Biosynthesis

In 1950 a biosynthetic pathway for the conversion of phy-toene to lycopene to /i-carotene was proposed (17). While the structures of several of these compounds were not proven at that time, it nevertheless was the first sequential pathway proposal.

The 1950s and 1960s were intense years in the polyene biosynthetic field because steroid and carotenoid biogenesis followed similar pathways. Thus when mevalonic acid (MVA) was discovered it was a breakthrough for both groups. The use of stereospecific [14C]-and [3H] mevalonic acids incorporated into cell-free systems provided a valuable tool for studying biosynthetic conversions. Acetyl-CoA may be considered the starting point in terpene biosynthesis. As can be seen in Figure 2, two acetyl-CoA molecules condense to form acetoacetyl-CoA. This in turn condenses to form the branched six-carbon acid /?-hydroxy-/?-methyl-glutaryl CoA (HMG-CoA). Through a series of reactions, HMG-CoA can also be formed from leucine (18). HMG-CoA is reduced from the dicarboxylic acid to a monoacidic-monohydroxyl compound, MVA. For most systems, MVA once formed cannot be converted back to HMG-CoA. MVA in the presence of ATP is converted to MVAP and then to MVAPP. With a third ATP, MVAPP is converted to isopen-tenyl pyrophosphate (IPP). This step involves a phosphorylation and a decarboxylation. IPP is the key intermediate to the terpenoids, which include rubber, sterols, bile acids, squalene, some sex hormones, ubiquinones, essential oils, the phytol side chain of chlorophyll, and vitamins E and K. It is isomerized to form dimethylallylpyrophosphate (DMAPP). IPP and DMAPP condense to form the C10 compound geranyl PP (GPP). The 10-carbon unit is further reacted with IPP to form the C15 farnesyl (FPP) and the C20 geranylgeranyl (GGPP). FPP can be dimerized to form squalene and the C20 GGPP, to form phytoene. The formation of phytoene follows a rather complicated pathway. By analogy to squalene, lycopersene with a saturated 1515' position was proposed as the first carotenoid and the precursor to phytoene. More recent studies have shown that the unlikely reduction to form lycopersene from GGPP and the oxidation to form phytoene from lycopersene does not occur; see Figure 2. Plants are able to form phytoene and the higher carotenoids, but animals can only make changes to preformed carotenoids.

More recently a new pathway to IPP has been reported (18). This pathway does not involve mevalonic acid, but follows five carbon intermediates, fi-carotene has been shown to be formed by this pathway. It remains to be seen how significant these findings are.

There is a branch of neurosporene leading into either lycopene or a- or /?-zeacarotenes. The data on the cycliza-

tion of neurosporene or lycopene seem to favor lycopene as the major pathway. In the red tomato, synthesis of /?-zeacarotene rules out lycopene as the sole precursor to /?-carotene because it is difficult to explain the higher temperature-selective inhibition of lycopene (19, Fig. 2). When tomatoes were treated with DMSO at various stages of maturity (20,21), it was found that the acyclic but not the cyclic carotenoids were inhibited. It was proposed that parallel pathways exist for phytoene to lycopene and phytoene to /i-carotene. By the use of a mutant tomato it was found that the DMSO inhibited the formation of lycopene at one stage and both pathways at an earlier stage of maturity. Also, the /j-carotene is found in the chloroplast, whereas the lycopene is found crystallized in the chromo-plasts.

Research has been reported on the use of cell-free ho-mogenates. However, the interpretation of the results of these cell-free systems was difficult because the cell was no longer intact. A number of inhibitors were used. These included mainly nitrogen-containing compounds. One compound, 2-(4-chlorophenyl)triethylamine (CPTA), inhibits the cyclization of lycopene and thus lycopene accumulates. When washing out the CPTa, y?-carotene is formed at the expense of lycopene. A number of other inhibitors cause an increase in /i-zeacarotene and a decrease in /^-carotene. Still other compounds have been found to stimulate /?-carotene and /i-zeacarotene synthesis. Clearly both pathways are operating and it is possible to "prove" a pathway by the choice of inhibitor, stimulant, or bioregulator (22).

The great deal of information on the biosynthesis of the carotenoids has come from the use of 14C/3H dual-labeled MVA. By use of MVA with 3H in the two and four positions and 14C in the two position, it was found that the a- and /?-rings are formed independently. Eight carbons and a number of 3H would be found in the entire molecule. Two 3H atoms are found in position four of the fi-ring and one in a-carotene. However, if the e-ring is converted to the firing, one 3H would be lost. This is not found experimentally. Likewise, the 4-3H from MVA is in the six position; 3H must be lost in the formation of /?-carotene but not in the direct formation of a-carotene. Because the 6'-3H is retained in a-carotene, the /?-ring is not converted to the firing (23). The nonrandomized dimethyl groups in torular-hodin were proved with double labeled MVA. This result suggested that the interconversion of IPP and DMAPP did not result in the randomization of the C-2 hydrogen from MVA (24).

The ring formation in the red pepper to form capsanthin and capsorubin has been suggested to follow a pathway through a postulated epoxide intermediate. It is generally thought that the insertion of oxygen occurs at a later stage in the biosynthetic pathway, and that the epoxide, hy-droxyl, and one-carboxyl oxygen came from molecular oxygen.

The view had long been held that the direction of biosynthesis was from saturated to unsaturated, from hydrocarbon to the xanthyphylls. Recently, however, it has been shown that some fish can convert astaxanthin to retinol. Bacteria have also been shown to form a series of 45- and 50-carbon carotenoids. Lycopene, leutein, and cellulose

Leucine

2 Acetyl-CoA -

Acetyl-CoA ยป Acetoacetyl-CoA-- /3-OH-0-methylglutaryl-CoA

O H CHS

Mevalonic acid atp (3)

Isopentenyl pyrophosphate

Sterols

Squalene -

Geranyl pyrophosphate C_i

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