Polyisoprenoid compounds

Polyisoprenoid compounds exist, e.g., rubber, but in a biochemical context, the ubiquinones and dolichols are particularly important (see Chap. 14). 

Cholesterol serves as the biosynthetic precursor for several vital compounds, including a variety of steroid hormones and bile acids. Many of these compounds, and many other polyisoprenoid compounds biosynthetically related to cholesterol, act biologically as important regulatory compounds [105]. In mammals such regulatory compounds include steroid hormones and vitamins A and D. Steroids and other isoprene derivatives also play important regulatory roles in other phyla. Several insect hormones, for example, are isoprenoid derivatives [106] (cf. Chapter 8). Memy of the floral scents of plants are isoprene derivatives. 

Rowland, R.L. and J.A. Giles Flue-cured tobacco. V. Polyisoprenoid compounds Tob. Sci. 4 (1960) 29-32. Rowland, R.L. and PH. Latimer Isolation of solane-syl esters from flue-cured tobacco RDR, 1958, No. 12, June 19, see www.rjrtdocs.com 500932361 -2372 12th Tobacco Chemists Research Conference, Program Booklet and Abstracts, Vol. 12, Paper No. 13, 1958, p. 5 Flue-cured tobacco. IV. Isolation of solanesyl esters Tob. Sci. 3 (1959) 1-3. 

Kauss has similarly observed the enzymic synthesis of D-man-nosyl-lipid by use of a particulate enzyme from mung-bean shoots. The results suggested that only the D-mannosyl group of GDP-d-mannose is transferred, because GDP, but not GMP, was incorporated into GDP-D-mannose by an exhange reaction. There is some evidence suggesting that the lipid is a polyisoprenoid compound, because prior incubation of the cells with mevaIonic-5-t acid resulted in the labeling of the acceptor lipid. 

Carotenoids are a class of lipophilic compounds with a polyisoprenoid structure. Most carotenoids contain a series of conjugated double bonds, which are sensitive to oxidative modification and cis-trans isomerization. There are six major carotenoids (ji-carotenc, a-carotene, lycopene, P-cryptoxanthin, lutein, and zeaxanthin) that can be routinely found in human plasma and tissues. Among them, p-carotene has been the most extensively studied. More recently, lycopene has attracted considerable attention due to its association with a decreased risk of certain chronic diseases, including cancers. Considerable efforts have been expended in order to identify its biological and physiochemical properties. Relative to P-carotene, lycopene has the same molecular mass and chemical formula, yet lycopene is an open-polyene chain lacking the P-ionone ring structure. While the metabolism of P-carotene has been extensively studied, the metabolism of lycopene remains poorly understood. 

In similar fashions, the core pathway up to C25 compounds (five isoprene units) is formed by sequential addition of C5 moieties derived from IPP to a starter unit derived from DMAPP. Thus, sesquiterpenes are formed form the precursor 2E, hS-farnesyl pyrophosphate (FPP), and diterpenes from 2E, 6E, IO -geranylgeranyl pyrophosphate (GGPP). The parents of triterpenes and tetraterpenes are formed by reductive coupling of two FPPs or GGPPs, respectively. Rubbers and other polyisoprenoids are produced from repeated additions of C5 units to the starter unit GGPP. 

Two molecules of farnesyl pyrophosphate combine, releasing pyrophosphate, and are reduced, forming the 30-carbon compound squalene. [Note Squalene is formed from six isoprenoid units. Because three ATP are hydrolysed per mevalonic acid residue converted to IPP, a total of eighteen ATP are required to make the polyisoprenoid squalene.]... 

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. 

BertoUno A, Altman LJ, Vasak J, Rilling HC. Polyisoprenoid amphiphiUc compounds as inhibitors of squalene synthesis and other microsomal enzymes. Biochem. Biophys. Acta -Lipids and Lipid Metab. 1978 530 17-23. 

The term vitamin E refers to two groups of compounds, the tocophenols and the tocotrienols. The structures of these compounds appear in Figure 9.90. All forms of the vitamin contain two parts, a "head" and a "tail." The head consists of an aromatic ring structure, called chroman or chromanol, and is the site of antioxidant action. The tail of tocopherols is a phytyl group, while the tail of tocotrienols is a polyisoprenoid group. The tail of vitamin K setv es to anchor the vitamin in lipid membranes, in the lipids of adipose tissue, and in the lipid surface and core of the lipoproteins. 

FIGURE 9.24 Wamin K and related compounds. Vitamin Kj, also called phylloquinone, is 2-methyl-3-phytyl-l,4-naphtiioquinone. Vitamin K2, also called menaquinone, occurs naturally with a polyisoprenoid tail containing from 5 to 13 isoprenoid units. The figure shows menaquinone-7 (MK-7), which contains a seven-isoprenoid-unit tail. Studies of human Uver have revealed that MK-7, MK-8, MK-10, MK-11, and MK-12 account for most of the vitamin K in this tissue, while phylloquinone accounts for about 10% of the vitamin K (Suttie, 1995). Vitamin K3 is a synthetic version of the vitamin. 

Retinoids are lipophilic, polyisoprenoids with a cyclohexane ring (Fig. 1). The term retinoid refers to a broad grouping of compounds from animal sources including retinol, retinal and retinoic acid (RA), as well as synthetic forms developed for pharmaceutical purposes. 

Once the nature of the unsaturation in the C17 chain was established, we considered if this structural feature had an active role in function or could we say nature has just been too lazy to reduce these double bonds to give a saturated polyisoprenoid group. Possibly related in function are the similarly unsaturated, though frequently much longer, isoprenoid chains of ubiquinones, vitamin K s, and related compounds, substances also implicated in electron-transfer and/or oxidative phosphorylation processes. Thus, the C17 group in heme A may be directly related to either electron transfer or coupling of phosphorylation in the oxidase. 

A basic question in which our laboratory has been interested over the last few years revolves around the problem of MVA synthesis and the flow of this compound to the major isopentenoid compounds in the plant cell. The pathway for the biosynthesis of polyisoprenoids and the position of the key-resulatins enzyme HMG-CoA reductase is summarized in Figure 1. Our studies and those of other groups have revealed that the regulatory role of HMG-CoA reductase does not seem to be confined only to mammals (1-8). but can also be extended to plants (9-22) and fungi (23-27). 

The formation of a 2,3- - or 2,3-Z-double bond is a consequence of the syn- or a ri-conformation of the double bonds of the precursors (Cori, 1983). Most, if not all, monoterpenes appear to arise from GPP (geranyl pyrophosphate) (with a 2,3- -double bond) and most of the numerous terpenes in nature are based on the -configuration mentioned above. Loss of the pro-S- roion to form compounds of Z-conformation (mostly polyisoprenoids) occurs in some plants (e.g., Hevea brasiliensis) (Cori, 1983) see Chapter 18). 

Although most bacteria do not make large quantities of terpenes, the Archaebacteria produce lipids that are C20 isoprenyl ethers of glycerol and its derivatives (in addition to some C20, C25, and C30 acyclic compounds). These bacteria do not synthesize fatty acids the lipids in their membranes are exclusively polyisoprenoid (Porter and Spurgeon, 1981). 

Mevalonate pathway products are actively biosynthesized in all cell studied. In plants more than 20 000 end-products differing in structure and functions resulting from this pathway were described. Biological role of many of these compounds is well characterized (for example vitamins, hormones, phytoalexines, antioxidants). However in some cases the function of the compound has not yet been defined. Among the most abundant compounds biosynthesized from farnesyl diphosphate - a branch point product of mevalonate pathway, are sterols, quinones (ubiquinone and plastoquinone) and polyisoprenoid alcohols. 

GGPP is a key branch point metabolite of polyisoprenoid metabolism. Apart from the cyclic diterpenes, it is the precursor of the tetraterpenes (carotenes, xanthophylls), and acyclic diterpenes (phytol). Cyclic diterpenes compete with compounds of established importance for either GGPP or its precursors (e.g., famesyl pyrophosphate). The spotty nature of resin diterpene distribution may in part be explained by the obvious demand for carotenoids and phytyls and the relatively unestablished requirement for these nongibberellin diterpenes. 

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