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Metabolism of Purines and Pyrimidines in Health and Disease

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Metabolism of Purines and Pyrimidines in Health and Disease 39th Meeting of the Polish Biochemical Society Gdañsk 16–20 September 2003 SESSION 6 Metabolism of purines and pyrimidines in health and disease Organized by A. C. Sk³adanowski, A. Guranowski 182 Session 6. Metabolism of purines and pyrimidines in health and disease 2003 323 Lecture The role of DNA methylation in cytotoxicity mechanism of adenosine analogues in treatment of leukemia Krystyna Fabianowska-Majewska Zak³ad Chemii Medycznej IFiB, Uniwersytet Medyczny, ul. Mazowiecka 6/8, 92 215 £ódŸ Changes in DNA methylation have been recognized tory effects of cladribine and fludarabine on DNA as one of the most common molecular alterations in hu- methylation, after 48 hr growth of K562 cells with the man neoplastic diseases and hypermethylation of drugs, are non-random and affect mainly CpG rich is- gene-promoter regions is one of the most frequent lands or CCGG sequences but do not affect sepa- mechanisms of the loss of gene functions. For this rea- rately-located CpG sequences. The analysis showed son, DNA methylation may be a tool for detection of that cladribine (0.1 mM) reduced the methylated early cell transformations as well as predisposition to cytosines in CpG islands and CCGG sequences to a sim- metastasis process. Moreover, DNA methylation seems ilar degree. The inhibition of cytosine methylation by to be a promissing target for new preventive and thera- fludarabine (3 mM) was observed mainly in CCGG se- peutic strategies. quences, sensitive to HpaII, but the decline in the meth- Our studies on DNA methylation and cytotoxicity ylated cytosine, located in CpG island was 2-fold lower mechanism of antileukemic drugs, cladribine and than that with cladribine. In contrast, the action of fludarabine (adenosine analogues), indicate that the decitabine (a commonly used potent inhibitor of DNA drugs lead to significant decrease of DNA methyltransferase activity) is non-specific to cytosine methyltransferase activity in K562, L1210 and human localization, because it causes a decrease of methylated stimulated T lymphocytes. Moreover, in our studies cytosines mainly in isolated CpG sequences and, to a with exogenic bacterial methylase enzyme, we observed lesser degree, in both CCGG sequences and CpG is- a significant decrease of DNA methylation level after lands. the growth of K562 and L1210 cells in the presence of The effects of both of the antileukemic drugs, leading cladribine and fludarabine. DNA methylation-de- to a substantial drop in methylated cytosine in CpG is- pendent restriction analysis with HpaII and BssHII en- lands may be significant in the therapy of cancers asso- zymes which recognize unmethylated CCGG and ciated with gene silencing due to hypermethylation of GCGCGC sequences, respectively, showed that inhibi- their regulatory regions. 324 Lecture Current knowledge about the metabolism of mono- and di-nucleoside polyphosphates in plants Andrzej Guranowski Department of Biochemistry and Biotechnology, University of Agriculture, ul. Wo³yñska 35, 60-637 Poznañ Mononucleoside polyphosphates (pnN), such as zymes occurring in plants such as phosphatase and adenosine 5’-tetraphosphate (p4A) and adenosine 5’-pen- apyrase [4], that can hydrolyze p4A or p5A, and taphosphate (p5A), and dinucleoside polyphosphates phosphodiesterase I, for which Ap3A and Ap4A are very (NpnN’), such as diadenosine 5’,5’’’-P1,P3-triphosphate good substrates [1]. (Ap3A) or diadenosine 5’,5’’’-P1,P4-tetraphosphate Several enzymes forming an acyl-adenylate interme- (Ap4A), presumably occur in all organisms, however, diate with concomitant release of PPi can catalyze the their presence in plants has not yet been demonstrated. synthesis of different pnNs and NpnN’s. Phenylalanyl- The existence of highly specific enzymes that catalyze the and seryl-tRNA synthetases from yellow lupin seeds [5] hydrolysis of (di)nucleoside polyphosphates, such as and recently described 4-coumarate:coenzyme A ligase (asymmetrical) dinucleoside tetraphosphatase (EC from Arabidopsis thaliana [6] are so far the only plant 3.6.1.17) [1], dinucleoside triphosphatase (EC 3.6.1.29) enzymes known to synthesize NpnN’s and/or pnNs. Ki- [1, 2] and nucleoside 5’-tetraphosphatase (EC 3.6.1.14) netic and molecular properties of enzymes involved in [3], indicates that these uncommon nucleotides may exist the metabolism of pnNs and NpnN’s in plants will be and have a function in planta. In addition, these com- presented and biological role of these compounds dis- pounds can be substrates for nonspecific catabolic en- cussed. 2003 39th Meeting of the Polish Biochemical Society 183 1. Jakubowski H, Guranowski A (1983) J Biol Chem, 258: 4. Guranowski A, Starzyñska E, Rataj-Guranowska M, 9982–9989. Günther Sillero MA (1991) Protein Expression Purif, 2: 2. Guranowski A, Starzyñska E, Bojarska E, Stêpiñski J, 235–239. Dar¿ynkiewicz E (1996) Protein Expression Purif, 8: 5. Jakubowski H (1983) Acta Biochim Polon, 30: 51–69. 416–422. 6. Pietrowska-Borek M, Stuible H-P, Kombrink E, Guranowski 3. Guranowski A, Starzyñska E, Brown, P, Blackburn GM A (2003) Plant Physiol, 131: 1401–1410. (1997) Biochem J, 328: 257–262. 325 Lecture Flaviviridae viruses NTPase/helicase: a new target for inhibitors Tadeusz Kulikowski Instytut Biochemii i Biofizyki, Polska Akademia Nauk, ul. Pawiñskiego 5A, 02-106 Warszawa The Flaviviridae family include small viruses, which volved in transcription and replication of viral RNA sin- genom consists of a single-stranded positive-sense gle-stranded genomes. The crucial role of the enzyme RNA. Among them are dangerous human and animal for the virus replication cycle was demonstrated in ex- pathogenic viruses such as hepatitis C virus (HCV), periments using NTPase/helicase specific inhibitors. West Nile virus (WNV), and viral encephalitis (JEV). This make the enzyme an attractive target for develop- The genome of these viruses encodes 3 structural and ment of Flaviviridae-specific antiviral therapies. The 7 non-structural proteins. The enzymatic activities of present study involves investigation of the broad spec- NTPase/helicase were detected in the carboxy-terminal trum of activators and inhibitors of the enzymatic activ- fragment of the non-structural protein 3 (NS3) of the vi- ities of Flaviviridae NTPase/ helicase and describes the ruses. RNA nucleoside triphosphatase (NTPase)/ different mechanisms by which the inhibitors could act. helicases represent a large family of proteins that are Some of them, especially some modified benzimi- ubiquitously distributed over a wide range of organ- dazoles and benzotriazoles, show potential utility as an- isms. These enzymes play essential role in cell develop- tiviral agents against Flaviviridae viruses. ment and differentiation, and some of them are in- 326 Lecture The role of insulin in adenosine metabolism and action Tadeusz Pawe³czyk Zak³ad Medycyny Molekularnej, Akademia Medyczna w Gdañsku, ul. Dêbinki 7, 80-211 Gdañsk Adenosine plays an important role in physiology of Adenosine exerts its physiological effect by coupling several organs. Once generated, adenosine could be to cell-surface receptors (A1, A2a, A2b, A3). It has been deaminated to inosine by adenosine deaminase, reported that the responsiveness of various tissues to phosphorylated to AMP by adenosine kinase (AK), or adenosine in diabetes is altered. Investigation of rat di- transported into extracellular fluid. Extracellular me- abetic tissues revealed that mRNA level of A1 receptor tabolism of nucleotides produces adenosine, which is was significantly increased in diabetic kidney and was taken up by the cell or deaminated to inosine. Under unchanged in diabetic heart and liver. The expression normal conditions most of the adenosine formed in the of A2b receptor was decreased in diabetic kidney and cell is phosphorylated to AMP by adenosine kinase. Re- was unchanged in diabetic heart and liver. The level of cently reported data indicate that the activity and A2a mRNA was decreased in diabetic liver, whereas in mRNA level of adenosine kinase is significantly low- diabetic heart and kidney expression of this receptor ered in diabetic rats suggesting that the expression was unchanged. Administration of insulin to diabetic level of AK gene is dependent on insulin. Further exper- rats restored normal level of mRNA for adenosine re- iments performed on cultured rat lymphocytes have ceptors. These data suggest that insulin may affect the demonstrated that insulin induces AK gene expression expression level of adenosine receptors in a tissue spe- in a dose- and time-dependent manner. It has been dem- cific manner. onstrated that insulin signal to AK gene in rat lympho- The affinity for adenosine varies between receptors, cytes is transmitted by the MAP kinases pathway. thus its activation depends on adenosine concentra- 184 Session 6. Metabolism of purines and pyrimidines in health and disease 2003 tion. On the other hand, the level of adenosine depends insulin. Whereas, decreased expression of ENT1 re- on its metabolism and transport across plasma mem- sulted from increased glucose concentration but not branes. Thus, carrier-mediated transport of adenosine from changes in insulin level. is likely to play an important role in modulating cell In conclusion, presented data indicate that insulin function, because efficiency of the transport processes has profound effect on adenosine metabolism, trans- may determine adenosine availability either to recep- port and receptors. Therefore, the above-mentioned al- tors or to metabolizing enzymes. In diabetic rats the ex-
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