De Novo Biosynthesis of Purine Nucleotides

Figure 22.4 summarizes the pathway leading from phosphoribosyl-1-pyrophosphate (PRPP) to inosine 5'-monophosphate (IMP). IMP, also called inosinic acid is the first fully formed purine nucleotide. It contains hypoxanthine as its base.

Important points about the synthesis of purine nucleotides to the point of IMP:

> 1. De novo purine nucleotide synthesis proceeds by the synthesis of the purine base upon the ribose sugar moiety.

> 2. Addition of an amine group in the first reaction causes the anomeric carbon to flip from the position in PRPP to the position in 5-phosphoribosylamine (PRA). All nucleotides have ribose/deoxyribose in the configuration.

> 3. Amine groups are donated by glutamine via amidotransferase-catalyzed reactions.

> 4. Single carbon units are added from 10-formyl-tetrahydrofolate in transformylase-catalyzed reactions (Figure 22.5)

> 5. Glycine and fumarate molecules are used to build the ring structure.

> 6. The reaction pathway is regulated allosterically by AMP, ADP, GMP, and GDP, which all inhibit PRPP amidotransferase, the first enzyme in the pathway. In E. coli, synthesis of the genes for the pathway is controlled by the purR repressor protein, which is activated by binding hypoxanthine or guanine.

Multifunctional enzymes in vertebrate cells contain several of these actvities in the same molecule.

Pathway from IMP to GMP and AMP:

Figure 22.6 shows that IMP is a branch point for the synthesis of guanosine monophosphate (GMP) or adenosine monophosphate (AMP). Note that the enzyme catalyzing the pathway to make AMP is inhibited by AMP and the enzyme catalyzing the pathway to make GMP is inhibited by GMP. Note, also, that energy requirements for the AMP pathway are met by GTP whereas energy requirements for the GMP pathway are met by ATP.

Cells exert a tremendous amount of control over the relative amounts of each nucleotide as demonstrated by the de novo synthetic reactions and in conversions of ribonucleotides to deoxyribonucleotides.

Conversion of GMP and AMP to GTP and ATP:

GMP and AMP are converted to diphosphates (see here) in reactions catalyzed by guanylate kinase and adenylate kinase, respectively. Conversion of nucleoside diphosphates to nucleoside triphosphates is catalyzed by nucleoside diphosphate kinase (see here). The reaction is reversible, thus providing a way to make both ATP and GTP. The enzyme is highly active, but has broad specificity for its phosphoryl group donor (nucleoside triphosphate) and receptor (nucleoside diphosphate).

See also: The Importance of PRPP, De Novo Pyrimidine Nucleotide Metabolism.

INTERNET LINKS:

> 1. Purine Metabolism

> 2. Purine and Pyrimidine Metabolism