Doctoral Dissertations

Date of Award

8-1996

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Walter R. Farkas

Committee Members

Donita Frazier, Charles Congdon, Lee Shugart

Abstract

There is a marked increase in the level of neopterin in the plasma and urine of people under stress. Neopterin is an intermediate that is made during biopterin synthesis. Primate macrophages lack the enzymes that convert dihydroneopterin to biopterin, thus secrete neopterin. Neopterin is found in the plasma of primates but not in laboratory animals such as mice and rats. The biological role of neopterin has not been established. Xanthine oxidase is involved in the oxidation of hypoxanthine and xanthine to uric acid. Excess uric acid in biological fluids is known to cause gouty arthritis, and kidney stones. Superoxide anions, O2.-, and other reactive oxygen species, are generated during the oxidation of hypoxanthine and xanthine. It is hypothesized that the role of elevated levels of neopterin in the body during stress are i). to reduce the formation of uric acid which can decrease the incidence of inflammation, ii). to make purines available for salvage for the synthesis of nucleic acid and purine nucleotide cofactors, and iii). to prevent the formation of reactive oxygen species. It is also hypothesized that uricotelic species produce neopterin. Studies were conducted to assess the effect(s) of neopterin (and related pteridines such as biopterin, pterin, and 6-formyl pterin) on enzymes that are involved in purine metabolism (xanthine oxidase, guanase, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyl transferase, and adenine phosphoribosyl transferase). High performance liquid chromatography, paper chromatography, and specific chemical modifications were used to study the inhibition of enzymes of purine degradation by neopterin and other pteridines. A comparative study was undertaken to investigate the presence of neopterin in different animals including human, cat, hamster, mouse, horse. cow, iguana, hawk, python, rat, pig, guinea pig, turkey, pigeon, goat, baboon, dog, rabbit. and chicken. The avian and reptilian species were of particular interest because, along with primates, these species excrete uric acid and also suffer from gout. The study showed that neopterin inhibits xanthine oxidase significantly at 10-7 M. No effect was seen in any other enzyme of purine catabolism. Also, there is a compound in the plasma of both birds (chicken, pigeon, hawk, and turkey) and reptiles (iguana and python) that has the same chromatographic properties as neopterin and inhibited xanthine oxidase. It is likely that neopterin or a similar compound has a role in the general regulation of purine metabolism.

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