The conversion of IMP to either AMP or GMP uses a two-step, energy-and nitrogen-requiring pathway (Fig. 22.8). [Note: AMP synthesis requires guanosine triphosphate (GTP) as an energy source and aspartate as a nitrogen source, whereas GMP synthesis requires ATP and glutamine.] Also, the first reaction in each pathway is inhibited by the end product of that pathway. This provides a mechanism for diverting IMP to the synthesis of the purine present in lesser amounts. If both AMP and GMP are present in adequate amounts, the de novo pathway of purine nucleotide synthesis is inhibited at the GPAT step.
showing feedback inhibition. NAD(H) = nicotinamide adenine dinucleotide; = pyrophosphate.
F. Nucleoside di-and triphosphate synthesis
Nucleoside diphosphates are synthesized from the corresponding nucleoside monophosphates by base-specific nucleoside monophosphate kinases (Fig. 22.9). [Note: These kinases do not discriminate between ribose or deoxyribose in the substrate.] ATP is generally the source of the transferred phosphate because it is present in higher concentrations than the other nucleoside triphosphates. Adenylate kinase is particularly active in the liver and in muscle, where the turnover of energy from ATP is high. Its function is to maintain equilibrium among the adenine nucleotides (AMP, ADP, and ATP). Nucleoside diphosphates and triphosphates are interconverted by nucleoside diphosphate kinase, an enzyme that, unlike the monophosphate kinases, has broad substrate specificity.
G. Purine salvage pathway
Purines that result from the normal turnover of cellular nucleic acids, or the small amount that is obtained from the diet and not degraded, can be converted to nucleoside triphosphates and used by the body. This is referred to as the salvage pathway for purines. [Note: Salvage is particularly important in the brain.] 1. purine base salvage to nucleotides: Two enzymes are involved: adenine phosphoribosyltransferase (APRT) and X-linked hypoxanthine– guanine phosphoribosyltransferase (HGPRT). Both use PRPP as the source of the ribose 5-phosphate group (Fig. 22.10). The release of pyrophosphate and its subsequent hydrolysis by pyrophosphatase makes these reactions irreversible. [Note: Adenosine is the only purine nucleoside to be salvaged. It is phosphorylated to AMP by adenosine kinase.] deficiencies of HGPRT are known. As the amount of functional enzyme increases, the severity of the symptoms decreases.] IMP, GMP, and AMP = inosine, guanosine, and adenosine monophosphates; PRPP = 5-phosphoribosyl1-pyrophosphate; PPi = pyrophosphate.