METHIONINE RECYCLING PATHWAYS AND ANTIMALARIAL DRUG DESIGN

5'-Deoxy-5'-(methylthio)adenosine (MTA) is an S-adenosylmethionine met abolite that is generated as a by-product of polyamine biosynthesis, I n mammalian cells, MTA undergoes a phosphorolytic cleavage catalyzed b y MTA phosphorylase to produce adenine and 5-deoxy-5-(methylthio)ribos e-1-phosphate (MTRP), Adenine is utilized in purine salvage pathways, and MTRP is subsequently recycled to methionine. Whereas some microorg anisms 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 t hese pathways may be operative in Plasmodium falciparum, we have exami ned a series of 5'-alkyl-substituted analogs of MTA and the related MT R analogs and compared their abilities to inhibit in vitro growth of t his 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 mu M). In comparison, the MTA anal ogs, 5'-deoxy-5'-(ethylthio)adenosine, 5'-deoxy-5'-(hydroxyethylthio)a denosine (HETA), and 5'-deoxy-5'-(monofluoroethylthio)adenosine, had 5 0% inhibitory concentrations of 80, 46, and 61 mu M, respectively, Ext racts of P. falciparum were found to have substantial MTA phosphorylas e activity, Coadministration of RITA with HETA partially protected the parasites against the growth-inhibitory effects of HETA. Results of t his study indicate that P. falciparum has an active MTA phosphorylase that can be targeted by analogs of MTA.