title: Crystal structure of a human mitochondrial deoxyribonucleotidase.
abstract: 5' nucleotidases are ubiquitous enzymes that dephosphorylate nucleoside monophosphates and participate in the regulation of nucleotide pools. The mitochondrial 5'-(3') deoxyribonucleotidase (dNT-2) specifically dephosphorylates dUMP and dTMP, thereby protecting mitochondrial DNA replication from excess dTTP. We have solved the structure of dNT-2, the first of a mammalian 5' nucleotidase. The structure reveals a relationship to the HAD family, members of which use an aspartyl nucleophile as their common catalytic strategy, with a phosphoserine phosphatase as the most similar neighbor. A structure-based sequence alignment of dNT-2 with other 5' nucleotidases also suggests a common origin for these enzymes. Here we study the structures of dNT-2 in complex with bound phosphate and beryllium trifluoride plus thymidine as model for a phosphoenzyme-product complex. Based on these structures, determinants for substrate specificity recognition and the catalytic action of dNT-2 are outlined.
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001608:Beryllium / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005459:Fluorides / Q000737:chemistry; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013936:Thymidine / Q000737:chemistry
chemical_list: C056920:beryllium trifluoride; C063766:5'(3')-nucleotidase; D015720:5'-Nucleotidase; D001608:Beryllium; D005459:Fluorides; D013936:Thymidine