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Crystal structures of human deoxyribonucleotidases
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human 5’-deoxyribonucleotidases are ubiquitous enzymes that catalyze the dephosphorylation of deoxyribonucleoside monophosphates to their nucleoside form. They participate in the regulation of deoxyribonucleotide pools and protect DNA replication from inbalance of precursors. The observed specificity of the cytosolic 5’-deoxyribonucleotidase (cdN) and the mitochondrial 5’-deoxyribonucleotidase (mdN) is similar and both enzymes prefer the pyrimidine-based nucleotides such as dUMP and dTMP as substrates although cdN can also dephosphorylate dIMP and dGMP.

The structures of the two isoforms of the human deoxyribonucleotidases have been determined using X-ray crystallography and allowed us to propose a catalytic mechanism for this family of enzymes and to map residues involved in substrate binding.

The structures of cdN and mdN reveal dimeric proteins belonging to the HAD structural family, with a phosphoserine phosphatase (PSP) as the closest structural neighbour. The subunit is formed by two domains with the active site located in a crevice in between the domains. The active site contains a Mg2+ ion and a cluster of four aspartic residues. Asp41 is proposed to serve as the catalytic nucleophile and Asp43 as having a dual function in a general acid/base catalysis. Several structural complexes have been determined, with substrates, products, inhibitors and analogs of reaction intermediates. These substrate/product complexes reveal important residues for substrate specificity recognition. AlF4-/BeF3--compounds have been used to form structurecomplexes, which mimic formation of phosphoenzyme intermediates during catalysis. The study of the structural differences between the two enzymes, cdN and mdN, makes it possible to understand the differences in substrate recognition and inhibition pattern.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2004.
Keyword [en]
crystal structure
URN: urn:nbn:se:su:diva-149ISBN: 91-7265-896-7OAI: diva2:190153
Public defence
2004-05-28, Magnélisalen, Arrheniuslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 14:00
Available from: 2004-05-07 Created: 2004-05-07Bibliographically approved

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