Bosch-Navarrete, Cristina

Castillo-Acosta, VM

González-Pacanowska, D.

Ruiz-Pérez, Luis Miguel

Valente, M

Yagüe-Capilla, M

English

Castillo-Acosta, Victor M.

Digital.CSIC

    18th Symposium on Purine and Pyrimidine Metabolism in Man 12th-14th of June 2019, Lyon, France       General information and program    3  S5.4 9.55-10.10 Chiara Rampazzo SAMHD1 deficiency affects DNA replication fidelity and telomere homeostasis in human fibroblasts S5.5 10.10-10.30 Miriam Yagüe Capilla Deciphering the role of HD52, a mitochondrial nucleotidase essential for pyrimidine homeostasis in Trypanosoma brucei S5.6 10.30-10.45 Ken Okamoto Effect of xanthine oxidoreductase inhibitors on purine metabolism in mouse brain under hypoxic environment S5.7 10.45-11.00 Paulina Mierzejewska Ecto-5’-nucleotidase (CD73) deficiency in mice leads to age dependent impaired L-arginine metabolism and endothelial dysfunction 11.00-11.35 Coffee break and Poster session 2 11.35-13.00 Session 6 Inborn errors of purine and pyrimidine metabolism 1 Chairs: Yolanda Cámara & Sylvain Latour S6.1 11.35-12.00 Aida Mata-Ventosa Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure S6.2 12.00-12.20 Jonathan Shintaku Ribonucleotide Reductase Subunit RRM1 is Required for Mitochondrial DNA Maintenance via Regulation of dNTP and rNTP Pools S6.3 12.20-12.40 Norbert Minet Characterization and complementation of cellular models of CTPS1 and CTPS2 deficiencies S6.4 12.40-13.00 Emmanuel Martin A homozygous hypomorphic mutation is responsible for CTPS1 immunodeficiency : immunological and molecular characterization from a cohort study 13.00-14.30 Lunch and Poster session 2 14.30-16.00 Session 7 Purines and pyrimidines in cancer 2 Chairs: Tormod Karlsen Bjånes & Takahiro Yamauchi S7.1 14.30-14.50 Btissame El Hassouni Acquired resistance to Fluorocyclopentenylcytosine (RX-3117) in non-small lung cancer cells is related to a decrease of active RX-3117 nucleotides S7.2 14.50-15.10 Claus Desler Madsen The importance of nucleotide metabolism for successful immunotherapy for cancer S7.3 15.10-15.25 Octavia Cadassou What roles for the 5’-nucleotidases cN-II and CD73 in the interplay between the cancer cell and its innate immune microenvironment? S7.4 15.25-15.40 Mihoko Morita How the combination of 6-mercaptopurine with febuxostat affects xanthine oxidase activity in vitro S7.5 15.40-16.00 Fiona McKissock Novel ProTide NUC-3373: a potent inhibitor of thymidylate synthase 17.00-18.30 Sightseeing in the old city of Lyon 19.30-21.00 PPS Board Meeting    Friday June 14th 2019 The Auditorium, IARC 8.30-9.50 Session 8 Inborn errors of purine and pyrimidine metabolism 2 Chairs: Sandra Pérez-Torras & André van Kuilenburg S8.1 8.30-8.45 Michio Hirano Deoxynucleoside Therapy for Mitochondrial DNA Depletion S8.2 8.45-9.00 Cora Blázquez-Bermejo Age-related metabolic changes limit efficacy of deoxynucleoside-based therapy in TK2-deficient mice  S8.3 9.00-9.15 Olga Součková Preparation of standards for LC-MS/MS detection of various metabolites of the de novo purine synthesis and their 39  Abstract S5.4 Deciphering the role of HD52, a mitochondrial nucleotidase essential for pyrimidine homeostasis in Trypanosoma brucei  Miriam Yagüe-Capillaa, Víctor M. Castillo-Acostaa, Maria Valentea, Cristina Bosch-Navarretea, Luis M. Ruiz-Péreza & Dolores González-Pacanowskaa  aInstituto de Parasitología y Biomedicina López-Neyra (Consejo Superior de Investigaciones Científicas)  E-mail of corresponding author: miyaca31@ipb.csic.es, dgonzalez@ipb.csic.es   Objectives: We aimed to elucidate the role of TbHD52, a nucleotidase that belongs to the SAMHD1 family, in dTTP biosynthesis and pyrimidine homeostasis in Trypanosoma brucei.  Methods: Intracellular localization of TbHD52 was determined by immunofluorescence studies. TbHD52 knock-out cell lines were generated upon thymidine supplementation to further establish the impact of TbHD52 on cell viability, cell cycle progression and pyrimidine homeostasis. Several cell lines overexpressing enzymes involved in pyrimidine metabolism, such as hDCTD or TbCDA, in a TbHD52-dKO background were also generated for a more comprehensive study. Additionally, metabolomics studies were performed in order to identify global disturbances, specifically in dNTP homeostasis, in the absence of TbHD52. Results: TbHD52 is an exclusive mitochondrial nucleotidase essential for Trypanosoma brucei viability, as knock-out cells are pyrimidine auxotrophs. Additionally, our findings show that the lack of HD52 can be counteracted by the expression of enzymes involved in dUMP formation. In the absence of exogenous thymidine or deoxyuridine supplementation, TbHD52-dKO cells show strong defects in cell cycle progression and nuclei and kinetoplast segregation. Furthermore, the metabolomics profile was severely perturbed, affecting profoundly cytosine- and thymidine-derived metabolites.  Conclusions: TbHD52 is an essential enzyme in Trypanosoma brucei and our results suggest that it plays a key role providing mitochondrial deoxycytidine and thymidine for dTTP biosynthesis via TK salvage. Thus, our findings firmly support that TbHD52 is a valuable drug target against African trypanosomiasis.    Relevant references:   Valente, M., J. Timm, et al. (2016). "Cell cycle regulation and novel structural features of thymidine kinase, an essential enzyme in Trypanosoma brucei." Mol Microbiol 102(3): 365-385.  Leija, C., F. Rijo-Ferreira, et al. (2016). "Pyrimidine salvage enzymes are essential for de novo biosynthesis of deoxypyrimidine nucleotides in Trypanosoma brucei." PLoS Pathog 12(11): e1006010.  Ji, X., C. Tang, et al. (2014). "Structural basis of cellular dNTP regulation by SAMHD1." Proc Natl Acad Sci U S A 111(41): E4305-14.  St Gelais, C., S. de Silva, et al. (2012). "SAMHD1 restricts HIV-1 infection in dendritic cells (DCs) by dNTP depletion, but its expression in DCs and primary CD4+ T-lymphocytes cannot be upregulated by interferons." Retrovirology 9: 105.  KEYWORDS: Trypanosoma brucei,  SAMHD1, pyrimidines, nucleotidase   

Deciphering the role of HD52, a mitochondrial nucleotidase essential for pyrimidine homeostasis in Trypanosoma brucei

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Deciphering the role of HD52, a mitochondrial nucleotidase essential for pyrimidine homeostasis in Trypanosoma brucei

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