Dimethylallyl pyrophosphate, condensation

Dihydroxyproline 80 Diiron desaturases 863 Diiron oxygenases 863 Diiron proteins 862-864 Diiron-tyrosinate proteins 862-863 Diisopropylfluorophosphate (DFP, diisopropylphosphofluoridate) 610s Dimethylallyl diphosphate 712s Dimethylallyl pyrophosphate, condensation of 527... 

The answer is d. (Murray, pp 505-626. Scrivei, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) In the first stage ol cholesterol formation, acetyl coenzyme A condenses to form mevalonate, which is then phosphorylated and decarboxylated to form isopentenyl pyrophosphate. Half of the isopentenyl pyrophosphate isomerizes to form dimethylallyl pyrophosphate. These two isomeric C5 pyrophosphate units (isopentenyl pyrophosphate and dimethylallyl pyrophosphate) condense to form a CIO compound called geranyl pyrophosphate. Isopentenyl pyrophosphate then condenses with geranyl pyrophosphate to form the C15 compound farne-syl pyrophosphate. Finally, two farnesyl pyrophosphates condense in the presence of NADPH to form the C30 compound squalene. Squalene is ultimately cyclized through a series of steps to form cholesterol. Thus, the correct sequence of events leading from C5 units to C30 squalene is sequential condensation of 5-carbon units until a 15-carbon unit is formed, then condensation of two 15-carbon units to form squalene. 

Alkylations and other types of transformation may, however, also proceed with free purines. In Dictyostelium for instance, dimethylallyl pyrophosphate condenses with AMP to produce isopentenyl adenine. In mammalian tissue 3-methyladenine is formed from adenine, and in plants theobromine and caffeine... 

Stage (J) Condensation of Six Activated Isoprene Units to Form Squalene Isopentenyl pyrophosphate and dimethylallyl pyrophosphate now undergo a head-to-tail condensation, in which one pyrophosphate group is displaced and a 10-carbon chain, geranyl pyrophosphate, is formed (Fig. 21-36). (The head is the end to which pyrophosphate is joined.) Geranyl pyrophosphate undergoes another head-to-tail condensation with isopentenyl pyro-... 

Cholesterol is formed from acetyl-CoA in a complex series of reactions, through the intermediates /3-hydroxy-/3-methylglutaryl-CoA, mevalonate, and two activated isoprenes, dimethylallyl pyrophosphate and isopentenyl pyrophosphate. Condensation of isoprene units produces the noncyclic squalene, which is cyclized to yield the steroid ring system and side chain. 

The steroid hormones (glucocorticoids, mineralocorticoids, and sex hormones) are produced from cholesterol by alteration of the side chain and introduction of oxygen atoms into the steroid ring system. In addition to cholesterol, a wide variety of isoprenoid compounds are derived from mevalonate through condensations of isopentenyl pyrophosphate and dimethylallyl pyrophosphate. 

Example condensation of dimethylallyl pyrophosphate with isopentenyl pyrophosphate)... 

A quantum chemical investigation of the biosynthesis of farnesyl pyrophosphate through the condensation of isopentenyl pyrophosphate and dimethylallyl pyrophosphate suggests that the mechanism is concerted, although the transition state has carbocationic character.164 Quantum chemical calculations were performed on the cyclization of the farnesyl cation to the sesquiterpene pentalenene.165 Two distinct pathways with similar activation barriers were identified, each differing from previous proposed mechanisms, and each involving unusual carbocationic intermediates. Mechanisms previously proposed for enzyme-catalysed formation of the sesquiterpene trichodiene involve carbocation intermediates with a 1,4-hydride transfer as the key step, e.g. (89) -> (90) - (91).166 Quantum chemical calculations, however, show a... 

All 27 carbon atoms of cholesterol are derived from acetyl Co A. First acetyl CoA and acetoacetyl CoA combine to form HMG CoA which, in turn, is reduced to mevalonate by HMG CoA reductase. Mevalonate is converted into the five-carbon isoprene compounds 3-isopentenyl pyrophosphate and its isomer dimethylallyl pyrophosphate. These two compounds condense to form the CIO geranyl pyrophosphate, which is elongated to the C15 farnesyl pyrophosphate by the addition of another molecule of isopentenyl pyrophosphate. Two molecules of farnesyl pyrophosphate condense to form the C30 squalene, which is then converted via squalene epoxide and lanosterol to cholesterol. 

The C5 isoprene units in isopentenyl pyrophosphate are then condensed to form the C30 compound squalene (Fig. 2). First, isopentenyl pyrophosphate isomerizes to dimethylallyl pyrophosphate (Fig. 2a), which reacts with another molecule of isopentenyl pyrophosphate to form the CIO compound geranyl pyrophosphate (Fig. 2b). Another molecule of isopentenyl pyrophosphate then reacts with geranyl pyrophosphate to form the C15 compound farnesyl pyrophosphate. Next, two molecules of farnesyl pyrophosphate condense to form squalene (Fig. 2b). 

Mevalonate molecules are condensed to a 30-carbon compound, squalene. The alcohol groups of mevalonate are first phosphorylated. Then they multiply phosphorylated mevalonate decarboxylates to make the two compounds isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). 

These isomeric C5 units condense to form a Cjq compound isopentenyl pyrophosphate attacks an allylic carbonium ion formed from dimethylallyl pyrophosphate to yield geranylpyrophosphate (Figure 26.9). The same kind of reaction takes place again geranyl pyrophosphate is converted into an allylic carbonium ion, which is attacked by isopentenyl pyrophosphate. The resulting C15 compound is called farnesylpyrophosphate. The same enzyme, geranyl transferase, catalyzes each of these condensations. 

Figure 26.9. Condensation Mechanism in Cholesterol Synthesis. The mechanism for joining dimethylallyl pyrophosphate and isopentenyl pyrophosphate to form geranyl pyrophosphate. The same mechanism is used to add an additional isopentenyl pyrophosphate to form famesyl pyrophosphate.

Cholesterol is a steroid component of eukaryotic membranes and a precursor of steroid hormones. The committed step in its synthesis is the formation of mevalonate from 3-hydroxy-3-methylglutaryl CoA (derived from acetyl CoA and acetoacetyl CoA). Mevalonate is converted into isopentenyl pyrophosphate (C5), which condenses with its isomer, dimethylallyl pyrophosphate (C5), to form geranyl pyrophosphate (Cjo)- The addition of a second molecule of isopentenyl pyrophosphate yields famesyl pyrophosphate (C15), which condenses with itself to form squalene (C30). 

The isoprene rule is a convenient formalism, but isoprene itself is not the biological precursor of terpenes. Nature instead uses two isoprene equivalents —isopentenyl pyrophosphate and dimethylallyl pyrophosphate. These five-carbon molecules are themselves made from condensation of three acetyl CoA units (Section 21.9). 

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. 

Maier et al. have observed that microsomes (from Ruta graveolens cell cultures) catalyze the condensation of 1,3-dihydroxy-lO-methylacridin-9(10//)-one 69 with isopentenyl p5Tophosphate or dimethylallyl pyrophosphate, in the presence of NADPH and O2, to produce rutacridone 327, and also that the reaction involved glycocitrine-II 265 as an intermediate (90MI2 93P691). A possible precursor 351 of rutacridone 327 has also been isolated from a reaction of glycocitrine-II 265 with m-chloroperbenzoic acid (MCPBA) (Scheme 67) (93CPB383). 

Mevalonate, the 6-carbon product formed by HMG-CoA reductase, Is converted In several steps Into the 5-carbon Iso-prenold compound Isopentenyl pyrophosphate (IPP) and Its stereoisomer dimethylallyl pyrophosphate (DMPP). These reactions are catalyzed by cytosolic enzymes, as are the subsequent reactions In which six IPP units condense to yield squalene, a branched-chain 30-carbon Intermediate. Enzymes bound to the ER membrane catalyze the multiple reactions that convert squalene into cholesterol In mammals or into related sterols In other species. 

The formation of terpenes and other isoprenoid lipids involves the condensation of dimethylallyl pyrophosphate with isopentenyl pyrophosphate (29). In this case (Scheme 11), the leaving group is the pyrophosphate (PP) of an allylic pyrophosphate, such as dimethylallyl pyrophosphate, generating an allylic carbonium ion derivative (and inorganic pyrophosphate, which forms as an ion pair with the carbonium ion). The electron-rich agent that adds to the electron-deficient center to form the carbon-carbon bond is the rr-electron density of the isopentenyl pyrophosphate. The stereochemical course of the biosynthesis of complex natural products has been determined and is consistent with such a mechanism (30). 

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially the same biosynthetic scheme (Fig. 8). The self-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid [150-97-0] (72). Phosphorylation of (72) followed by concomitant decarboxylation and dehydration processes produce isopentenyl pyrophosphate. Isopentenyl pyrophosphate isomerase establishes an equilibrium between isopentenyl pyrophosphate and 3,3-dimethylallyl pyrophosphate (73). The head-to-tail addition of these isoprene units forms geranyl pyrophosphate. The addition of another isopentenyl pyrophosphate unit results in the sesquiterpene (C15) famesyl pyrophosphate (74). Both of these head-to-tail additions are catalyzed by prenyl transferase. Squalene synthetase catalyzes the head-to-head addition of two achiral molecules of famesyl pyrophosphate, through a chiral cyclopropane intermediate, to form the achiral triterpene, squalene (75). 

All these easy condensations of 2-methylbut-3-ene-2-ol or 3-methylbut-2-enol (y,y-dimethylallyl alcohol) with mono- and dihydric pheniols under very mild acidic conditions do support the biogenetic theory of C-isopentenylation with y,y-dimethylallyl pyrophosphate (ref.1). 

In bacteria and plastids of plants, formation of prenyl pyrophosphates, which are the precursors of carotenoids, proceeds via an alternative—the glyceraldehyde-3-phosphate pyruvate pathway. The pathway is apparently the sole source of isoprenoid compounds for the unicellular algae Scenedesmus (Metzler 2003). Initially, pyruvate is decarboxylated by a l-deoxyxylulose-5-phosphate synthase and condensed with D-glyceraldehyde 3-phosphate to form 1-deoxyxylulose 5-phosphate. This product may be the branching point for independent routes to isopentyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). 

By means of the biogenetic scheme set out in Fig. 13.8 the interrelationships of the hydrocarbons present in the essential oil can be seen. This scheme is produced by analogy with work with other plants and had not been confirmed for the hop. The biological isoprenylating agents isopentenyl pyrophosphate (32) and dimethylallyl pyrophosphate (33) can condense together to form ... 

Lynen and co-workers (1959) were the first to realize that dimethylallyl pyrophosphate (6) corresponds to Ruzicka s active isoprene and that this compound (and homologous allylic pyrophosphates) is involved in repetitive condensations with isopentenyl pyrophosphate (4) (Poulter and Rilling, 1981). 

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