Terpenoid Quinones

Quinones are potentially derivable by oxidation of suitable phenolic compounds, cat-echols (1,2-dihydroxybenzenes) giving rise to ortho-quinones and quinols (1,4-dihydroxyben-zenes) yielding para-quinones (see page 25). Accordingly, quinones can be formed from phenolic systems generated by either the acetate or shikimate pathways, provided a catechol or quinol

ubiquinone-« (coenzyme Qn)

phylloquinone (vitamin Kf, phytomenadione)

plastoquinone-n plastoquinone-n

menaquinone-n (vitamin K2)

R1 = R2 = Me, a-tocopherol R1 = H, R2 = Me, P-tocopherol R1 = Me, R2 = H, Y-tocopherol R1 = R2 = H, 5 -tocopherol

(vitamin E)

CO2H

Figure 4.50

plants / animals

4-coumaric acid CO2H

chorismic acid

CO2H

C-alkylation with a Oh polyisoprenyl PP

4-hydroxybenzoic CH3COCO2H acid

CO2H

CO2H

C-alkylation with a Oh polyisoprenyl PP

ubiquinone-n

1. C-methylation

2. hydroxylation

3. O-methylation

SAM O2 SAM

oxidation to quinone

jr 1. hydroxylation

O 2. O-methylation 1 sam 3. decarboxylation or: 3, 1, 2

oxidation to quinone

system has been elaborated, and many examples are found in nature. A range of quinone derivatives and related structures containing a terpenoid fragment as well as a shikimate-derived portion are also widely distributed. Many of these have important biochemical functions in electron transport systems for respiration or photosynthesis, and some examples are shown in Figure 4.50.

Ubiquinones (coenzyme Q) (Figure 4.50) are found in almost all organisms and function as electron carriers for the electron transport chain in mitochondria. The length of the terpenoid chain is variable (n = 1-12), and dependent on species, but most organisms synthesize a range of compounds, of which those where n = 7-10 usually predominate. The human redox carrier is coenzyme Q10. They are derived from 4-hydroxybenzoic acid (Figure 4.51), though the origin of this compound varies according to organism (see pages 123, 141). Thus, bacteria are known to transform chorismic acid by enzymic elimination of pyruvic acid, whereas plants and animals utilize a route from phenylalanine or tyrosine via 4-hydroxycinnamic acid (Figure 4.51). 4-Hydro-xybenzoic acid is the substrate for C-alkylation ortho to the phenol group with a polyisoprenyl diphosphate of appropriate chain length (see page 231). The product then undergoes further elaboration, the exact sequence of modifications, i.e. hydroxylation, O-methylation, and decarboxy-lation, varying in eukaryotes and prokaryotes. Quinone formation follows in an O2-dependent combined hydroxylation - oxidation process, and ubiquinone production then involves further hydro-xylation, and O- and C-methylation reactions.

Plastoquinones (Figure 4.50) bear considerable structural similarity to ubiquinones, but are not derived from 4-hydroxybenzoic acid. Instead, they are produced from homogentisic acid, a pheny-lacetic acid derivative formed from 4-hydroxyphe-nylpyruvic acid by a complex reaction involving decarboxylation, O2-dependent hydroxylation, and subsequent migration of the —CH2CO2H side-chain to the adjacent position on the aromatic ring (Figure 4.52). C-Alkylation of homogentisic acid ortho to a phenol group follows, and involves a polyisoprenyl diphosphate with n = 3 — 10, but most commonly with n = 9, i.e. solanesyl diphos-phate. However, during the alkylation reaction, the —CH2CO2H side-chain of homogentisic acid suffers decarboxylation, and the product is thus an alkyl methyl p-quinol derivative. Further aromatic methylation (via S-adenosylmethionine) and oxidation of the p-quinol to a quinone follow to yield the plastoquinone. Thus, only one of the two methyl groups on the quinone ring of the plastoquinone is derived from SAM. Plastoquinones are involved in the photosynthetic electron transport chain in plants.

Tocopherols are also frequently found in the chloroplasts and constitute members of the vitamin E* group. Their biosynthesis shares many of the features of plastoquinone biosynthesis, with an additional cyclization reaction involving the p-quinol and the terpenoid side-chain to give a chroman ring (Figure 4.52). Thus, the tocopherols, e.g. a-tocopherol and -/-tocopherol, are not in fact quinones, but are indeed structurally related to plastoquinones. The isoprenoid side-chain added, from phytyl diphosphate, contains only four iso-prene units, and three of the expected double bonds have suffered reduction. Again, decarboxylation of homogentisic acid cooccurs with the alkylation reaction. C-Methylation steps using SAM, and the cyclization of the p-quinol to y-tocopherol, have been established as in Figure 4.52. Note once again that one of the nuclear methyls is homogentisate-derived, whilst the others are supplied by SAM.

The phylloquinones (vitamin K1) and mena-quinones (vitamin K2) are shikimate-derived na-phthoquinone derivatives found in plants and algae (vitamin K1*) or bacteria and fungi (vitamin K2). The most common phylloquinone structure (Figure 4.50) has a diterpenoid side-chain, whereas the range of menaquinone structures tends to be rather wider with 1 -13 isoprene units. These quinones are derived from chorismic acid via its isomer isochorismic acid (Figure 4.55). Additional carbons for the naphthoquinone skeleton are provided by 2-oxoglutaric acid, which is incorporated by a mechanism involving the coen-zyme thiamine diphosphate (TPP). 2-Oxoglutaric acid is decarboxylated in the presence of TPP to give the TPP anion of succinic semialdehyde, which attacks isochorismic acid in a Michael-type reaction. Loss of the thiamine cofactor, elimination of pyruvic acid, and then dehydration yield the intermediate o-succinylbenzoic acid (OSB). This is activated by formation of a coenzyme A ester, and a Dieckmann-like condensation allows ring formation. The dihydroxynaphthoic acid is the a complex sequence involving hydroxylation, migration of side-chain, and decarboxylation

4-hydroxyphenyl-pyruvic acid

4-hydroxyphenyl-pyruvic acid

2 ho2c

homogentisic acid f PPO

C-alkylation ortho to phenol; H also decarboxylation

C-alkylation ortho to phenol; H also decarboxylation

homogentisic acid f PPO

co2 s r

C-methylation ortho to phenol phytyl PP

C-methylation ortho to phenol co2 s phytyl PP

C-methylation ortho to phenol

oxidation of 0 quinol to quinone

plastoquinone-n plastoquinone-n cyclization to 6-membered ring via protonation of double bond

cyclization to 6-membered ring via protonation of double bond

y-tocopherol

y-tocopherol

C-methylation ortho to phenol

a-tocopherol a-tocopherol

Figure 4.52

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