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Structural Studies of Human 5'-Nucleotidases
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Responsible organisation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

5’-Nucleotidases (5’NTs) are catabolic enzymes of the nucleotide metabolism. They catalyze dephosphorylation of deoxyribo- and ribonucleoside monophosphates and constitute an important control point in the regulation of intracellular nucleotide pools for the maintenance of correct DNA and RNA synthesis.

By removing the alfa-phosphate group from a nucleotide, the 5’NTs release the nucleoside to pass the plasma membrane by facilitated diffusion. Depending on the cellular need for nucleotides, the nucleosides can either exit the cell for reuse elsewhere or be imported and subsequently phosphorylated by nucleoside and nucleotide kinases.

The knowledge of how nucleotides are metabolized has been used for rational design of nucleoside analogues that are used in treatment of cancer and viral diseases. These drugs are phosphorylated within the cell to become active. Their dephosphorylation by 5’NTs might be one of the mechanisms behind the resistance experienced by patients towards such drugs.

This thesis describes structure-function studies on four of the seven known human 5’-NTs. The focus of the work is on the substrate specificity and regulation of these enzymes. Inactive variants of the mitochondrial and cytosolic deoxynucleotidases and the cytosolic 5’-nucleotidase II were used to characterize the structural basis for their substrate specificity in high detail.

Based on structures of the apoprotein and activator/activator+substrate complexes of cytosolic 5’-nucleotidase II, a mechanism for the allosteric activation of this enzyme was presented. In this mechanism, the activator induces a conformational change that involves conserved residues of the active site. The conformational change drastically increases the enzyme affinity for the phosphate moiety of the substrate.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2008. , 78 p.
Keyword [en]
Nucleotidases, nucleotide, nucleoside, nucleoside analogue
National Category
Other Industrial Biotechnology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:su:diva-8169ISBN: 978-91-7155-718-6 (print)OAI: oai:DiVA.org:su-8169DiVA: diva2:199743
Public defence
2008-09-17, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Opponent
Supervisors
Available from: 2008-09-10 Created: 2008-09-10Bibliographically approved
List of papers
1. Structural Basis for Substrate Specificity of the Human Mitochondrial Deoxyribonucleotidase
Open this publication in new window or tab >>Structural Basis for Substrate Specificity of the Human Mitochondrial Deoxyribonucleotidase
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2005 In: Structure, ISSN 0969-2126, Vol. 13, 1081-1088 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25452 (URN)
Note
Part of urn:nbn:se:su:diva-8169Available from: 2008-09-10 Created: 2008-09-10Bibliographically approved
2. Crystal Structures of Human and Murine Deoxyribonucleotidases: Insights into Recognition of Substrates and Nucleotide Analogues
Open this publication in new window or tab >>Crystal Structures of Human and Murine Deoxyribonucleotidases: Insights into Recognition of Substrates and Nucleotide Analogues
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2007 In: Biochemistry, ISSN 0006-2960, Vol. 46, 13809-13818 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25453 (URN)000251241500014 ()
Note
Part of urn:nbn:se:su:diva-8169Available from: 2008-09-10 Created: 2008-09-10Bibliographically approved
3. Crystal Structure of Human Cytosolic 5'-Nucleotidase II: Insights into Allosteric Regulation and Substrate Specificity
Open this publication in new window or tab >>Crystal Structure of Human Cytosolic 5'-Nucleotidase II: Insights into Allosteric Regulation and Substrate Specificity
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2007 In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 282, no 24, 17828-17836 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25454 (URN)
Note
Part of urn:nbn:se:su:diva-8169Available from: 2008-09-10 Created: 2008-09-10Bibliographically approved
4. Mechanism for Allosteric Activation and Substrate Recognition of Human Cytosolic 5'-Nucleotidase II
Open this publication in new window or tab >>Mechanism for Allosteric Activation and Substrate Recognition of Human Cytosolic 5'-Nucleotidase II
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-25455 (URN)
Note
Part of urn:nbn:se:su:diva-8169Available from: 2008-09-10 Created: 2008-09-10 Last updated: 2010-01-13Bibliographically approved

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