DUTP diphosphatase
| dUTP diphosphatase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 3.6.1.23 | ||||||||
| CAS no. | 37289-34-2 | ||||||||
| Databases | |||||||||
| BRENDA | enzyme data | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | enzyme entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| Rhea | reactions | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
| dUTPase | |||||||
|---|---|---|---|---|---|---|---|
 crystal structures of feline immunodeficiency virus dutp pyrophosphatase and its nucleotide complexes in three crystal forms. | |||||||
| Identifiers | |||||||
| Symbol | dUTPase | ||||||
| Pfam | PF00692 | ||||||
| Pfam clan | CL0153 | ||||||
| InterPro | IPR008180 | ||||||
| SCOP2 | 1dup / SCOPe / SUPFAM | ||||||
| |||||||
| dUTPase_2 | |||||||
|---|---|---|---|---|---|---|---|
 the crystal structure of a complex of campylobacter jejuni dutpase with substrate analogue dupnhp | |||||||
| Identifiers | |||||||
| Symbol | dUTPase_2 | ||||||
| Pfam | PF08761 | ||||||
| Pfam clan | CL0231 | ||||||
| InterPro | IPR014871 | ||||||
| SCOP2 | 1w2y / SCOPe / SUPFAM | ||||||
| |||||||
dUTP diphosphatase (EC 3.6.1.23) is an enzyme that catalyzes the hydrolysis of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP) and pyrophosphate (PPi):
This enzyme has a dual function: on one hand, it removes dUTP from the deoxynucleotide pool, which reduces the probability of this base being incorporated into DNA by DNA polymerases, while on the other hand, it produces the thymidine triphosphate precursor dUMP. Lack or inhibition of dUTPase action leads to harmful perturbations in the nucleotide pool resulting in increased uracil content of DNA that activates a hyperactive futile cycle of DNA repair. In human cancer cells, the enzyme allows tumours to resist drugs which target thymidylate metabolism.
Structural studies
As of late 2007, 48 structures have been solved for this class of enzymes, with PDB accession codes PDB: 1DUC, PDB: 1DUD, PDB: 1DUN, PDB: 1DUP, PDB: 1DUT, PDB: 1EU5, PDB: 1EUW, PDB: 1F7D, PDB: 1F7K, PDB: 1F7N, PDB: 1F7O, PDB: 1F7P, PDB: 1F7Q, PDB: 1F7R, PDB: 1MQ7, PDB: 1OGH, PDB: 1OGK, PDB: 1OGL, PDB: 1PKH, PDB: 1PKJ, PDB: 1PKK, PDB: 1RN8, PDB: 1RNJ, PDB: 1SEH, PDB: 1SIX, PDB: 1SJN, PDB: 1SLH, PDB: 1SM8, PDB: 1SMC, PDB: 1SNF, PDB: 1SYL, PDB: 1VYQ, PDB: 1W2Y, PDB: 2BSY, PDB: 2BT1, PDB: 2CJE, PDB: 2D4L, PDB: 2D4M, PDB: 2D4N, PDB: 2HQU, PDB: 2HR6, PDB: 2HRM, PDB: 2OKB, PDB: 2OKD, PDB: 2OKE, PDB: 2OL0, PDB: 2OL1, and PDB: 2PY4.
There are at least two structurally distinct families of dUTPases. The crystal structure of human dUTPase reveals that each subunit of the dUTPase trimer folds into an eight-stranded jelly-roll beta barrel, with the C-terminal beta strands interchanged among the subunits. The structure is similar to that of the Escherichia coli enzyme, despite low sequence homology between the two enzymes.
The second family has a novel all-alpha fold, members of this family are unrelated to the all-beta fold found in dUTPases of the majority of organisms.
Nomenclature
This enzyme is a hydrolase, specifically one acting on acid anhydrides in phosphorus-containing anhydrides. The systematic name of this enzyme class is dUTP nucleotidohydrolase. Other names in use include deoxyuridine-triphosphatase, dUTPase, dUTP pyrophosphatase, desoxyuridine 5'-triphosphate nucleotidohydrolase, and desoxyuridine 5'-triphosphatase.
See also
References
- ↑ Bertani, L. Elizabeth; Häggmark, Agneta; Reichard, Peter (1963). "Enzymatic Synthesis of Deoxyribonucleotides". Journal of Biological Chemistry. 238 (10): 3407–3413. doi:10.1016/S0021-9258(18)48681-4.
- ↑ Vertessy BG, Toth J (2009). "Keeping uracil out of DNA". Accounts of Chemical Research. 42 (1): 97–106. doi:10.1021/ar800114w. PMC 2732909. PMID 18837522.
- ↑ Varga, Balázs; Barabás, Orsolya; Kovári, Júlia; et al. (2007). "Active site closure facilitates juxtaposition of reactant atoms for initiation of catalysis by human dUTPase". FEBS Letters. 581 (24): 4783–4788. doi:10.1016/j.febslet.2007.09.005. PMID 17880943.
- ↑ Tsesmetzis, Nikolaos; Paulin, Cynthia B. J.; Rudd, Sean G.; Herold, Nikolas (2018). "Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism". Cancers. 10 (7): 240. doi:10.3390/cancers10070240. PMC 6071274. PMID 30041457.
- ↑ Mol CD, Harris JM, McIntosh EM, Tainer JA (September 1996). "Human dUTP pyrophosphatase: uracil recognition by a beta hairpin and active sites formed by three separate subunits". Structure. 4 (9): 1077–92. doi:10.1016/S0969-2126(96)00114-1. PMID 8805593.
- ↑ Moroz, Olga V.; Harkiolaki, Maria; Galperin, Michael Y.; Vagin, Alexei A.; González-Pacanowska, Dolores; Wilson, Keith S. (2004). "The Crystal Structure of a Complex of Campylobacter jejuni dUTPase with Substrate Analogue Sheds Light on the Mechanism and Suggests the "Basic Module" for Dimeric d(C/U)TPases". Journal of Molecular Biology. 342 (5): 1583–1597. doi:10.1016/j.jmb.2004.07.050. PMID 15364583.
- ↑ Enzyme 3.6.1.23 at KEGG Pathway Database.
