Evolution of Urate-Degrading Enzymes in Animal Peroxisomes

Abstract

The end product of purine metabolism varies from species to species. The degradation of purines to urate is common to all animal species, but the degradation of urate is much less complete in higher animals. The comparison of subcellular distribution, intraperoxisomal localization forms, molecular structures, and some other properties of urate-degrading enzymes (urate oxidase, allantoinase, and allantoicase) among animals is described. Liver urate oxidase (uricase) is located in the peroxisomes in all animals with urate oxidase. On the basis of the comparison of intraperoxisomal localization forms, mol wt, and solubility of liver urate oxidase among animals, it is suggested that amphibian urate oxidase is a transition form in the evolution of aquatic animals to land animals. Allantoinase and allantoicase are different proteins in fish liver, but the two enzymes form a complex in amphibian liver. The subcellular localization of allantoinase and allantoicase varies among fishes. Hepatic allantoinase is located both in the peroxisomes and in the cytosol in saltwater fishes, and only in the cytosol in freshwater fishes. Hepatic allantoicase is located on the outer surface of the peroxisomal membrane in the mackerel group and in the peroxisomal matrix in the sardine group. Amphibian hepatic allantoinase-allantoicase complex is probably located in the mitochondria. On the basis of previous data, changes of allantoinase and allantoicase in molecular structure and intracellular localization during animal evolution may be as follows: Fish liver allantoinase is a single peptide with a mol wt of 54,000, and is located both in the peroxisomes and in the cytosol, or only in the cytosol. Fish liver allantoicase consists of two identical subunits with a mol wt of 48,000, and is located in the peroxisomal matrix or on the outer surface of the peroxisomal membrane. The evolution of fishes to amphibia resulted in the dissociation of allantoicase into subunits, and in the association of allantoinase with the subunit of allantoicase. This amphibian enzyme was lost by further evolution.

EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy

“…The physiologic level of uric acid in rats is lower because of the existence of uricase, which can convert uric acid into allantoin. 64 However, because this metabolic pathway is not present in humans as a result of a lack of uricase, uric acid is mostly excreted directly in urine and is easily accumulated in the human kidney. [65][66][67] The higher basal level of uric acid in humans may trigger an adaptive mechanism that protects the kidney against injury when uric acid level is slightly increased.…”

Molecular Basis of Nucleobase Transport Systems in Mammals

“…Interestingly, a genetic deficiency in uricase, which is an enzyme that converts purine nucleobases to the final metabolite of urate, is also known in higher primates as a case of genetic silencing during the course of evolution. 23,24) The physiological relationship between the two genes is currently unclear. Therefore, the possibility should be considered that the metabolism and disposition of exogenous nucleobases and nucleobase analogues in humans may differ from those in experimental animals such as the mouse, rat, and dog, which are commonly used in preclinical studies in drug development and discovery.…”

Ürik Asidin Antioksidan ve Pro-Oksidan Özellikleri ile İlgili Kavram ve Tartışmalarının Derlemesi

“…These mutations have been interpreted as clear evidence of an important evolutionary advantage for the early primates that had increased UA 3,4,5 . As purine degradation is much less complete in higher animals than in others, it is obvious that certain enzymes had been lost during animal evolution and it is assumed that it provided some evolutionary advantage 6 .…”