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De novo synthesis of purine ring: inosine monophosphate (IMP)
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The de novo synthesis of IMP provides the cell with the capacity to construct the purine ring ab initio, thereby insuring a source of nucleotides for cellular processes. Figure 29.2 shows portions of the pathway of purine biosynthesis along with the metabolic origin of each of the atoms in the purine ring. Synthesis is an energy-demanding process. AdenosineView drug information 5'-triphosphate (ATP) is required at each of the kinase, synthetase, and ring-closure steps. The starting material for purine biosynthesis is ribose 5-phosphate, a product of the pentose phosphate pathway.
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Figure 29.1 Classification of nucleotides. Basic structure of purines and pyrimidines.
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Table 29-1. Names and structures of important purines and pyrimidines.
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Names and structures of purines and pyrimidines
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StructureFree baseNucleosideNucleotide
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 adenineadenosineView drug informationAMP
ADP
ATP
cAMP
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 guanineguanosineGMP
GDP
GTP
cGMP
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 hypoxanthineinosineIMP
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 uraciluridineUMP
UDP
UTP
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 cytosinecytidineCMP
CDP
CTP
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 thyminethymidineTMP
TDP
TTP
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The designation NTP refers to the ribonucleotide. The prefix d, as in dATP, is used to identify deoxyribonucleotides. dTTP is usually written as TTP, with the d-prefix implied.
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The first step, catalyzed by ribose phosphate pyrophosphokinase (PRPP synthetase), generates the activated form of pentose phosphate by transferring a pyrophosphate group from ATP to form 5-phosphoribosyl-pyrophosphate (PRPP). PRPP is also used in other biosynthetic reactions including nucleotide salvage and the biosynthesis of tryptophan and histidine.
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In the second step, catalyzed by amidophosphoribosyl transferase, an amino group from glutamine displaces the pyrophosphate group. In a reaction that is similar to the formation of a peptide bond, glycineView drug information is added to the β-5-phosphoribosylamine to yield glycinamide ribonucleotide (GAR), catalyzed by GAR synthetase. The free amino group of GAR is then modified by addition of a formyl group by GAR transformylase to make formylglycinamide ribonucleotide (FGAR). The formyl group comes from N10-formyl tetrahydrofolate.
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In step 5, a second amino group is added onto FGAR to form formylglycinamidine ribonucleotide (FGAM). As for other amino group additions, the donor is glutamine. The enzyme catalyzing this addition is termed FGAM synthetase. The imidazole ring is now closed to form 5-aminoimidazole ribonucleotide (AIR) by action of AIR synthetase.
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The second 6-member ring is built by adding the three atoms, followed by cyclization. The first atom to be added is the C-6 carbon forming carboxyaminoimidazole ribonucleotide (CAIR). In an unusual reaction, catalyzed by AIR carboxylase, this carbon atom arises directly from CO2, without involvement of biotin. The nitrogen atom at position 1 of the mature purine ring is now added in a two-step reaction, using aspartate as the nitrogen donor. The first step is the formation of an aspartate-CAIR covalent intermediate termed 5-aminoimidazole-4-(N-succinylocarboxamide) ribonucleotide (SACAIR), catalyzed by SACAIR synthetase. The four-carbon dicarboxylic acid, fumarate, is then released from SACAIR by the action of adenylosuccinate lyase to form 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR).
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The last purine-ring carbon is added as a formyl group from N10-formyl tetrahydrofolate, by AICAR transformylase; the product is 5-formylaminoimidazole-4-carboxamide ribonucleotide (FAICAR). Finally, IMP synthase catalyzes closure of the second purine ring to form IMP.
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