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A unique insertion of low complexity amino acid sequence underlies protein-protein interaction in human malaria parasite orotate phosphoribosyltransferase and orotidine 5'-monophosphate decarboxylase

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Asian Pacific Journal of Tropical Medicine 2014年第3期7卷 184-192页

作者： Waranya Imprasittichai Sittiruk Roytrakul Sudaratana R.Krungkrai Jcrapan Krungkrai Department of Biochemistry.Faculty of Medicine.Chulalongkorn University National Center for Genetic Engineering and Biotechnology Unit of Biochemistry.Department of Medical Science.Faculty of Science Rangsit University

Objective:To investigate the multienzyine complex formation of human malaria parasite Plasmodium falciparum[P.falciparum)orotate phosphoribosyltransferase(OPRT)and orotidine5'-monophosphate decarboxylase(OMPDC),the fifth and sixth enzyme of the de novo pyrimidine biosynthetic palhway.Previously,we have clearly established that the two enzymes in the malaria parasite exist physically as a heterotetrameric(OPRT)_2(OMPDG)_2 complex containing two subunits each of OPRT and OMPDC.and that the complex have catalytic kinetic advantages over the monofunetional enzyme.Methods:Both enzymes were cloned and expressed as recombinant proteins.The protein-protein interaction in the enzyme complex was identified using bifunctionul chemical cross-linker,liquid chromatography-mass spectrometric analysis and homology modeling,Results:The unique insertions of low complexity region at the a 2 and a 5 helices of the parasite OMPDC,characterized by single amino acid repeat sequence which was not found in homologous proteins from other organisms,was located on the OPRT-OMPDC interface.The structural models for the protein-prolein interaction of the helerotetrameric(OPRT)_2(OMPDC)_2multienzyme complex were proposed.Conclusions:Based on the proteomic data and structural modeling,it is surmised that the human malaria parasite low complexity region is responsible for the OPRT-OMPDC interaction.The structural complex of the parasite enzymes,thus,represents an efficient functional kinetic advantage,which in line with co-localization principles of evolutional origin,and allosteric control in protein-protein-interactions.

关键词： Malaria Plasmodium falciparum Pyrimidine biosynthesis Orotate phosphoribosyltransferase Orotidine 5’-monophosphate decarboxylase Multienzyme complex Proteomics

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X-Ray Induced Mutation Frequency at the <i>Hypoxanthine phosphoribosyltransferase</i>Locus in Clinically Relevant Radioresistant Cells

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International Journal of Medical Physics, Clinical Engineering and Radiation Oncology 2017年第4期6卷 377-391页

作者： Yoshikazu Kuwahara Mehryar Habibi Roudkenar Yusuke Urushihara Yohei Saito Kazuo Tomita Amaneh Mohammadi Roushandeh Tomoaki Sato Akihiro Kurimasa Manabu Fukumoto Division of Radiation Biology and Medicine Faculty of Medicine Tohoku Medical and Pharmaceutical University Sendai Japan Department of Applied Pharmacology Graduate School of Medical and Dental Sciences Kagoshima University Kagoshima Japan Medical Biotechnology Research Center Paramedicine Faculty Guilan University of Medical Science Rasht Iran Fukushima Project Headquarters National Institute for Quantum and Radiological Science and Technology Fukushima Japan Department of Radiopharmacy Faculty of Pharmaceutical Science Tohoku Medical and Pharmaceutical University Sendai Japan Department of Anatomical Sciences School of Medicine Hamadan University of Medical Sciences Hamadan Iran Department of Molecular Pathology Tokyo Medical University Tokyo Japan

To elucidate the molecular mechanisms underlying cellular radioresistance, clinically relevant radioresistant cell lines were established via long-term exposure to X-rays with stepwise dose escalation. Established cells continue to proliferate despite exposure to 2 Gy X-rays/day for more than 30 days, a standard protocol in cancer radiotherapy. DNA repair fidelity in radioresistant and the parental cells by evaluating the mutation frequency at the hypoxanthine phosphoribosyltransferase (HPRT) locus after exposure to X-rays was determined. Mutation spectrum at the HPRT locus was examined by multiplex polymerase chain reaction. Rejoining kinetics of X-ray-induced DNA double strand breaks (dsbs) was evaluated by the detection of phosphorylated histone H2AX (γH2AX) after X-irradiation. The fold increase in the HPRT mutation frequency due to acute radiation was similar between radioresistant and the parental cell lines. However, fractionated radiation (FR) consisting of 2 Gy X-rays/day increased the mutation frequency at the HPRT locus in parental but not in radioresistant cells. Analysis of the FR-induced mutations at the HPRT locus revealed a high frequency of deletion mutations (>70%) in parental but not in radioresistant cells. As assessed by γH2AX immunostaining, DNA dsbs induced by acute exposure to 10 Gy of X-rays were repaired to the control level within 7 days in radioresistant but not in the parental cells. Moreover, 2 Gy × 5 FR increased the number of γH2AX-positive cells in parental cultures but not in radioresistant cultures. DNA dsbs induced by 2 Gy/day FR are repaired with fidelity in radioresistant but not in parental cells.

关键词： Clinically Relevant Radioresistant (CRR) Cell Hypoxanthine phosphoribosyltransferase (HPRT) Mutation Frequency Phosphorylated Histone H2AX (γH2AX) X-Rays

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Adenine phosphoribosyltransferase deficiency: Leave no stone unturned

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World Journal of Clinical Urology 2014年第3期3卷 218-226页

作者： Guillaume Bollée Michel Daudon Irène Ceballos-Picot Division of Nephrology and Research Center of the Centre Hospitalier de l’Université de Montréal and Université de Montréal Montréal Québec H2L 4M1 Canada Service d’Explorations Fonctionnelles Assistance Publique H?pitaux de ParisH?pital Tenon75020 Paris France Université Paris Descartes Assistance Publique H?pitaux de Paris Laboratoire de Biochimie Métabolomique et protéomiqueH?pital Necker-Enfants Malades75015 Paris France

Adenine phosphoribosyltransferase(APRT)deficiency is a rare autosomal recessive disease leading to generation of large amounts of 2,8-dihydroxyadenine(DHA).DHA is excreted in urine,where it precipitates into crystals due to its low solubility.DHA crystals can aggregate into stones or cause injury to the renal parenchyma(DHA nephropathy).Recurrent urolithiasis and DHA nephropathy are the two clinical manifestations of APRT deficiency.Diagnosis of APRT deficiency can be made during childhood as well as adulthood.Diagnosis mainly relies on the recognition of DHA in stones or urine crystals.Measurement of APRT activity and genetic testing are useful for confirmation of diagnosis,for family screening and should be considered in difficult cases of urolithiasis or crystalline nephropathy.Allopurinol therapy is the cornerstone of treatment and is highly effective in preventing recurrence of stones and kidney disease.High fluid intake and dietary modifications are also recommended.Early diagnosis and treatment are of paramount importance to prevent renal damage.Unfortunately,diagnosis of APRT deficiency is often overlooked and irreversible renal failure still occurs in a substantial proportion of patients.Clinicians must be alert to the possibility of APRT deficiency and consider the appropriate diagnostic tests in certain cases.This review discusses the genetic and biochemical mechanisms of APRT deficiency,and the issues of diagnosis and management.

关键词： Adenine phosphoribosyltransferase Dihydroxyadenine Urolithiasis Crystalline nephropathy 2,8-dihydroxyadenine nephropathy

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A live attenuated RHΔompdcΔuprt mutant of Toxoplasma gondii induces strong protective immunity against toxoplasmosis in mice and cats

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Infectious Diseases of Poverty 2023年第3期12卷 51-66页

作者： Yu Shen Bin Zheng Hao Sun Songrui Wu Jiyuan Fan Jianzu Ding Meng Gao Qingming Kong Di Lou Haojie Ding Xunhui Zhuo Shaohong Lu School of Basic Medical Sciences and Forensic Medicine Hangzhou Medical CollegeHangzhouZhejiangChina Engineering Research Center of Novel Vaccine of Zhejiang Province Hangzhou Medical CollegeHangzhouChina Key Laboratory of Bio-Tech Vaccine of Zhejiang Province Hangzhou Medical CollegeHangzhouChina

Background Toxoplasma gondii is an obligate intracellular apicomplexan parasite and is responsible for zoonotic toxoplasmosis.It is essential to develop an effective anti-T.gondii vaccine for the control of toxoplasmosis,and this study is to explore the immunoprotective effects of a live attenuated vaccine in mice and cats.Methods First,theompdc anduprt genes of T.gondii were deleted through the CRISPR-Cas9 system.Then,the intracellular proliferation and virulence of this mutant strain were evaluated.Subsequently,the immune responses induced by this mutant in mice and cats were detected,including antibody titers,cytokine levels,and subsets of T lymphocytes.Finally,the immunoprotective effects were evaluated by challenge with tachyzoites of different strains in mice or cysts of the ME49 strain in cats.Furthermore,to discover the effective immune element against toxoplasmosis,passive immunizations were carried out.GraphPad Prism software was used to conduct the log-rank(Mantel–Cox)test,Student’st test and one-way ANOVA.Results The RHΔompdcΔuprt were constructed by the CRISPR-Cas9 system.Compared with the wild-type strain,the mutant notably reduced proliferation(P<0.05).In addition,the mutant exhibited virulence attenuation in both murine(BALB/c and BALB/c-nu)and cat models.Notably,limited pathological changes were found in tissues from RHΔompdcΔuprt-injected mice.Furthermore,compared with nonimmunized group,high levels of IgG(IgG1 and IgG2a)antibodies and cytokines(IFN-γ,IL-4,IL-10,IL-2 and IL-12)in mice were detected by the mutant(P<0.05).Remarkably,all RHΔompdcΔuprt-vaccinated mice survived a lethal challenge with RHΔku80 and ME49 and WH6 strains.The immunized sera and splenocytes,especially CD8^(+)T cells,could significantly extend(P<0.05)the survival time of mice challenged with the RHΔku80 strain compared with naïve mice.In addition,compared with nonimmunized cats,cats immunized with the mutant produced high levels of antibodies and cytokines(P<0.05),and notably decreased the shedding numbers of oocysts in fec

关键词： Toxoplasma gondii Orotidine-5’-monophosphate decarboxylase phosphoribosyltransferase Live attenuated vaccine Immunization Mouse Cat

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OPRT Is a Potential Predictive Factor for the Response to S-1 in Gastric Cancer

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Journal of Cancer Therapy 2013年第1期4卷 104-111页

作者： Tao Li Meiha Leong Jing Yuan Juan Li Lin Chen Department of General Surgery Chinese PLA General Hospital Beijing China Department of Pathology Chinese PLA General Hospital Beijing China.

Objective: To analyze the impact of mRNA expression of oral fluoropyrimidine (S-1) metabolism (thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase [OPRT]), on treatment outcomes in locally advanced gastric cancer patients receiving preoperative S-1 combined with oxaliplatin chemotherapy. Methods: Preoperative stage III gastric cancer patients received S-1 (80 mg/m2/day;days 1-14) and oxaliplatin (130 mg/m2;day 1) every 3 weeks and subsequently received gastrectomy with D1/D2 lymphadenectomy. Paired tumor and normal fresh frozen tissues were collected to evaluate mRNA levels of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, and orotate phosphoribosyltransferase using quantitative reverse-transcriptase polymerase chain reaction. Results: Between December 2009 and October 2010, thirty-five patients were enrolled in this study. 24 (68.5%) patients had clinical tumor response and 10 (28.6%) patients achieved histological response. Quantitative reverse-transcriptase polymerase chain reaction results showed that orotate phosphoribo-syltransferase (OPRT) mRNA expression was significantly higher in histological responders than non-responders (3.75 vs. 1.81, P = 0.005). Diffuse-type gastric cancer patients demonstrated higher orotate phosphoribosyltransferase (OPRT) expression levels than intestinal-type ones (2.79 vs. 1.60, P = 0.014). Similar results were not found when comparing thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression levels. Conclusion: Orotate phosphoribosyltransferase (OPRT) expression level may be a potential predictive biomarker in advanced gastric cancer patients treated with oral fluoropyrimidine (S-1) based chemotherapy. Mini Abstract: Orotate phosphoribosyltransferase (OPRT) expression level may be a potential predictive biomarker in advanced gastric cancer patients treated with oral fluoropyrimidine (S-1) based chemotherapy.

关键词： S-1 Chemotherapy Gastric Cancer Orotate phosphoribosyltransferase Biomarker

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