No 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 M). In comparison, the MTA analogs, 5-deoxy-5-(ethylthio)adenosine, 5-deoxy-5-(hydroxyethylthio) adenosine (HETA), and 5-deoxy-5-(monofluoroethylthio)adenosine, had 50% inhibitory concentrations of 80, 46, and 61 M, 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.Inhibitors of polyamine metabolism have emerged recently as promising agents for the chemotherapy of cancer (16) and of parasitic diseases (1). Polyamine biosynthetic enzymes which serve as drug targets include ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase, and spermine synthase. In addition, enzymes which degrade the polyamine biosynthesis by-product, 5Ј-deoxy-5Ј-(methylthio)adenosine (MTA), are potentially exploitable for chemotherapy, since MTA metabolism in microorganisms (8,13,18) and tumor cells (20) differs in significant ways from MTA metabolism in normal mammalian cells.In mammalian cells, MTA is rapidly cleaved by a highly specific MTA phosphorylase to yield adenine and 5-deoxy-5-(methylthio)ribose-1-phosphate (MTRP) (Fig. 1). Adenine is then salvaged, and MTRP is converted into methionine. MTA phosphorylase is absent in many solid tumors and leukemias (6). It is also absent in microorganisms such as Giardia lamblia (17) and Klebsiella pneumoniae (14, 15), which utilize an alternative pathway not present in mammalian cells for metabolism of MTA to MTRP. In this alternate pathway, MTA is cleaved to adenine and 5-deoxy-5-(methylthio)ribose (MTR) by MTA nucleosidase. MTR, once formed, is phosphorylated to MTRP by MTR kinase (Fig. 1). It has previously been reported that Plasmodium falciparum utiliz...

.[1] The interpolative decomposition (ID) is combined with the multilevel fast multipole algorithm (MLFMA), denoted by ID-MLFMA, to handle multiscale problems. The ID-MLFMA first generates ID levels by recursively dividing the boxes at the finest MLFMA level into smaller boxes. It is specifically shown that near-field interactions with respect to the MLFMA, in the form of the matrix vector multiplication (MVM), are efficiently approximated at the ID levels. Meanwhile, computations on far-field interactions at the MLFMA levels remain unchanged. Only a small portion of matrix entries are required to approximate coupling among well-separated boxes at the ID levels, and these submatrices can be filled without computing the complete original coupling matrix. It follows that the matrix filling in the ID-MLFMA becomes much less expensive. The memory consumed is thus greatly reduced and the MVM is accelerated as well. Several factors that may influence the accuracy, efficiency and reliability of the proposed ID-MLFMA are investigated by numerical experiments. Complex targets are calculated to demonstrate the capability of the ID-MLFMA algorithm.Citation: Pan, X.-M., J.-G. Wei, Z. Peng, and X.-Q. Sheng (2012), A fast algorithm for multiscale electromagnetic problems using interpolative decomposition and multilevel fast multipole algorithm, Radio Sci., 47, RS1011,