Terpenoids, biosynthesis molecules

Biosynthesis (Chapter 6).— E>etailed studies have been reported with individual enzymes responsible for the early stages of terpenoid biosynthesis. The mechanism whereby two molecules of famesyl pyrophosphate couple to furnish squalene is still uncertain and the structure of the C30 pyrophosphate intermediate isolated by Rilling in 1966 remains elusive. The genesis of the monoterpenoid portion of the indole alkaloids has been intensively studied. Of special interest was the discovery of the bismonoterpenoid foliamenthin, which is a derivative of the indole alkaloid precursor secologanin. The biosynthesis of the gibberellins has received detailed attention on both sides of the Atlantic. nr-kaurene, the parent, is formed via geranylgeranyl pyrophosphate and enr-copalyl pyrophosphate and this seems to follow a... 

The isoprenoids are derived from mevalonic acid (MVA), which is formed from three molecules of acetyl-CoA (Fig. 3). Two molecules of acetyl-CoA are condensed, yielding acetoacetyl-CoA. Subsequently, this product is coupled with another molecule of acetyl-CoA to yield 35-hydroxy-3-methylglutaryl-CoA (HMG-CoA). By reduction of HMG-CoA MVA is obtained. MVA is further converted in some steps to yield the Cs-unit isopentenyl diphosphate (IPP), which is then isomerized to dimethy-lallyl diphosphate (DMAPP), the starter molecule of the isoprenoid pathway. Coupling of DMAPP with one or more IPP molecules yields the basic structures which form the backbone of terpenoid biosynthesis. A number of reviews on the early steps in the terpenoid biosynthesis have been published (70-77). 

BRs belong to the class of molecules known as triterpenoids. Because BRs are a group of modified sterols, the BR biosynthetic pathway can be divided into two major parts the sterol-specific pathway (which converts squalene to campesterol) and the BR-specific pathway (which converts campesterol to the BR). In the sterol-specific pathway, mevalonic acid (which is the starting material in terpenoid biosynthesis) is condensed and cyclized to produce 2,3-oxidosqualene. This precursor is further modified to form the major plant sterols such as sitosterol and campesterol. To become bioactive BRs, sterols must be processed by the BR-specific pathway. 

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. 

At first glance, it is not at all clear that steroids are terpenoid in origin. The 5n numbers are absent— cholesterol is a C27 compound while the others variously have 20,21, or 23 carbon atoms. Studies with labelled mevalonic acid showed that cholesterol is terpenoid, and that it is formed from two molecules of farnesyl pyrophosphate (2 x C45 = C30 so three carbon atoms must be lost). Labelling of one or other of the methyl groups (two experiments combined in one diagram ) showed that two of the green carbon atoms and one of the black carbon atoms were lost during the biosynthesis. 

All carotenoids are derived from the isoprenoid or terpenoid pathway. From prenyl diphosphates of different chain lengths, specific routes branch off into various terpenoid end products. The prenyl diphosphates are formed by different prenyl transferases after isomerization of IPP to DMAPP by successive T-4 condensations with IPP molecules. Condensation of one molecule of dimethylallyl diphosphate (DMADP) and three molecules of isopentyl diphosphate (IDP) produces the diter-pene geranylgeranyl diphosphate (GGDP) that forms one-half of all C40 carotenoids. The head-to-head condensation of two GGDP molecules results in the first colorless carotenoid, phytoene. Phytoene synthesis is the first committed step in C40 carotenoid biosynthesis (Britton et al. 1998, Sandmann 2001). 

Interest in enzyme stereospecificity and the stereochemistry of prochiral centres, such as the methylene groups of mevalonic acid, has necessitated more precise definitions of the stereochemistry of the various molecules involved and of the enzymological consequences. The use of multiply labelled mevalonic acid in terpenoid and steroid biosynthesis has been reviewed by Hanson. The Proceedings of the 1970 Phytochemical Society symposium have been published. They include a general discussion of terpenoid pathways of biosynthesis by Clayton and specific chapters on monoterpenoids, diterpenoids, eedysones, carotenoids, isoprenoid quinones, and chromanols. Other reviews concerning biosynthesis have appeared on furanocoumarins, indole alkaloids, monoterpenoids, and diterpenoids. ... 

The first specific precursor for terpenoids in the cytoplasma is the Cg molecule mevalonic acid (MVA), which is built via the classical acetate/mevalonate pathway and converted by a series of phosphorylating and decarboxylation reactions into C5 isopentenyldiphosphate (IPP), the universal building block for chain elongation up to C20. In the chloroplasts, the biosynthesis of IPP starts from glyceraldehyde-3-phosphate and pyruvate to give l-deoxy-D-xylulose-5-phosphate (DOXP) via the non-mevalonate pathway as a recently detected alternative IPP route [19]. The reaction is catalyzed by the enzyme DOXP synthase and can be inhibited by a breakdown product of the herbicide clomazone [12]. 

There are two biosynthetic pathways, (1) the mevalonate pathway and (2) the MEP/ DOXP pathway, responsible for the production of the terpenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which serve as the basis for the biosynthesis of molecules used in processes as diverse as terpenoid/ steroid/hormone synthesis, protein prenylation, protein anchoring, cell membrane maintenance, and N-glycosylation. 

Biosynthetically, majority of terpenoids are formed via the mevalonic acid, but they may also be formed through methyl-erythritol-4-phosphate (MEP) pathway. The C5 isoprene unit which can be linked together head to tail to form linear chains or cyclized to form rings is considered the building blocks of terpenes. Rather the C5 units exist as isopentenyl pyrophosphate or its isomer dimethylallyl pyrophosphate by enzymatic conversion and phosphorylation from mevalonic acid. The IPP may be considered as the precursor of hemiterpenes. In the biosynthesis of mono- and higher terpenes/terpenoids, the starting molecule is DMAPP, which... 

Carotenoids are synthesized from the basic C5 terpenoid precursor isopentenyl pyrophosphate (IPP) and dimethylallyl diphosphate (DMAPP). These precursors can be obtained from two distinct pathways the mevalonate pathway (MVA) and the non-MVA pathway also known as 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway [84, 85]. All eukaryotes use the MVA pathway, whereas plant plastids and most bacteria use the MEP pathway [86,87]. Some bacteria also use the MVA pathway [84]. In the MEP pathway, the first step in IPP biosynthesis is the formation of l-deoxy-D-xylulose-5-phosphate (DXP) from pyruvate and glyceraldehyde-3-phosphate catalyzed by DXP synthase (Figure 10.7). DXP is then reduced to MEP by DXP reductase. Additional MEP pathway enzymes are then used in subsequent reactions for converting MEP to IPP, which is isomer-ized to DMAPP by the enzyme IPP isomerase. The MVA pathway begins with the conversion of three molecules of acetyl-CoA to MVA through acetoacetyl-CoA... 

Triterpenes and Steroids in Invertebrates Insects.—Terpenoid metabolism in insects will be considered separately from other invertebrates. Although insects do not possess the complete machinery required for biosynthesis of sterols from small molecules, it has been reported that a Sarcophaga bullata homogenate converts squalene into a compound with the chromatographic properties of squalene 2,3-oxide. However, this report warrants substantiation. The major insect juvenile hormone (133 R = Me) becomes labelled from [ C]acetate and also from l-[ H or... 

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