5hzx
From Proteopedia
Crystal structure of zebrafish MTH1 in complex with TH588
Structural highlights
Function8ODP_DANRE Oxidized purine nucleoside triphosphate hydrolase which is a prominent sanitizer of the oxidized nucleotide pool (PubMed:26862114, PubMed:30304478). Catalyzes the hydrolysis of 2-oxo-dATP (2-hydroxy-dATP) into 2-oxo-dAMP (PubMed:26862114). Has also a significant hydrolase activity toward 2-oxo-ATP, 8-oxo-dGTP and 8-oxo-dATP (PubMed:26862114, PubMed:30304478). Through the hydrolysis of oxidized purine nucleoside triphosphates, prevents their incorporation into DNA and the subsequent transversions A:T to C:G and G:C to T:A (PubMed:26862114, PubMed:30304478). Also catalyzes the hydrolysis of methylated purine nucleoside triphosphate preventing their integration into DNA (PubMed:32144205, PubMed:30304478). Through this antimutagenic activity protects cells from oxidative stress (PubMed:32144205, PubMed:26862114, PubMed:30304478).[1] [2] [3] Publication Abstract from PubMedCancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific non-oncogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in non-malignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity. Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathological upregulation of the HIF1alpha response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pre-treatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance. Hypoxic signaling and the cellular redox tumor environment determine sensitivity to MTH1 inhibition.,Brautigam L, Pudelko L, Jemth AS, Gad H, Narwal M, Gustafsson R, Karsten S, Carreras-Puigvert J, Homan E, Berndt C, Warpman Berglund U, Stenmark P, Helleday T Cancer Res. 2016 Feb 9. pii: canres.2380.2015. PMID:26862114[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Danio rerio | Large Structures | Berglund UW | Berndt C | Brautigam L | Carreras-Puigvert J | Gad H | Gustafsson R | Helleday T | Homan E | Jemth A-S | Karsten S | Narwal M | Pudelko L | Stenmark P
