SVIBOR - Project code: 1-07-220

MINISTRY OF SCIENCE AND TECHNOLOGY

Strossmayerov trg 4, HR - 10000 ZAGREB
tel.: +385 1 459 44 44, fax: +385 1 459 44 69
E-mail: ured@znanost.hr

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Project code: 1-07-220


OXIDATIVE TRANSFORMATIONS OF PURINES


Main researcher: POJE, MIRKO (37773)


Assistants
Type of research: basic
Duration from: 01/01/91. to 12/31/95.
Papers on project (total): 20
Papers on project quoted in Current Contents: 12
Institution name: Prirodoslovno-matematički fakultet, Prirodoslovni odjeli, Zagreb (119)
Department/Institute: Laboratory of Organic Chemistry Department of Chemistry, Faculty of Science University of Zagreb
Address: Strossmayerov trg 14
City: 10000 - Zagreb, Croatia
Communication
Phone: 385 (0)1 426370
Fax: 385 (0)1 272066
E-mail: mirko.poje@x400.irb.hr
E-mail: poje@olimp.irb.hr
E-mail: Mirko.Poje@public.srce.hr
Fax: 385 (0)1 432526
Summary: Our recent investigations that have elucidated most of the classical controversies and presented the proofs of structure of uricolytic products having special biochemical significance now make it possible to approach such problems as the antioxidant function of uric acid, the mechanisms of enzymic reactions, and the biochemical defects associated with certain metabolic diseases. Redefinition of the biochemical reactivity and biological role of urate is necessary in order to include short-lived radical and quinoid species. This study will develop the model chemistry of the urate/dehydrourate system in order to create a structural basis for the interpretation of biochemical data. In a thorough treatment of various biological uricolytic pathways, the course at both the regio- and stereochemical level would have to be considered. Mechanisms of enzymic transformations will be studied using chemically modified or labelled substrates; the advantage of NMR/heavy-isotope tracers is that the observations can be made without chemical manipulation of the labelled substrates, and even without isolating the product in pure form. One of the key problems in the study of oxidative pathways of urate is the identification of transient intermediates immediately following the initial enzyme-catalysed interaction with molecular oxygen. Thus, the primary task is to establish the structure and stereochemistry of key intermediates. The covalent adducts of the quinoid dehydrouric acid will be studied in more details for the purpose of understanding biologically important purine ring transformations.

Keywords: allantoin, alloxan, alloxanic acid, antioxidants, dehydrouric acid, diabetes, enzymes, 5-hydroxyisouric acid, intermediates, isotope-labelling, covalent adducts, configuration, uric acid, NMR, oxidation, regiochemistry, stereochemistry, uricolysis, uricase, X-ray crystallography

Research goals: The main purpose of the project is to examine in depth the urate/dehydrourate redox system, which is the focal point in chemical and biological oxidative transformations of purines. The following specific aims are identified: 1) To investigate the redox properties and solution chemistry of the three states of oxidoreduction. 2) To advance the model chemistry of covalent adducts of dehydrouric acid in the light of their postulated role as key intermediates in biological oxidative transformations of purines. Regio- and stereochemistry of ring-modifying reactions will be studied in more details. 3) To identify metabolic pathways capable of generating toxic species and to establish their specific metabolic targets. The study will advance knowledge of the mechanisms of antioxidant action and the nature of the biologically important interactions. Investigation of the ring-modifying reactions of purines will provide further understanding of biologically important degradation pathways. Identification and structural elucidation of uricolytic intermediates may contribute to the fundamental aspects of the chemistry inherent in the quinoid redox state. The studies on the uricase reaction mechanism will provide fundamental information of importance for understanding the enyzmic catalysis of dioxygen-substrate interactions. Analogues of dehydrourate are of great importance not only for mechanistic considerations but also because they are cytotoxic agents; toxic intermediates derived from urate are crucial to the plausible hypothesis that endogenous alloxan-like molecules may play a role in the etiology of diabetes mellitus.

COOPERATION - PROJECTS


  1. Name of project: ALA/MED Biological Oxidations of Urate: Chemistry, Biochemistry, and Biological Potential
    Name of institution: University of Zagreb and University of Oxford
    City: OX - Oxford, UK

COOPERATION - INSTITUTIONS


  1. Name of institution: Dyson Perrins Laboratory, University of Oxford
    Type of institution: University/Faculty
    Type of cooperation: Joint project
    City: OX - Oxford, UK

  2. Name of institution: Nuffield Department of Clinical Biochemistry, University of Oxford
    Type of institution: University/Faculty
    Type of cooperation: Joint project
    City: OX - Oxford, UK

  3. Name of institution: Chemical Crystallography Laboratory, University of Oxford
    Type of institution: University/Faculty
    Type of cooperation: Joint publishing of scientific papers
    City: OX - Oxford, UK

  4. Name of institution: Department of Organic Chemistry, Eotvos Lorand University Budapest
    Type of institution: University/Faculty
    Type of cooperation: Joint publishing of scientific papers
    City: 36-1- - Budimpešta, Madžarska
Other information about the project.
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Last update: 10/12/95
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