24.4. Purine Salvage Pathways
The synthesis of purines is an energy expensive pathway and only a small amount of energy is recovered during their degradation. To save energy the cell recycles as many of the purine nucleotides as possible using the Purine Salvage Pathways.
During the digestion of food stuffs and cellular metabolism, the purine nucleotides are broken down to phosphate, ribose (deoxyribose) and the bases adenine, guanine, and/or hypoxanthine. Hypoxanthine is the purine base present on Inosine-5´-monophosphate, its the base on IMP.
The purine bases are salvaged by the action of two enzymes. Adenine phosphoribosyl Transferase couples the adenine base to 5-phosphoribosyl-α1-pyrophosphate (PRPP) to form AMP. Hypoxanthine-Guanine phosphoribosyl Transferase joins the hypoxanthine base to PRPP to form IMP and/or it attaches guanine to PRPP to form GMP. Bacteria have a salvage pathway for the pyrimidine bases.
Excess purines and pyrimidines originating from ingested nucleotides or from routine turnover of cellular nucleic acids are catabolized. Most intracellular purine bases are salvaged and pyrimidine salvage probably occurs. Purine breakdown yields only waste products that must be excreted, whereas the pyrimidines yields molecules that can enter metabolism for energy generation.
During the catabolic process AMP can be converted to IMP by AMP Deaminase and then the IMP is converted to inosine (a nucleoside) by the enzyme 5´-Nucleotidase, or AMP is first dephosphorylated to adenosine (a nucleoside) by 5´-Nucleotidase and then the adenosine is converted to inosine by Adenosine Deaminase. The net result of these two pairs of reactions is the conversion of AMP (a nucleotide) to inosine (a nucleoside). The inosine is then phosphorolytically cleaved, phosphate is added across the N-glycosidic bond, to yield the base hypoxanthine and ribose-1-phosphate by the enzyme Purine Nucleoside Phosphorylase.
Hypoxanthine is converted to xanthine by the action of the enzyme Xanthine Oxidase. This enzyme uses molecular oxygen (O2) to oxidize hypoxanthine to xanthine and hydrogen peroxide (H2O2). Hydrogen peroxide is a very destructive compound to have within the cell. It is rapidly and quantitatively destroyed by the enzyme Catalase. Xanthine Oxidase resides in lysosomes and peroxisomes.
Xanthine is then converted to uric acid, the final excretory product in mammals, by a second reaction catalyzed by Xanthine Oxidase. GMP catabolism is similar. GMP is first dephosphorylated to guanosine (a nucleoside) by the action of 5´- Nucleotidase. The guanine base is then released from the nucleoside by Purine Nucleoside Phosphorylase.
The guanine base is converted to xanthine by the enzyme Guanase. Once formed, xanthine is converted to uric acid by the action of Xanthine Oxidase.
In Mammals the uric acid is usually oxidized to Allantoin by Urate Oxidase and the allantoin is the major secretory product.
24.5. Pyrimidine Catabolism
The pyrimidine nucleotides are converted to their respective nucleosides by the action of 5´-Nucleotidase.
Cytidine (nucleoside) is converted to uridine (nucleoside) by the action of Cytidine deaminase.
Ribose is removed from uridine by the enzyme Uridine Phosphorylase to release the free base uracil, and it is removed from thymidine by the action of thymidine phosphorylase to release the free base thymine.
The enzyme dihydrouracil dehydrogenase reduces the bases uracil and thymine to dihydrouracil and dihydrothymine, respectively.
These two compounds are then acted upon by the enzyme. Dihydropyrimidinase to form uridopropionate or uridoisobutyrate.
The enzyme Uridopropionase hydrolytically removes NH4+ and HCO3– from these compounds to form β-alanine (from uracil) and β-aminoisobutyrate (from thymine).
An aminotransferase (Transaminase) converts β-alanine into malonic semialdehyde and converts β-aminoisobutyrate into methylmalonic semialdehyde.
A dehydrogenase complex oxidizes malonic semialdehyde and couples it to coenzyme A to form malonyl-CoA. The malonyl-CoA can enter fatty acid biosynthesis or more likely it is decarboxylated by malonyl-CoA decarboxylase to acetyl-CoA. and the acetyl-CoA oxidized for energy (ATP).
The same or a similar dehydrogenase complex oxidizes methylmalonic semialdehyde and couples it to CoA forming D-methylmalonyl-CoA. D-methylmalonyl-CoA is an intermediate in the metabolism of odd chain length fatty acids and the amino acids, Met, Val, Thr, and Ile. D-methylmalonyl-CoA is ultimately converted to succinyl-CoA as described previously.
After the base is phosphorylytically released from the deoxyribose by nucleoside Phosphorylase or thymidine phosphorylase the phosphate is moved from C-1 to C-5 by phosphopentose mutase to form deoxyribose-5-phosphate. The deoxyribose-5-phosphate is cleaved to ethanal and glyceraldehyde-3-phosphate by 2-deoxyribose-5-phosphate Aldolase. Carbon 1 & 2 becomes the ethanal and 3, 4, &5 become glyceraldehyde-3-phosphate. The glyceraldehyde-3-phosphate enters glycolysis or gluconeogenesis depending upon the tissue and blood glucose levels. Ethanal is oxidized to acetate by aldehyde dehydrogenase and then the acetate is coupled to Coenzyme A by Acetyl-CoA Synthetase. Acetyl-CoA enters any of the pathways that utilizes Acetyl-CoA, most likely the TCA cycle.