Isoprenoids mammals

Bark beetles primarily utilize isoprenoid derived pheromones [100,101] and have been the most studied regarding their biosynthesis [8,98]. Earlier work indicated that the isoprenoid pheromones could be produced by the beetle altering host derived isoprenoids however more recent work indicates that for the most part bark beetles are producing pheromones de novo. The production of isoprenoids follows a pathway outlined in Fig. 4 which is similar to the isoprenoid pathway as it occurs in cholesterol synthesis in mammals. Insects cannot synthesize cholesterol but can synthesize farnesyl pyrophosphate. Insects apparently do not have the ability to cyclize the longer chain isoprenoid compounds into steroids. The key enzymes in the early steps of the isoprenoid... 

Prenylation (covalent attachment of an isoprenoid see Fig. 27-30) is a common mechanism by which proteins are anchored to the inner surface of cellular membranes in mammals (see Fig. 11-14). In some of these proteins the attached lipid is the 15-carbon farnesyl group others have the 20-carbon geranylgeranyl group. Different enzymes attach the two types of lipids. It is possible that prenylation reactions target proteins to different membranes, depending on which lipid is attached. Protein prenylation is another important role for the isoprene derivatives of the pathway to cholesterol. 

Longer chain isoprenoids are synthesized via two other isoprenyl diphosphate enzyme systems in mammals [21]. Long E-isoprenyl diphosphate synthase (IDS) produces the side chains of ubiquinone. The length of the side chain varies amongst species, and in humans a C50 synthase has been identified [22]. Dehydrodolichyl diphosphate synthase, the only Z-IDS found in mammals, is responsible for the synthesis of the sugar carriers dohchol and dolichyl phosphate [23]. Plants have additional Z-IDS which can catalyze the production of very long isoprene species, such as natural... 

Figure 5.3 Outline of the mevalonate pathway for the formation of C5 isoprenoid units. Most research has focused on HMC-CoA reductase (HMCR), the rate-determining step in terpenoid biosynthesis in mammals. P indicates a phosphate moiety. HMC-CoA, 3-hydroxy-3 methylglutaryl coenzyme A NADPH, nicotinamide adenine dinucleotide phosphate (reduced form) SCoA, S-Coenzyme A (to which acetate is attached) CoASH, free coenzyme A.

Coenzyme Q is a quinone derivative with a long isoprenoid tail. The number of five-carbon isoprene units in coenzyme Q depends on the species. The most common form in mammals contains 10 isoprene units (coenzyme Qio) For simplicity, the subscript will be omitted from this abbreviation because all varieties function in an identical manner. Quinones can exist in three oxidation states (Figure 18.10). In the fully oxidized state (Q), coenzyme Q has two keto groups. The addition of one electron and one proton results in the semiquinone form (QH ). The semiquinone form is relatively easily deprotonated to form a semiquinone radical anion (Q ). The addition of a second electron and proton generates ubiquinol (QH2), the fiilly reduced form of coenzyme Q, which holds its protons more tightly. Thus, ybr quinones, electron-transfer reactions are coupled to proton binding and release, a property that is key to transmembrane proton transport. 

The answer is a. (Murray, pp 505—626. Scriver, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) In mammals, p-carotene is the precursor of retinal, which is the basic chromophore of all visual pigments. Isopen-tenyl pyrophosphate and dimethylallyl pyrophosphate are isoprenoid isomers formed from the repeated condensation of acetyl CoA units. By continued condensation in mammalian systems, cholesterol can be formed. In plant systems, carotenoids are formed. In addition to producing the color of tomatoes and carrots, carotenoids serve as the light-absorbing molecules of photosynthesis. Ketone bodies are derived from condensation of acetyl CoA units but not from isoprenoid units. Vitamin C (ascorbic acid), carnitine, and thiamine (vitamin BO are not derived from isoprenoid units. 

Like all steroids, brassinosteroids derive from a single common precursor mevalonic acid. Some phytohormones are synthesized totally or in part via the isoprenoid pathway, such as absdsic acid, gibberellins and cytokinins. The importance of this biosynthetic pathway in processes involved with cell cycle regulation and tumorigenesis in mammals is well documented. Having in mind the similarities between certain regulatory systems in plants and animals the question arose whether brassinosteroids as putative plant steroid hormones would show a specific effect on plant tumor cells. 

Isoprenoid biosynthetic pathways produce an astonishing variety of products in different cell types and different species. Despite this diversity, the beginning of isoprenoid biosynthesis appears to be identical in most of the species investigated (e.g., yeast, mammals, and plants). (HMG-CoA = / -hydroxy-/3-methylglutaryl-CoA)... 

HMG-CoA reductase activity has been detected in mammals, birds, insects, reptiles, fish, higher plants, moulds, yeast and bacteria [112]. HMG-CoA reductase probably is present in any life form capable of synthesizing isoprenoids. In mammals, HMG-CoA reductase activity has been detected in many tissues (Table 3). The highest quantities are present in liver and intestine, which together provide 2/3-3/4... 

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. 

The biosynthesis of the juvenile hormones is not yet fully known. Their similarity to famesol, an intermediate product in the biosynthesis of steroles in mammals, leads one to assume that their formation is analogous to that of farnesol. This obvious assumption seems to be supported by publications that have appeared in the early 1970s. Barnes and Goodfellow (1971) showed that isoprenoid biosynthesis in the larva of Sarcophaga bullata proceeds with the participation of mevalonate kinase. This enzyme regulates the formation of mevalonic acid pyrophosphate, an important intermediate product in steroid biosynthesis of mammals. Isopentenyl pyrophosphate, the C, unit of isoprenoid biosynthesis, is formed from mevalonic acid pyrophosphate by decarboxylation and, with the participation of ATP, by dehydration. 

Hydroxy-P-methylglutaryl coenzyme A reductase (HMG-CoA reductase) is widespread in bacteria, yeasts, higher plants, insects, and mammals and is present in all tissues that synthesize isoprenoid compounds. In mammals, this enzyme is localizied in the endoplasmic reticulum in yeasts, in the mitochondrial matrix and, in plants, both chlo-roplasts and cytoplasm have HMG-CoA reductase activity... 

Phylloquinone (V.K antihemorrhagic V. coagulation V.) is a group of fat-soluble naphthoquinone compounds, with varying sizes of isoprenoid side chain. Mammals can synthesize the side chain but not the naphthoquinone moiety. VK is plentiful in green plants. V.K2 (famoquinone menaquinone-6 2-methyl-l,4-naphthoquinone) is found chiefly in... 

The isoprenoid quinones, e.g. the ubiquinones 5.36), are essential metabolites, being involved in electron transport in living systems. In the ubiquinones a particular chain length is favoured from n = 6 in certain micro-organisms to w = 10 in most mammals. Mevalonic acid (5.55) is well established as the source of polyprenyl side-chains in these metabolites. It is probable that the side-chain is assembled as a polyprenyl pyrophosphate which then couples with the aromatic fragment. The evidence is that polyprenyl pyrophosphate synthetases and 4-hydroxybenzoate polyprenyltransferases have been isolated from living systems and ubiquinones co-occur with polyprenyl alcohols [as (5.57)] [26, 27]. 

IPP is produced from carbohydrates in plants, bacteria, algae, and mammals, including humans. The production of IPP is regulated by a series of chemical equilibria our rendition of the isoprenoid cycle is shown in Figure 4.7. The IPP monomer is first synthesized through a multi-step pathway from carbohydrates. Then IPP is isomerized into dimethylallyl pyrophosphate (DMAPP) by the isomerase enzyme. 

Squalene, a hydrocarbon CaoHso, was first isolated from shark liver and is found in small amounts also in mammals. As is evident from the biosynthesis just discussed, squalene is an isoprenoid composed of two symmetrical halves. Among the formulas shown here, two ways of writing the same molecule are presented. The spatial arrangement indicated in the second formula permits cyclization to the steroid skeleton, after a preliminary hydroxylation. The first isolable product is lanosterol ... 

---