Biology:NUDT15
 Generic protein structure example |
Nudix hydrolase 15 is a protein that in humans is encoded by the NUDT15 gene.[1]
Function
This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphates, including substrates like 8-oxo-dGTP, which are a result of oxidative damage, and can induce base mispairing during DNA replication, causing transversions. The encoded enzyme is a negative regulator of thiopurine activation and toxicity. Mutations in this gene result in poor metabolism of thiopurines, and are associated with thiopurine-induced early leukopenia. Multiple pseudogenes of this gene have been identified.
NUDT15 germline variants (e.g., a missense SNP:rs116855232, inducing R139C) have been linked to clinical usage of thiopurines (e.g., mercaptopurine) in acute lymphoblastic leukemia[2][3] as well as inflammatory bowel diseases to avoid thiopurine-induced leukopenia.[4][5] These variants also exhibit ethnicity-specific (e.g.,variant allele of rs116855232 is high is East Asians and Hispanics but low in Caucasians and Africans). Rare functional variants even singletons in this gene have also been identified to be related to thiopurine-induced myelotoxicity,[6] suggesting the whole gene screening should be taken to determine the initial dosage using of thiopurine.
References
- ↑ "Entrez Gene: Nudix hydrolase 15". https://www.ncbi.nlm.nih.gov/gene/55270.
- ↑ "NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity". Nature Genetics 48 (4): 367–73. April 2016. doi:10.1038/ng.3508. PMID 26878724.
- ↑ "Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia". Journal of Clinical Oncology 33 (11): 1235–42. April 2015. doi:10.1200/JCO.2014.59.4671. PMID 25624441.
- ↑ "A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia". Nature Genetics 46 (9): 1017–20. September 2014. doi:10.1038/ng.3060. PMID 25108385.
- ↑ "Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose". Oncotarget 8 (8): 13575–13585. February 2017. doi:10.18632/oncotarget.14594. PMID 28088792.
- ↑ "Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry". Blood 130 (10): 1209–1212. September 2017. doi:10.1182/blood-2017-05-782383. PMID 28659275.
Further reading
- "Proliferating cell nuclear antigen is protected from degradation by forming a complex with MutT Homolog2". The Journal of Biological Chemistry 284 (29): 19310–20. July 2009. doi:10.1074/jbc.M109.015289. PMID 19419956.
- "Suppression of mutagenesis by 8-hydroxy-2'-deoxyguanosine 5'-triphosphate (7,8-dihydro-8-oxo-2'-deoxyguanosine 5'-triphosphate) by human MTH1, MTH2, and NUDT5". Free Radical Biology & Medicine 48 (9): 1197–201. May 2010. doi:10.1016/j.freeradbiomed.2010.02.002. PMID 20144704.
- "A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia". Nature Genetics 46 (9): 1017–20. September 2014. doi:10.1038/ng.3060. PMID 25108385.
- "Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia". Journal of Clinical Oncology 33 (11): 1235–42. April 2015. doi:10.1200/JCO.2014.59.4671. PMID 25624441.
- "Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia". British Journal of Haematology 171 (1): 109–15. October 2015. doi:10.1111/bjh.13518. PMID 26033531.
- "NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD". The Pharmacogenomics Journal 16 (3): 280–5. June 2016. doi:10.1038/tpj.2015.43. PMID 26076924.
- "Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2". Nature Communications 6: 7871. August 2015. doi:10.1038/ncomms8871. PMID 26238318. Bibcode: 2015NatCo...6.7871C.
- "NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia". Haematologica 101 (1): e24-6. January 2016. doi:10.3324/haematol.2015.134775. PMID 26405151.
- "NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia". The Pharmacogenomics Journal 16 (6): 536–539. November 2016. doi:10.1038/tpj.2015.75. PMID 26503813.
External links
- Overview of all the structural information available in the PDB for UniProt: Q9NV35 (Nucleotide triphosphate diphosphatase NUDT15) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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