NUDT15

NUDT15
已知的結構
PDB	直系同源搜索: PDBe RCSB
PDBID列表
	5BON
識別號
别名	NUDT15；, MTH2, NUDT15D, nudix hydrolase 15
外部ID	OMIM：615792 MGI：2443366 HomoloGene：10109 GeneCards：NUDT15
基因位置（人类）
染色体	13號染色體
终止	48,047,221 bp
基因位置（小鼠）
染色体	小鼠14号染色体
终止	73,785,682 bp
基因本體
分子功能	• 8-oxo-7,8-dihydroguanosine triphosphate pyrophosphatase activity; • 水解酶活性; • 金屬離子結合; • 8-oxo-7,8-dihydrodeoxyguanosine triphosphate pyrophosphatase activity; • nucleoside-diphosphatase activity; • nucleotide diphosphatase activity; • 血浆蛋白结合; • NADH pyrophosphatase activity; • nucleoside-triphosphate diphosphatase activity;
細胞組分	• 细胞质基质;
生物學過程	• nucleobase-containing small molecule catabolic process; • dGTP catabolic process; • 有絲分裂; • purine nucleotide catabolic process; • DNA protection; • regulation of proteasomal protein catabolic process; • nucleoside phosphate catabolic process; • response to reactive oxygen species; • purine deoxyribonucleoside triphosphate catabolic process;
	Sources:Amigo / QuickGO
直系同源
	55270
	214254
	ENSG00000136159
	ENSMUSG00000033405
	Q9NV35
	Q8BG93
	NM_018283; NM_001304745
	NM_172527; NM_001360484
	NP_001291674; NP_060753
	NP_766115; NP_001347413
	維基數據
檢視/編輯人類	檢視/編輯小鼠

Nudix 水解酶 15是一種在人類中由 NUDT15 基因編碼的蛋白質^[5]。

功能

此基因編碼的是一種屬於Nudix 水解酶（英语：Nudix hydrolase）超家族的酶。該超家族的成員能催化核苷酸的水解，包括像 8-oxo-dGTP 這樣的基質，這些基質是氧化損傷的產物，它們在DNA複製期間會誘導鹼基錯配且顛換突變。編碼的酶是硫嘌呤活化和毒性的負調節器。此基因突變會使硫嘌呤代謝不良，並與硫嘌呤產生的早期白血球减少症有關。已識別出此基因的多個假基因。

NUDT15 種系變異（例如，一種錯義 SNP:rs116855232，誘導 R139C）已經與硫嘌呤（例如，mercaptopurine、6-巯嘌呤（6-MP）、硫唑嘌呤（AZA，azathioprine））在臨床上治療急性淋巴性白血病^[6]^[7]及發炎性腸道疾病時，宜減量或停用以避免硫嘌呤造成的白血球低下^[8]^[9]。這些變異具有種族特異性（例如，rs116855232 的變異等位基因在東亞人和西班牙裔人中較高，但在高加索人和非洲人較低）。此基因上的罕見功能變異，甚至是單一點位變異，也已識別出與硫嘌呤造成的骨髓抑制有關^[10] ，並建議在決定硫嘌呤的初始劑量時，應進行全基因篩檢。

臨床重要性

硫嘌呤類藥物常用於治療自體免疫疾病、防止器官移植排斥和血液病的藥物。然而，其活性代謝物會經由硫嘌呤甲基轉移酶 (Thiopurine methyltransferase，TPMT) 及 Nudix 水解酶 15（此水解酶由 NUDT15 基因編碼）兩種酵素，進行代謝及去活化作用。根據研究，TPMT 基因表現為弱代謝型者，發生於歐美及非裔族群之機率較高（約 0.3%），於東亞裔族群之發生機率較為罕見；NUDT15基因表現為弱代謝型者，發生於東亞裔族群之機率約為 2%（具風險之基因變異頻率約為9.8%），於歐美族群中較為罕見（<1%）^[11]。

根據印度以研究，以硫唑嘌呤治療發炎性腸道疾病時，帶有 NDUT15 弱代謝型者發生白血球低下的發生率為 53.8%（7/13），帶有 TPMT 弱代謝型者發生白血球低下的發生率為 20.0%（1/5），而未帶這兩類弱代謝型者發生白血球低下的發生率為 24.5%（25/102）。NUDT15 而非 TPMT 基因變異與白血球低下的發生率有關。但雖有弱代謝型基因者，仍有 40% 以上沒有副作用，到沒帶弱代謝型基因者，也有 20% 的機會可能有副作用。總結，有此弱代謝型基因者未必發生副作用，沒此弱代謝型基因者也可能發生副作用，臨床使用上，仍需特別小心與注意^[12]。

參考文獻

^ ^1.0 ^1.1 ^1.2 GRCh38: Ensembl release 89: ENSG00000136159 - Ensembl, May 2017
^ ^2.0 ^2.1 ^2.2 GRCm38: Ensembl release 89: ENSMUSG00000033405 - Ensembl, May 2017
^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Entrez Gene: Nudix hydrolase 15.
^ Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nature Genetics. April 2016, 48 (4): 367–73. PMC 5029084 . PMID 26878724. doi:10.1038/ng.3508.
^ Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. Journal of Clinical Oncology. April 2015, 33 (11): 1235–42. PMC 4375304 . PMID 25624441. doi:10.1200/JCO.2014.59.4671.
^ Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature Genetics. September 2014, 46 (9): 1017–20. PMC 4999337 . PMID 25108385. doi:10.1038/ng.3060.
^ Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, et al. Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose. Oncotarget. February 2017, 8 (8): 13575–13585. PMC 5355121 . PMID 28088792. doi:10.18632/oncotarget.14594.
^ Moriyama T, Yang YL, Nishii R, Ariffin H, Liu C, Lin TN, et al. Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood. September 2017, 130 (10): 1209–1212. PMC 5606007 . PMID 28659275. doi:10.1182/blood-2017-05-782383.
^ 含azathioprine成分藥品安全資訊風險溝通表. [2023-12-31] （中文（臺灣））.
^ TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India.. BMC Gastroenterol: 327. [2023-12-31]. doi:10.1186/s12876-021-01900-8.

延伸閱讀

Yu Y, Cai JP, Tu B, Wu L, Zhao Y, Liu X, et al. Proliferating cell nuclear antigen is protected from degradation by forming a complex with MutT Homolog2. The Journal of Biological Chemistry. July 2009, 284 (29): 19310–20. PMC 2740556 . PMID 19419956. doi:10.1074/jbc.M109.015289 .
Hori M, Satou K, Harashima H, Kamiya H. 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. May 2010, 48 (9): 1197–201. PMID 20144704. doi:10.1016/j.freeradbiomed.2010.02.002. hdl:2115/43020 .
Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature Genetics. September 2014, 46 (9): 1017–20. PMC 4999337 . PMID 25108385. doi:10.1038/ng.3060.
Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. Journal of Clinical Oncology. April 2015, 33 (11): 1235–42. PMC 4375304 . PMID 25624441. doi:10.1200/JCO.2014.59.4671.
Tanaka Y, Kato M, Hasegawa D, Urayama KY, Nakadate H, Kondoh K, et al. Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. British Journal of Haematology. October 2015, 171 (1): 109–15. PMID 26033531. doi:10.1111/bjh.13518 .
Kakuta Y, Naito T, Onodera M, Kuroha M, Kimura T, Shiga H, et al. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. The Pharmacogenomics Journal. June 2016, 16 (3): 280–5. PMID 26076924. doi:10.1038/tpj.2015.43 .
Carter M, Jemth AS, Hagenkort A, Page BD, Gustafsson R, Griese JJ, et al. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nature Communications. August 2015, 6: 7871. Bibcode:2015NatCo...6.7871C. PMC 4532830 . PMID 26238318. doi:10.1038/ncomms8871.
Chiengthong K, Ittiwut C, Muensri S, Sophonphan J, Sosothikul D, Seksan P, et al. NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica. January 2016, 101 (1): e24–6. PMC 4697903 . PMID 26405151. doi:10.3324/haematol.2015.134775.
Liang DC, Yang CP, Liu HC, Jaing TH, Chen SH, Hung IJ, et al. NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. The Pharmacogenomics Journal. November 2016, 16 (6): 536–539. PMID 26503813. S2CID 13955512. doi:10.1038/tpj.2015.75.

外部連節

PDB中UniProt可用的所有結構信息之概述：Q9NV35 (Nucleotide triphosphate diphosphatase NUDT15) 在PDBe-KB（英语：PDBe-KB）。

NUDT15引用了美国国家医学图书馆提供的資料，这些資料属于公共领域。

[refGRCh38Ensembl-1] 1.0 ^1.1 ^1.2 GRCh38: Ensembl release 89: ENSG00000136159 - Ensembl, May 2017

[refGRCm38Ensembl-2] 2.0 ^2.1 ^2.2 GRCm38: Ensembl release 89: ENSMUSG00000033405 - Ensembl, May 2017

[3] Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] Entrez Gene: Nudix hydrolase 15.

[6] Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nature Genetics. April 2016, 48 (4): 367–73. PMC 5029084 . PMID 26878724. doi:10.1038/ng.3508.

[7] Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. Journal of Clinical Oncology. April 2015, 33 (11): 1235–42. PMC 4375304 . PMID 25624441. doi:10.1200/JCO.2014.59.4671.

[8] Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature Genetics. September 2014, 46 (9): 1017–20. PMC 4999337 . PMID 25108385. doi:10.1038/ng.3060.

[9] Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, et al. Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose. Oncotarget. February 2017, 8 (8): 13575–13585. PMC 5355121 . PMID 28088792. doi:10.18632/oncotarget.14594.

[10] Moriyama T, Yang YL, Nishii R, Ariffin H, Liu C, Lin TN, et al. Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood. September 2017, 130 (10): 1209–1212. PMC 5606007 . PMID 28659275. doi:10.1182/blood-2017-05-782383.

[11] 含azathioprine成分藥品安全資訊風險溝通表. [2023-12-31] （中文（臺灣））.

[12] TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India.. BMC Gastroenterol: 327. [2023-12-31]. doi:10.1186/s12876-021-01900-8.

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