Disease relevance of sinefungin

• Both enzymes were found to be inhibited by S-adenosylhomocysteine (D and L forms), S-adenosyl-L-ethionine, and sinefungin [1].
• Sinefungin (SIN), a natural S-adenosyl-l-methionine analog produced by Streptomyces griseolus, is a potent inhibitor of methyltransferases [2].
• Vesicular stomatitis viruses resistant to the methylase inhibitor sinefungin upregulate RNA synthesis and reveal mutations that affect mRNA cap methylation [2].
• These data suggest that sinefungin could be considered as a candidate molecule in the treatment of human cryptosporidiosis, considered to be the most significant enteric opportunistic infection in AIDS [3].
• Using a bacterial orthologue of TPMT from Pseudomonas syringae, we have used NMR spectroscopy to describe the consequences of binding sinefungin, a SAM analogue, on the structure and dynamics of the TPMT protein backbone [4].

High impact information on sinefungin

• The effects of sinefungin on SL RNA methylation and on trans splicing were correlated by labeling of cells incubated in the presence of the antibiotic [5].
• We find that the sensitivity of Saccharomyces cerevisiae to growth inhibition by sinefungin is diminished when Abd1 is overexpressed [6].
• Mutational Analysis of Encephalitozoon cuniculi mRNA Cap (Guanine-N7) Methyltransferase, Structure of the Enzyme Bound to Sinefungin, and Evidence That Cap Methyltransferase Is the Target of Sinefungin's Antifungal Activity [6].
• S-Adenosyl-L-homocysteine is an inhibitor of the enzyme, whereas the AdoMet analogue sinefungin can act as cofactor, indicating that a positive charge is required for catalysis [7].
• The structures of RsrI DNA methyltransferase (M.RsrI) bound to the substrate S-adenosyl-l-methionine (AdoMet), the product S-adenosyl-l-homocysteine (AdoHcy), the inhibitor sinefungin, as well as a mutant apo-enzyme have been determined by x-ray crystallography [8].

Chemical compound and disease context of sinefungin

• The effect of two DNA-methyltransferase inhibitors, 5-azacytidine (5azaC) and sinefungin (Sf), on the development of Streptomyces antibioticus ETH7451 (Sa) was studied [9].
• The agents studied are curative for African trypanosomiasis infections, either clinically (DFMO) or in model infections (MDL 73811, sinefungin) and thus highlight interference with AdoMet metabolism and methylation reactions as biochemical consequences of these agents [10].

Biological context of sinefungin

• The extent of labeling and protein methylation was found to be inhibited by S-adenosyl-L-homocysteine, S-adenosyl-L-ethionine, and sinefungin, which are known to compete with AdoMet for the same binding site on the enzyme [11].
• A second nitroaldol condensation between 4 and N-benzyloxycarbonly-L-aspartic acid-beta-semialdehyde alpha-benzyl ester (5) followed by acetylation and borohydride reduction leads to a fully protected 6'-nitro modification of sinefungin and its C6'-epimer (7) [12].
• Sinefungin and taxol effects on cell cycle and cytoskeleton of Leishmania donovani promastigotes [13].
• The involvement of a carrier for sinefungin (SF) uptake in Leishmania donovani promastigotes is indicated by saturation kinetics, competition studies and SF accumulation against a 270-fold concentration gradient across the cell membrane [14].
• The latter observation shows that the enhancing effect of AdoMet or sinefungin on the DNA cleavage was not related to the process of DNA methylation [15].

Anatomical context of sinefungin

• Neither sinefungin nor formycin B was active in combination with DFMO in curing the central nervous system experimental infection [16].
• During sinefungin treatment, zygote formation, but not karyogamy, was affected [17].
• Correlation between inhibition of myelin basic protein (arginine) methyltransferase by sinefungin and lack of compact myelin formation in cultures of cerebral cells from embryonic mice [18].
• In vitro studies using Leishmania-infected murine peritoneal macrophages showed sinefungin as a powerful inhibitory drug, mean ED50 for the several Leishmania isolates studied being 50 ng/ml [19].
• The antifungal antibiotic sinefungin as a very active inhibitor of methyltransferases and of the transformation of chick embryo fibroblasts by Rous sarcoma virus [20].

Associations of sinefungin with other chemical compounds

• Here, we show that incubation of procyclic-form T. brucei in the presence of the S-adenosylmethionine analog, sinefungin, leads to a rapid inhibition of SL RNA methylation [5].
• The effects of a transmethylase inhibitor, sinefungin, and of the ornithine decarboxylase inhibitor, DL-alpha-difluoromethylornithine (Ornidyl; DFMO), on methionine metabolism were also observed [21].
• The antifungal antibiotic sinefungin, a potent inhibitor of methyl transferases and a potential inhibitor of polyamine biosynthesis, exhibited marked cytolytic activity against Entamoeba histolytica in vitro with respect to all the amoeba strains tested [22].
• Caprine Trypanosoma (N.) congolense infections were treated with sinefungin, an antifungal antibiotic nucleoside [23].

Gene context of sinefungin

• Whereas the peripheral, inserted structural elements of the TPMT topology are conformationally stabilized by the presence of sinefungin, a consistent increase in backbone mobility is observed for the central, conserved structural elements [4].
• Sinefungin, a potent inhibitor of virion mRNA(guanine-7-)-methyltransferase, mRNA(nucleoside-2'-)-methyltransferase, and viral multiplication [24].
• Surprisingly, taxol, a microtubule-stabilizing drug, induced the same morphological modifications as sinefungin although it interfered with the G2/M progression [13].
• The crystal structures of the binary complexes of the DNA methyltransferase M.TaqI with the inhibitor Sinefungin and the reaction product S-adenosyl-L-homocysteine were determined, both at 2.6 A resolution [25].
• Cell cycle progression was analyzed to establish that sinefungin irreversibly blocks the promastigotes in early S phase [13].

Analytical, diagnostic and therapeutic context of sinefungin

• According to immunofluorescence studies, the stable microtubular network is apparently affected neither by taxol nor by sinefungin [13].
• The circular dichroism spectrum of the abortive complex between the enzyme, DNA and sinefungin is dominated by the conformational properties of the binary complex of enzyme and sinefungin alone [26].
• Diploid formation by haploid cells of Saccharomyces cerevisiae was tested during and after treatment with chemical agents which bring about arrest at the cell cycle regulatory step "start." All compounds, except sinefungin, allowed efficient mating [17].
• Using inbred BALB/c and C57BL/6 mice as animal models for American cutaneous leishmaniasis, we evaluated the inhibitory effect of sinefungin on foot-pad infection produced by 5 different Leishmania isolates [19].
• Enzyme immunoassay detection of Cryptosporidium parvum inhibition by sinefungin in sporozoite infected HCT-8 enterocytic cells [27].

References