Methionine Recycling Pathways and Antimalarial Drug Design

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 1995 Nov 1

PMID 8585735

Citations 26

Authors

J R Sufrin

S R Meshnick

A J Spiess

X Q Pan

C J Bacchi

Affiliations

Soon will be listed here.

Abstract

5'-Deoxy-5'-(methylthio)adenosine (MTA) is an S-adenosylmethionine metabolite that is generated as a by-product of polyamine biosynthesis. In mammalian cells, MTA undergoes a phosphorolytic cleavage catalyzed by MTA phosphorylase to produce adenine and 5-deoxy-5-(methylthio)ribose-1-phosphate (MTRP). Adenine is utilized in purine salvage pathways, and MTRP is subsequently recycled to methionine. Whereas some microorganisms metabolize MTA to MTRP via MTA phosphorylase, others metabolize MTA to MTRP in two steps via initial cleavage by MTA nucleosidase to adenine and 5-deoxy-5-(methylthio)ribose (MTR) followed by conversion of MTR to MTRP by MTR kinase. In order to assess the extent to which these pathways may be operative in Plasmodium falciparum, we have examined a series of 5'-alkyl-substituted analogs of MTA and the related MTR analogs and compared their abilities to inhibit in vitro growth of this malarial parasite. The MTR analogs 5-deoxy-5-(ethylthio)ribose and 5-deoxy-5-(hydroxyethylthio)ribose were inactive at concentrations up to 1 mM, and 5-deoxy-5-(monofluoroethylthio)ribose was weakly active (50% inhibitory concentration = 700 microM). In comparison, the MTA analogs, 5'-deoxy-5'-(ethylthio)adenosine,5'-deoxy-5'-(hydroxyethylthio)ade nosine (HETA), and 5'-deoxy-5'-(monofluoroethylthio)adenosine, had 50% inhibitory concentrations of 80, 46, and 61 microM, respectively. Extracts of P. falciparum were found to have substantial MTA phosphorylase activity. Coadministration of MTA with HETA partially protected the parasites against the growth-inhibitory effects of HETA. Results of this study indicate that P. falciparum has an active MTA phosphorylase that can be targeted by analogs of MTA.

Citing Articles

Biochemical and structural characterization of tyrosine aminotransferase suggests broad substrate specificity and a two-state folding mechanism in Leishmania donovani.

Sasidharan S, Saudagar P FEBS Open Bio. 2019; 9(10):1769-1783.

PMID: 31393078 PMC: 6768288. DOI: 10.1002/2211-5463.12715.

Enzyme homologues have distinct reaction paths through their transition states.

Zoi I, Motley M, Antoniou D, Schramm V, Schwartz S J Phys Chem B. 2015; 119(9):3662-8.

PMID: 25650981 PMC: 4385586. DOI: 10.1021/jp511983h.

Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate.

Moreno M, Alonso A, Alcolea P, Abramov A, Garcia de Lacoba M, Abendroth J Int J Parasitol Drugs Drug Resist. 2014; 4(3):347-54.

PMID: 25516846 PMC: 4266777. DOI: 10.1016/j.ijpddr.2014.06.001.

Structural and biochemical characterization of Chlamydia trachomatis hypothetical protein CT263 supports that menaquinone synthesis occurs through the futalosine pathway.

Barta M, Thomas K, Yuan H, Lovell S, Battaile K, Schramm V J Biol Chem. 2014; 289(46):32214-32229.

PMID: 25253688 PMC: 4231696. DOI: 10.1074/jbc.M114.594325.

Structural determinants of the 5'-methylthioinosine specificity of Plasmodium purine nucleoside phosphorylase.

Donaldson T, Ting L, Zhan C, Shi W, Zheng R, Almo S PLoS One. 2014; 9(1):e84384.

PMID: 24416224 PMC: 3885546. DOI: 10.1371/journal.pone.0084384.

References

Riscoe M, Ferro A, Fitchen J . Methionine recycling as a target for antiprotozoal drug development. Parasitol Today. 1989; 5(10):330-3. DOI: 10.1016/0169-4758(89)90128-2. View

Riscoe M, Ferro A, Fitchen J . Analogs of 5-methylthioribose, a novel class of antiprotozoal agents. Antimicrob Agents Chemother. 1988; 32(12):1904-6. PMC: 176044. DOI: 10.1128/AAC.32.12.1904. View

Fitchen J, Riscoe M, Dana B, Lawrence H, Ferro A . Methylthioadenosine phosphorylase deficiency in human leukemias and solid tumors. Cancer Res. 1986; 46(10):5409-12. View

Makler M, Ries J, Williams J, Bancroft J, Piper R, Gibbins B . Parasite lactate dehydrogenase as an assay for Plasmodium falciparum drug sensitivity. Am J Trop Med Hyg. 1993; 48(6):739-41. DOI: 10.4269/ajtmh.1993.48.739. View

Tower P, Alexander D, Johnson L, Riscoe M . Regulation of methylthioribose kinase by methionine in Klebsiella pneumoniae. J Gen Microbiol. 1993; 139(5):1027-31. DOI: 10.1099/00221287-139-5-1027. View

Myers R, Abeles R . Conversion of 5-S-ethyl-5-thio-D-ribose to ethionine in Klebsiella pneumoniae. Basis for the selective toxicity of 5-S-ethyl-5-thio-D-ribose. J Biol Chem. 1989; 264(18):10547-51. View

Yarlett N, Bacchi C . Effect of DL-alpha-difluoromethylornithine on methionine cycle intermediates in Trypanosoma brucei brucei. Mol Biochem Parasitol. 1988; 27(1):1-10. DOI: 10.1016/0166-6851(88)90019-9. View

TRAGER W, Jensen J . Human malaria parasites in continuous culture. Science. 1976; 193(4254):673-5. DOI: 10.1126/science.781840. View

Pegg A . Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 1988; 48(4):759-74. View

10.

Miller R, Toorchen D . MTA phosphorylase in protozoa: a potential target for chemotherapeutic attack. Adv Exp Med Biol. 1988; 250:211-8. DOI: 10.1007/978-1-4684-5637-0_19. View

11.

Kuhn R, Jahn W . [On the thio ether and S-oxide derivatives of adenosine]. Chem Ber. 1965; 98(6):1699-704. DOI: 10.1002/cber.19650980603. View

12.

Myers R, Abeles R . Conversion of 5-S-methyl-5-thio-D-ribose to methionine in Klebsiella pneumoniae. Stable isotope incorporation studies of the terminal enzymatic reactions in the pathway. J Biol Chem. 1990; 265(28):16913-21. View

13.

Kikugawa K, Iizuka K, Higuchi Y, Hirayama H, Ichino M . Platelet aggregation inhibitors. 2. Inhibition of platelet aggregation by 5'-, 2-, 6-, and 8-substituted adenosines. J Med Chem. 1972; 15(4):387-90. DOI: 10.1021/jm00274a015. View

14.

TRAGER W, Tershakovec M, Chiang P, CANTONI G . Plasmodium falciparum: antimalarial activity in culture of sinefungin and other methylation inhibitors. Exp Parasitol. 1980; 50(1):83-9. DOI: 10.1016/0014-4894(80)90010-7. View

15.

TRAGER W, Lederer E . Antimalarial activity of S-isobutyl adenosine against Plasmodium falciparum in culture. FEBS Lett. 1978; 85(2):264-6. DOI: 10.1016/0014-5793(78)80469-4. View

16.

TOOHEY J . Methylthioadenosine nucleoside phosphorylase deficiency in methylthio-dependent cancer cells. Biochem Biophys Res Commun. 1978; 83(1):27-35. DOI: 10.1016/0006-291x(78)90393-5. View

17.

Fairfield A, Meshnick S, Eaton J . Malaria parasites adopt host cell superoxide dismutase. Science. 1983; 221(4612):764-6. DOI: 10.1126/science.6348944. View

18.

Bacchi C, Sufrin J, Nathan H, Spiess A, Hannan T, Garofalo J . 5'-Alkyl-substituted analogs of 5'-methylthioadenosine as trypanocides. Antimicrob Agents Chemother. 1991; 35(7):1315-20. PMC: 245164. DOI: 10.1128/AAC.35.7.1315. View

19.

Byers T, Bush T, McCann P, Bitonti A . Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-L-methionine. Biochem J. 1991; 274 ( Pt 2):527-33. PMC: 1150171. DOI: 10.1042/bj2740527. View

20.

Desjardins R, Canfield C, Haynes J, Chulay J . Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother. 1979; 16(6):710-8. PMC: 352941. DOI: 10.1128/AAC.16.6.710. View