Ribose-1,5 diphosphate

A ray of hope appeared when a synthetic route was developed in the laboratory of Albert Eschenmoser in Zurich, leading in good yields to ribose-2,4-diphosphate (in racemic form). The starting material was glycol aldehyde, which was phospho-rylated in the 2-position and then incubated with formaldehyde. Unfortunately the synthetic conditions are only those of a modern laboratory, but could the reaction have taken place on the primeval Earth (Muller et al., 1990). 

According to Muller (1990) this aldehyde can give ribose-2,4-diphosphate in the presence of formaldehyde via a two-step, base-catalysed reaction. This reaction provides a route to ribose derivatives, and thus to the nucleic acids. 

As already shown in Sect. 4.4, ribose-2,4-diphosphate is obtained in a base-catalysed condensation of glycolaldehyde phosphate in the presence of formaldehyde (Muller et al., 1990). The phosphate group in the 4 position of the sugar prevents the formation of a 5-membered furanose ring, but a 6-membered pyranose structure can be formed. 

FIGURE 5.2 Synthesis of ribose-2,4-diphosphate from glycolaldehyde phosphate, as proposed by Eschenmoser. 

In the presence of formaldehyde (0.5 mol equiv.), sugar phosphates were formed in up to 45% yield, with pentose-2,4-diphosphates dominating over hexose triphosphates by a ratio of 3 1 (Scheme 13.2, Route B). The major component was found to be D,L-ribose-2,4-diphosphate with the ratios of ribose-, arabinose-, lyxose-, and xylose-2,4-diphosphates being 52 14 23 11, respectively. The aldomerization of 2 in the presence of H2CO is a variant of the formose reaction. It avoids the formation of complex product mixtures as a consequence of the fact that aldoses, which are phosphorylated at the C(2) position, cannot undergo aldose-ketose tautomerization. The preference for ribose-2,4-diphosphate 5 and allose-2,4,6-triphosphate formation might be relevant to a discussion of the origin of ribonucleic acids. 

In the presence of formaldehyde (0.5 mol-equiv.) sugar phosphates were formed in up to 45% yield, with pentose 2,4-diphosphates dominating over hexose triphosphates by a ratio of 3 1 (O Scheme 2, route B). The preference for ribose 2,4-diphosphate 5 and allose 2,4,6-triphosphate formation might have significance for the discussion concerning the origin of ribonucleic acids. 

Eschenmoser et al. have also postulated that the Btlrgi-Dunitz trajectory must be taken into account in discussions of the kinetic preference for formation of allose 2,4,6-triphosphate in the hexose series and of ribose 2,4-diphosphate in the pentose series, by aldomerization of glycolaldehyde phosphate in aqueous NaOH solution [37]. In this analysis, however, an additional interaction between the donor and acceptor substituents (b <-> f in Figure 6.40) is supposed to increase when the approach is non-perpendicular. 

Both L- and D-ribose occur in this complex mixture, but are not particularly abundant. Since all carbohydrates have somewhat similar chemical properties, it is difficult to envision simple mechanisms that could lead to the enrichment of ribose from this mixture, or how the relative yield of ribose required for the formation of RNA could be enhanced. However, the recognition that the biosynthesis of sugars leads not to the formation of free carbohydrates but of sugar phosphates, lead Albert Eschenmoser and his associates to show that under slightly basic conditions the condensation of glycoaldehyde-2-phosphate in the presence of formaldehyde considerable selectivity exist in the synthesis of ribose-2,4-diphosphate 54). This reaction has also been shown to take place under neutral conditions and low concentrations in the presence of minerals (55), and is particularly attractive given the properties of pyranosyl-RNA (p-RNA), a 2 ,4 -linked nucleic acid analogue whose backbone includes the six-member pyranose form of ribose-2,4-diphosphate 56). 

Pentostatin (Fig. 42.25) is a ring-expanded purine ribonuoleoside that inhibits adenosine deaminase and is used in the treatment of hairy cell leukemia. The elevated levels of deoxyadenosine triphosphate that result from inhibition of this degradative enzyme inhibit the action of ribonucleotide reductase (the enzyme that converts ribose diphosphate to deoxyribose diphosphate), thus halting DNA synthesis within the tumor cell. 

Other molecules that can accept two electrons are flavins FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide). The former coenzyme is formed by adenine-ribose-diphosphate, followed by a linear sugar-type molecule and, finally, the aromatic ring (isoalloxazine) of Figure 11.7. FMN is missing adenine, ribose, and one of the phosphates at the beginning of the chain. Flavins are prosthetic groups in fiavoproteins involved in the ET chain of Complex 11. 

Nicotinamide is incorporated into NAD and nicotinamide is the primary ckculating form of the vitamin. NAD has two degradative routes by pyrophosphatase to form AMP and nicotinamide mononucleotide and by hydrolysis to yield nicotinamide adenosine diphosphate ribose. 

Crystalline phosphoric acid has also been used to prepare sugar diphosphates, e.g. a-D-ribose 1,5-diphosphate (62) and hexose 1,6-diphosphates. 

The synthesis of pentose-2,4-diphosphate referred to above gave the best yields of a ribose derivative. Thus, the search for an effective synthesis leading to necessary starting materials such as glycol aldehyde phosphate (GAP) was important Krishnamurthy et al. (1999, 2000) reported new synthetic routes to GAP glycol aldehyde is allowed to react with amidotriphosphate (AmTP) in dilute aqueous solution. The triphosphate derivative is formed from trimetaphosphate and NH4OH. 

Nicotinamide adenine dinucleotide (NAD) Fructose 1,6-diphosphate Glucose-6-phosphate Isopentenyl pyrophosphate Ribose-6-phosphate-l-pyrophosphate... 

Phosphoglucomutase acts not only on D-glucose and D-mannose phosphates (see p. 204) but also on D-ribose phosphates, the interconversion of D-ribosyl phosphate and D-ribose 5-phosphate being similarly accelerated by D-glucose 1,6-diphosphate,193 which appears to generate D-ribose 1,5-diphos-phate as cofactor.199(a) (b) (o) D-Ribose 5-phosphate is formed from D-ribose and ATP in the presence of yeast ribokinase.m... 

Deoxynucleotides for DNA synthesis are made at the nucleoside diphosphate level and then have to be phosphorylated up to the triphosphate using a kinase and ATP. The reducing equivalents for the reaction come from a small protein, thioredoxin, that contains an active site with two cysteine residues. Upon reduction of the ribose to the 2 -deoxyri-bose, the thioredoxin is oxidized to the disulfide. The thioredoxin(SS) made during the reaction is recycled by reduction with NADPH by the enzyme thioredoxin reductase. 

Kannan MS Modulation of calcium signaling by interleukin-13 in human airway smooth muscle role of CD38/cyclic adenosine diphosphate ribose pathway. Am J Respir Cell Mol 9 Biol 2004 31 36-42. 

Certain bacterial exntoxins are enzymes that attach the adenosine diphosphate (ADP)-ribose residue of NAD to Ga subunits, an activity known as ADP-ribosylation ... 

The deoxyribonucleotides, except for deoxythymidine nucleotide, are formed from the ribonucleotides by the action of an enzyme complex, which comprises two enzymes, ribonucleoside diphosphate reductase and thioredoxin reductase (Figure 20.11). The removal of a hydroxyl group in the ribose part of the molecule is a reduction reaction, which requires NADPH. This is generated in the pentose phosphate pathway. (Note, this pathway is important in proliferating cells not only for generation... 

The nucleotide cyclic AMP (3, 5 -cyclic adenosine monophosphate, cAMP) is a cyclic phosphate ester of particular biochemical significance. It is formed from the triester ATP by the action of the enzyme adenylate cyclase, via nucleophilic attack of the ribose 3 -hydroxyl onto the nearest P=0 group, displacing diphosphate as leaving group. It is subsequently inactivated by hydrolysis to 5 -AMP through the action of a phosphodiesterase enzyme. 

A common intermediate for all the nucleotides is 5-phosphoribosyl-l-diphosphate (PRPP), produced by successive ATP-dependent phosphorylations of ribose. This has an a-diphosphate leaving group that can be displaced in Sn2 reactions. Similar Sn2 reactions have been seen in glycoside synthesis (see Section 12.4) and biosynthesis (see Box 12.4), and for the synthesis of aminosugars (see Section 12.9). For pyrimidine nucleotide biosynthesis, the nucleophile is the 1-nitrogen of uracil-6-carboxylic acid, usually called orotic acid. The product is the nucleotide orotidylic acid, which is subsequently decarboxylated to the now recognizable uridylic acid (UMP). 

In standard conditions, the change in free enthalpy AG° (see p. 18) that occurs in the hydrolysis of phosphoric acid anhydride bonds amounts to -30 to -35 kj mol at pH 7. The particular anhydride bond of ATP that is cleaved only has a minor influence on AG° (1-2). Even the hydrolysis of diphosphate (also known as pyrophosphate 4) still yields more than -30 kJ mol . By contrast, cleavage of the ester bond between ribose and phosphate only provides -9 kJ mol (3). 

First, the amino acid is bound by the enzyme and reacts there with ATP to form diphosphate and an energy-rich mixed acid anhydride (aminoacyl adenylate). In the second step, the 3 -OH group (in other ligases it is the 2 -OH group) of the terminal ribose residue of the tRNA takes over the amino acid residue from the aminoacyl adenylate. In aminoacyl tRNAs, the carboxyl group of the amino acid is therefore esterified with the ribose residue of the terminal adenosine of the sequence. ..CCA-3. ... 

The sirtuins (silent information regulator 2-related proteins class III HDACs) form a specific class of histone deacetylases. First, they do not share any sequence or structural homology with the other HDACs. Second, they do not require zinc for activity, but rather use the oxidized form of nicotinamide adenine dinucleotide (NAD ) as cofactor. The reaction catalyzed by these enzymes is the conversion of histones acetylated at specific lysine residues into deacetylated histones, the other products of the reaction being nicotinamide and the metabolite 2 -0-acetyl-adenosine diphosphate ribose (OAADPR) [51, 52]. As HATs and other HDACs, sirtuins not only use acetylated histones as substrates but can also deacetylate other proteins. Intriguingly, some sirtuins do not display any deacetylase activity but act as ADP-ribosyl transferases. 

This enzyme [EC 2.4.2.7], also referred to as AMP pyro-phosphorylase and transphosphoribosidase, catalyzes the reaction of AMP and pyrophosphate (or, diphosphate) to generate adenine and 5-phospho-a-ribose 1-diphosphate. In the reverse reaction, 5-amino-4-imidaz-olecarboxyamide can replace adenine. 

This enzyme [EC 2.4.2.17], also known as phosphoribo-syl-ATP pyrophosphorylase, catalyzes the reaction of ATP with 5-phospho-a-D-ribose 1-diphosphate to generate l-(5-phospho-D-ribosyl)-ATP and pyrophosphate. 

This enzyme [EC 3.6.1.6] catalyzes the hydrolysis of a nucleoside diphosphate to produce a nucleotide (that is, a nucleoside monophosphate) and orthophosphate. NDP substrates include IDP, GDP, UDP, as well as d-ribose 5-diphosphate. 

This enzyme [EC 2.4.2.30] (also referred to as NAD+ ADP-ribosyltransferase, poly(ADP) polymerase, poly-(adenosine diphosphate ribose) polymerase, and ADP-ribosyltransferase (polymerizing)) catalyzes the reaction of NAD+ with [ADP-D-ribosyl] to produce nicotinamide and [ADP-D-ribosyl]( + i). The ADP-d-ribosyl group of NAD+ is transferred to an acceptor carboxyl group on a histone or on the enzyme itself, and further ADP-ribosyl groups are transferred to the 2 -position of the terminal adenosine moiety, building up a polymer with an average chain length of twenty to thirty units. 

This enzyme [EC 2.4.2.19], also referred to as nicotinate mononucleotide pyrophosphorylase (carboxylating), catalyzes the reversible reaction of pyridine 2,3-dicar-boxylate and 5-phospho-a-o-ribose 1-diphosphate to produce nicotinate D-ribonucleotide, carbon dioxide, and pyrophosphate. 

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