Current Protein and Peptide Science - Volume 2, Issue 4, 2001

Prevention of incorporation of dUTP into DNA is essential for maintenance of the genetic information. Prompt and specific removal of dUTP from the nucleotide pool, as expedited by the ubiquitous enzyme dUTPase, is therefore required for full viability in most biological systems. Conserved structural features perpetuate specificity in choice of substrate, which is crucial as hydrolysis of the structurally closely related nucleotid Read More

Deoxyuridine pyrophosphatase (dUTPase) cleaves the α-β phosphodiester bond of dUTP to form pyrophosphate and dUMP, preventing incorporation of uracil into DNA and providing the substrate for dTTP synthesis. Similar to other nucleotide binding proteins, dUTPase also consists of a sequence motif rich in glycine residues known as P-loop motif. The P-loop motif of the nucleotide binding proteins are involved in su Read More

The ubiquity of the dut gene in Eukarya, Eubacteria, and Archaea implies its existence in the last common ancestor of the three domains of life. The dut gene exists as single, tandemly duplicated, and tandemly triplicated copies. The dUTPase is encoded as an auxiliary gene in the genomes of several DNA viruses and two distinct lineages of retroviruses. A comprehensive analysis of dUTPase amino acid sequence relationships e Read More

Sequences of dUTPases encoded by Alpha- and Gamma herpesviruses resemble other dUTPases in their possession of five conserved motifs, but differ in having greater chain lengths (about twice as long) and in the location of Motif 3 at an N-terminal location relative to the other motifs. It was proposed that the herpesvirus gene arose by intragenic duplication of a standard dUTPase coding sequence and subsequent loss of one Read More

The absence of uracil from DNA genomes is a consequence of enzyme functions that eliminate intracellular dUTP pools and that purposefully recognize and remove uracil moieties from DNA. These enzymatic functions are dUTP nucleotidohydrolase (dUTPase) and uracil-DNA glycosylase (UDG), respectively. There are distinct nuclear and mitochondrial isoforms of each of these enzymes in human cells. The mitochondrial i Read More

With the exception of brain, most human tissues analysed contain dUTPase protein detectable by immunohistochemistry. Non-dividing tissues like untreated peripheral blood lymphocytes (PBL's) contain basal levels of cytoplasmic dUTPase and express additional, nuclear dUTPase upon mitogenic stimulation. Normal, proliferating tissues like intestinal mucosa or germinal centres within tonsils contain cytoplasmic as well a Read More

Thymidylate metabolism is an important target for chemotherapeutic agents that combat a variety of neoplastic diseases including head and neck, breast and gastrointestinal cancers. Therapeutic strategies applied to this pathway target the thymidylate synthase (TS) reaction that catalyzes the reductive methylation of deoxyuridylate (dUMP) to form thymidylate (TMP). This reaction represents the sole de novo source of TMP req Read More

The human herpesviruses are a well characterized group of viruses that are responsible for a wide spectrum of human diseases. Included in this group of pathogens are the alphaherpesviruses (herpes simplex types 1 and 2 and varicella-zoster virus), the betaherpesviruses (cytomegalovirus, human herpesvirus types 6 and 7) and the gammaherpesviruses (Epstein -Barr virus and human herpesvirus 8). An important feature of Read More

Several retroviruses, including equine infectious anemia virus (EIAV), visna virus, caprine arthritis-encephalitis virus (CAEV) and feline immunodeficiency virus (FIV) encode dUTPase. The role of this enzyme in the replication of these viruses has been scrutinized, with particular emphasis on potential roles for dUTPase in virulence and viral mutation rate. Overall, the results of these studies have indicated a centr Read More

Parasites of the Trypanosomatidae family are responsible for diseases that afflict several million people worldwide. Currently there is an urgent need for new drugs against these diseases and an approach to drug discovery is the study of biochemical and structural properties of a potential target and the subsequent design of specific compounds. Trypanosomatid genes coding for enzymes which distinctively hydrolyze dUTP Read More