7b7v
From Proteopedia
Structure of NUDT15 in complex with Acyclovir monophosphate
Structural highlights
FunctionNUD15_HUMAN Mediates the hydrolysis of some nucleoside diphosphate derivatives. Can degrade 8-oxo-dGTP in vitro, suggesting that it may remove an oxidatively damaged form of guanine (7,8-dihydro-8-oxoguanine) from DNA and the nucleotide pool, thereby preventing misincorporation of 8-oxo-dGTP into DNA thus preventing A:T to C:G transversions. Its substrate specificity in vivo however remains unclear (By similarity). May have a role in DNA synthesis and cell cycle progression through the interaction with PCNA.[1] [2] Publication Abstract from PubMedNucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects. NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir.,Nishii R, Mizuno T, Rehling D, Smith C, Clark BL, Zhao X, Brown SA, Smart B, Moriyama T, Yamada Y, Ichinohe T, Onizuka M, Atsuta Y, Yang L, Yang W, Thomas PG, Stenmark P, Kato M, Yang JJ Nat Commun. 2021 Jul 7;12(1):4181. doi: 10.1038/s41467-021-24509-7. PMID:34234136[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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