carotenoid Structures. A mutant strain of Rhizobium lupini contains a new nor-carotenoid, 2, 3 -trans-dihydroxy-2-nor-/3,/3-carotene-3,4-dione (1)." The wild-type R. lupini, when cultured in the presence of the cyclization inhibitors nicotine or CPTA, produced three new monocyclic carotenoids, 2,3-h-ans-dihydroxy-/3,-caroten-4-one (2), 3-hydroxy-/3,(/ -caroten-4-one (3), and p,tf/-carotene-2,3-trans-dio (4)," which were characterized by m.s. and n.m.r. The light absorption and mass spectra of a carotenoid from Rhodopseudomonas capsulata allowed its identification" as demethylspheroidenone [l-hydroxy-3,4-didehydro-l,2,7, 8 -tetrahydro- /f,(/f-caroten-2-one (5)]. 

Stereochemistry. "C-Labelling has been used for the first time in the carotenoid field to study the stereochemical course of the cyclization reaction."" When [2- "C]mevalonate was incubated with a Flavobacterium species, grown in the presence of the cyclization inhibitor nicotine, "C n.m.r. spectroscopy showed that... 

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