Structural basis for the dual thymidine and thymidylate. In the aim of finding a new target, the thymidylate tmp kinase from vaccinia virus, the prototype of orthopoxvirus, has been overexpressed in escherichia coli after cloning the gene a48r. Structure of vaccinia virus thymidine kinase in complex. Pdf virus encodes an active thymidylate kinase that nts. The vaccinia virus thymidylate kinase gene has been cloned and identified by homology with yeast thymidylate kinase 42% identity. Molecular characterization ofthemurine thymidylate kinase. European journal of medicinal chemistry 2015, 91, 7290. It is present in two forms in mammalian cells, tk1 and tk2. Molecular characterization ofthemurine thymidylate kinase gene penghang,2lidiaaverboukh, weimin zhu, theresa haley, andarthur b. Thymidylate medical definition merriamwebster medical. With inhibition of ts, an imbalance of deoxynucleotides and increased levels of dump arise.
Viral thymidine kinasedeficient hsv1 impaired viral replication. Certain tks, such as those from herpes simplex virus type 1 hsv1 and varicella zoster virus vzv have, in addition, thymidylate kinase activity allowing the conversion of. Bacillus anthracis is well known in connection with biological warfare. Characterization of herpes simplex virus type 1 thymidine. The search for new drug targets and antibiotics is highly motivated because of upcoming multiresistant strains. Some herpes viruses encode only 1 enzyme catalyzing both reactions, a peculiarity used for prodrug activation to obtain maximum specificity. Tk thymidine kinase human herpesvirus 1 hhv1 tk gene. Thymidylate synthase ts is critical to dna synthesis as it catalyzes the rate limiting step in the only biosynthetic pathway for deoxythymidine monophosphate dtmp.
Thymidylate kinase an overview sciencedirect topics. Specific inhibitors and alternative substrates of pox tmp kinase should contribute to virus replication inhibition. Mechanisms of substrate selectivity for bacillus anthracis. Maga g, focher f, wright ge, capobianco m, garbesi a, bendiscioli a, spadari s. Herpes simplex virus type 1 hsv1 thymidine kinase tk is currently the most widely used suicide agent for gene therapy of cancer. Human herpesvirus 1 hhv1 human herpes simplex virus 1.
Epinotia aporema granulovirus epapgv is a baculovirus that causes a. Epsteinbarr virus thymidine kinase is a centrosomal resident. In silico design and synthesis of tetrahydropyrimidinones and tetrahydropyrimidinethiones as potential thymidylate kinase inhibitors exerting antitb activity against mycobacterium. It belongs to the family of nucleoside monophosphate kinases, several of which. The vaccinia virus thymidylate kinase gene has been cloned and identified. Herpes simplex virus type 1 hsv 1 thymidine kinase tk exhibits an. Pdf modifying human thymidylate kinase to potentiate. View all proteins of this organism that are known to be involved. Herpes simplex virus type 1 hsv 1 1 thymidine kinase tk is a multifunctional enzyme that possesses kinase activities normally performed by three separate cellular. Do you really need to use pc antivirus software these days. These functions include those of thymidine kinase, deoxycytidine kinase, thymidylate kinase, deoxycytidylate deaminase, ribonucleotide reductase and dna polymerase.
Compulsory order of substrate binding to herpes simplex. Tomato thymidine kinasebased suicide gene therapy for. Antibody mab4 recognizes a 36 kda protein identified as thymidylate synthase ts, which is a target for the fluoropyrimidine group of antineoplastic drugs used to treat solid tumors. Arg93, which is part of the drx motif of thymidylate kinases, is the only. Design of inhibitors of thymidylate kinase from variola virus as new selective drugs against smallpox. Kinetic studies with n2phenylguanines and with lthymidine indicate that herpes simplex virus. Building new software for automated crystallographic structure determination. Thymidylate kinase dtymk is a ubiquitous enzyme of about 25 kd which belongs to thymidylate kinase family. Thymidylate kinase from variola virus vartmpk is proposed as a new drug target. The thymidine kinase tk encoded by epsteinbarr virus ebv differs not. A vaccinia virus open reading frame orf previously predicted to encode thymidylate kinase tmpk is shown to encode an active enzyme.
Tmk thymidylate kinase vaccinia virus strain western. Substrate specificity of vaccinia virus thymidylate kinase. The large substrate specificity is explained by the presence of a canal connecting the edge of the dimer interface to the tmp base binding pocket, canal not found in the human homolog. The vaccinia virus thymidylate kinase gene has been cloned and identi. White spot syndrome virus wssv genome contains an open reading frame orf454 that encodes a thymidine kinase and tmk domains in a single polypeptide. Crystal structure of vaccinia virus thymidylate kinase bound to tdp. A novel viral thymidylate kinase with dual kinase activity. Plasmodium falciparum thymidylate kinase pftmk showed structural and catalytic distinctions from the host enzyme rendering it a hopeful antiprotozoal drug target. Pa530010 targets thymidylate kinase in wb applications and shows reactivity with human samples. Thymidylate kinase tmk is a key enzyme which plays an important role in dna synthesis. Acyclovir acvresistant acvr herpes simplex virus type 1 hsv1. The complex of the anticancer therapeutic, bw1843u89. A promising new target for antifungal drug development.
Substrate diversity of herpes simplex virus thymidine kinase. Herpesviruses are large doublestranded dna dsdna viruses with a. Virus detection additional resources our collection of vwr brands. Structure of thymidylate synthase from varicella zoster virus introduction varicella zoster virus vzv is a highly contagious human herpesvirus that causes varicella, which is commonly. The goal of this study was to improve the therapeutic index of the herpes simplex virus thymidine kinase ganciclovir hsv tk gcv system by the addition of thymidylate. Compulsory order of substrate binding to herpes simplex virus type 1 thymidine kinase a calorimetric study received for publication, january 24, 2000. Thymidylate kinases tmpk are solely responsible for converting dtmp to dtdp, an essential. Design of inhibitors of thymidylate kinase from variola. Crystal structures of equine herpesvirus type4 thymidine kinase ehv4tk in complex with i thymidine and adp, ii thymidine and so4 and the bisubstrate analogs, iii tp4a, and iv. We demonstrate that human herpesvirus 8, obtained from the lymphoma cell line bc3 as well as from kaposis sarcoma lesions, carries a gene that encodes a functional thymidylate synthase. Structure of the varicella zoster virus thymidylate. Quantification and analysis of thymidine kinase expression from.
The preparation for dna synthesis during g 1 or during conversion of nongrowing cells to a proliferative state is accompanied by an increase in dna polymerase, ribonucleotide reductase, deoxycytidylate deaminase, thymidine kinase, thymidylate kinase, and a number of other enzymes involved in dna precursor synthesis and in dna synthesis. Structural and functional analyses suggest that the cdna codes for authentic human dtmp kinase. The pa530010 immunogen is recombit fragment corresponding to a region within. Cidofovir and acyclovir were used as leads to the drug design of inhibitors. Thymidine kinase is an enzyme, a phosphotransferase a kinase. Subunit associations of vaccinia virus and human tmp kinases. The function of dtmp kinase in eukaryotes comes from the study. September 21, 2017 a promising new target for antifungal drug development. Human thymidylate kinase htmpk conversion of the antihiv prodrug 3. Tomato thymidine kinasebased suicide gene therapy for malignant gliomaan alternative for herpes simplex virus1 thymidine kinase skip to main content thank you for.
Human herpesvirus 8 gene encodes a functional thymidylate. Molecular characterization of thymidine kinase and thymidylate kinase in ureaplasma urealyticum and bacillus anthracis. Association between sensitivity of viral thymidine kinaseassociated. Structural and kinetic characterization of thymidine.
Structural studies of a hyperthermophilic thymidylate. Tumor cells that express hsv1 thymidine kinase are. Thymidylate kinase recombinant protein, prosci vwr. Alphaherpesvirus thymidine kinase tk genes are virulencerelated genes. Thymidylate kinase is a ubiquitous enzyme of about 25 kd and is important in the dttp synthesis pathway for dna synthesis. The structural basis of unique substrate recognition by. Tortricidae is an important pest of legume crops in south america. Although several kinases, which include sr protein kinases srpks one and a pair of, clksty, dualspecificity tyrosineregulated kinase, crkrs, dna topoisomerase i, glycogen synthase. Thymidylate synthase is an enzyme that catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. The function of dtmp kinase in eukaryotes comes from the study of a cell cycle mutant, cdc8, in saccharomyces cerevisiae. Certain viruses also have genetic information for expression of viral thymidine.
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