Purine biosynthesis, scheme

One example of a naturally occurring diazirine, duazomycin A (137 Scheme 11.20), has been reported, isolated in 1985 from a Streptomyces species during a screen for herbicidal compounds [196], It was fotind to inhibit de novo starch synthesis and it was suggested that this is due to direct inhibition of protein synthesis. Duazomycin A is structurally related to 6-diazo-5-oxo-L-norleucine (138), also reported as a natural product from Streptomyces [197], which acts as a glutamine antagonist and inhibits purine biosynthesis [198],... 

The imidazole ring of histidine (30) arises by a quite different route to that used for the formation of the imidazole ring in purine biosynthesis. The sources of the carbon and nitrogen atoms of histidine were established as a result of a series of labelling experiments with T4C and 15N substrates coupled with degradation of the labelled histidines. A summary of these results is given in Scheme 7 (59JBQ234)586). 

FR901483 in suppressing the immune system results from an antimetabolite activity whereby adenylosuccinate synthetase and/or adenylosuccinate lyase are inhibited. These enzymes function as key catalysts in the de novo purine nucleotide biosynthetic pathway. Addition of adenosine or deoxyadenosine (but not deoxyguanosine, deoxycytidine, uridine or thymidine) results in elimination of the immunosuppressive activity of FR901483. Thus, FR901483 may inhibit one of the key steps for adenosine biosynthesis (Scheme 1). 

It should be realized at the outset that all organisms have to possess the capacity to make deoxyribonucleotides firom ribonucleotides. This is the only process which permits the cell to utilize one fraction of the total nucleotides formed de novo in pyrimidine and purine biosynthesis for DNA replication there is no alternative biochemical route producing 2-deoxyribose, its phosphates, or N-glycosides from other molecules (Scheme II). 

The pyrimidine ring moiety of thiamine has recently been shown to be derived in part from an intermediate in the pathway of purine biosynthesis de novo, although many details regarding this synthesis still remain unclear. The proposed scheme is shown in Fig. 3-3. Aspartate may provide the other part of this ring. 

As noted in Scheme 12.87, the early stages of purine biosynthesis involve the generation of 5-aminoimidazole ribotide [5-amino-2-(5 -phosphoribosyl)imidazole]. In vertebrates, carboxylation of 5-aminoimidazole ribotide (Scheme 12.96) is effected with carbon dioxide (CO2) under the influence of phosphoribosylaminoimidazole... 

Much of the biosynthetic pathway for the formation of caffeine has already been discussed in the context of purine biosynthesis (Chapter 12). Thus, as shown in Scheme 12.87 (reproduced here as Scheme 13.66), following a more comprehensive... 

Dihydrofolate reductase (DHFR) catalyzes the reduction of 7,8-dihydrofolate (H2F) by nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form 5,6,7,8-telrahydrofolate (H4F), a key step in furnishing the parental cofactor needed for de novo pyrimidine and purine biosynthesis. The enzyme has been the target of antitumor and antimicrobial drugs. A complete Idnelic scheme (Fig. 6) obtained primarily throngh transient kinetics has been described for the enzyme bosaEscherichia coli as well as other sources and provides a second case smdy as to how to define the catalytic process. 

Subsequent knowledge of the stmcture, function, and biosynthesis of the foHc acid coenzyme gradually allowed a picture to be formed regarding the step in this pathway that is inhibited by sulfonamides. The biosynthetic scheme for foHc acid is shown in Figure 1. Sulfonamides compete in the step where condensation of PABA with pteridine pyrophosphate takes place to form dihydropteroate (32). The amino acids, purines, and pyrimidines that are able to replace or spare PABA are those with a formation that requkes one-carbon transfer catalyzed by foHc acid coenzymes (5). 

The bases occurring in nucleic acids are derivatives of the aromatic heterocyclic compounds purine and pyrimidine (see p. 80). The biosynthesis of these molecules is complex, but is vital for almost all cells. The synthesis of the nucleobases is illustrated here schematically. Complete reaction schemes are given on pp. 417 and 418. 

The pathway which is now thought to be involved in riboflavin biosynthesis by microorganisms is outlined in Scheme 9. The role of a purine derivative as an early precursor was... 

All the carbon atoms of the purine ring were supposedly provided by HCN molecules through a complex step-by-step condensation process. In particular, oligomers of HCN, such as the HCN-trimer aminomaleonitrile (AMN) and the HCN-tetramer diaminomaleonitrile (DAMN), were found to be intermediates in this transformation (Scheme 1) [43,44]. In accordance with the present-day biosynthesis of purines in the cell, two 4,5-di-substituted imidazole derivatives, 4-aminoimidazole-5-carbonitrile (AICN) and 4-aminoimidazole-5-carboxamide (AICA) were successively formed from AMN and DAMN by chemical or, most probably, photochemical reactions [45-47]. Finally, a ring-closure process of AICA and HCN yielded adenine 1. 

A new intermediate in purine nucleotide de novo biosynthesis in E. coli, namely 7V(5)-carboxy-aminoimidazole ribotide (35) has been identified together with two new enzymatic activities involving the carboxylation of the 5-amino group of 5-aminoimidazole ribotide (AIR) and the rearrangement of the /V-carboxy derivative to the C-carboxy derivative (CAIR) (Scheme 21) <94B2269>. 

The salvage pathway does not involve the formation of new heterocyclic bases but permits variation according to demand of the state of the base (B), i.e. whether at the nucleoside (N), or nucleoside mono- (NMP), di- (NDP) or tri- (NTP) phosphate level. The major enzymes and routes available (Scheme 158) all operate with either ribose or 2-deoxyribose derivatives except for the phosphoribosyl transferases. Several enzymes involved in the biosynthesis of purine nucleotides or in interconversion reactions, e.g. adenosine deaminase, have been assayed using a method which is based on the formation of hydrogen peroxide with xanthine oxidase as a coupling enzyme (81CPB426). 

The overall scheme of pyrimidine nucleotide biosynthesis differs from that of purine nucleotides in that the pyrimidine ring is assembled before it is attached to ribose-5-phosphate. The carbon and nitrogen atoms of the pyrimidine ring come from carbamoyl phosphate and aspartate. The production of carbamoyl phosphate for pyrimidine biosynthesis takes place in the cytosol, and the nitrogen donor is glutamine. (We already saw a reaction for the production of carbamoyl phosphate when we discussed the urea cycle in Section 23.6. That reaction differs from this one because it takes place in mitochondria and the nitrogen donor is NH/). 

Scheme 4. Biosynthesis of the purine alkaloids caffeine and theobromine. Molecular clones have been isolated for all enzymes shown. Abbreviations CS, caffeine synthase MXN, 7-methyIxanthosine nucleosidase MXS, 7-methyIxanthosine synthase.

Thus, from the Solanaceae, hyoscyamine, a tropane alkaloid, which we now know to be derived from ornithine and/or arginine (Arg, R, Scheme 12.7), and nicotine, derived from a combination of nicotinic acid (see Scheme 12.103, et seq.) and ornithine, serve as examples of alkaloids based on nonaromatic amino adds. In the benzylisoquinoline alkaloids, only morphine, arguably the first alkaloid isolated in purified form and known to be derived from tyrosine (Tyr, T), itself a prephenic acid derivative, is discussed. For the indole alkaloids, the single example of this rich family to be illustrated is vinblastine, a (relatively) recently isolated base of some medicinal value and which is shown to be composed of two different expressions of tryptophan (Trp, W) and mevalonate (Scheme 11.40). Finally, caffeine is chosen as the member of the purine alkaloids, a relatively small family of compounds but one of major commercial import and one whose biosynthesis is closely tied to the library of life. 

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