The cyanobacterial toxin cylindrospermopsin inhibits pyrimidine nucleotide synthesis and alters cholesterol distribution in mice.
The hepatotoxin Cylindrospermopsin, a sulfated-guanidinium alkaloid with substituted dioxypyrimidine (uracil) moiety, was isolated from several cyanobacteria species. Our previous studies on the toxicity of cylindrospermopsin and its derivatives suggested that the uracil moiety is crucial for the toxicity and that such toxicity could partly stem from competitive binding of the toxin to a catalytic site(s) involved in the synthesis of pyrimidine nucleotides (i.e., uridine). In the present study we demonstrated that cylindrospermopsin inhibited in a noncompetitive manner the in vitro activity of uridine monophosphate (UMP) synthase complex (responsible for the conversion of orotic acid to UMP) in a cell free liver extract from mice, with an inhibition constant, KI, of 10 microM. Exposure of mice to cylindrospermopsin at subacute concentrations, via drinking water, only slightly affected the in vitro activity of UMP synthase. The typical metabolic disorder associated with the inhibition of UMP synthase activity, known as "orotic aciduria," was not observed under these conditions, but other anomalous metabolic responses related to cholesterol metabolism were developed.
Reisner
M
M
Department of Food Engineering and Biotechnology, Technion, Israel Institute of Technology, Haifa 32000 Israel.
Carmeli
S
S
Werman
M
M
Sukenik
A
A
D000470:Alkaloids; D000740:Anemia / Q000139:chemically induced / Q000473:pathology; D000747:Anemia, Hypochromic / Q000097:blood; D000818:Animals; D001427:Bacterial Toxins; D002784:Cholesterol / Q000378:metabolism*; D000458:Cyanobacteria / Q000737:chemistry*; D000087522:Cyanobacteria Toxins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects; D006400:Hematocrit; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009929:Organ Size / Q000187:drug effects; D009962:Orotate Phosphoribosyltransferase / Q000037:antagonists & inhibitors; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors; D011742:Pyrimidine Nucleotides / Q000096:biosynthesis*; D014018:Tissue Distribution; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014542:Uridine Monophosphate / Q000378:metabolism
D000470:Alkaloids; D001427:Bacterial Toxins; D000087522:Cyanobacteria Toxins; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011742:Pyrimidine Nucleotides; C089595:cylindrospermopsin; D014498:Uracil; C027157:uridine 5'-monophosphate synthase; D002784:Cholesterol; D014542:Uridine Monophosphate; D009962:Orotate Phosphoribosyltransferase; D009964:Orotidine-5'-Phosphate Decarboxylase