The activator-binding site of Onchocerca volvulus S-adenosylmethionine decarboxylase, a potential drug target.
S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in polyamine biosynthesis. In many eukaryotes its activity is stimulated specifically by putrescine. The AdoMetDC of the filarial parasite Onchocerca volvulus, however, is not only stimulated by putrescine but also by the naturally occuring polyamines spermidine and spermine. Several diamines, acetylated polyamines and polyamine analogues were used to analyse what molecular prerequisites are needed to stimulate nematode AdoMetDC activity. In the absence of an activator, the O. volvulus enzyme exhibits an extremely low specific activity. This fact, together with the unspecificity of activator binding, was thought to be useful for a new strategy to inhibit nematode AdoMetDC activity. Therefore, different polyamine analogues were tested as competitive inhibitors towards the stimulatory effect putrescine has on the O. volvulus and, in comparison, on the Caenorhabditis elegans and human AdoMetDC. Bis(aralkyl)- and bis(alkyl)-substituted polyamine analogues with a 3-7-3 backbone were found to inhibit AdoMetDC activities, however, probably without interfering with the putrescine stimulation. The best inhibitor, BW-1, was about 10-fold more effective against O. volvulus AdoMetDC than against the human enzyme. Unexpectedly, BW-1 was determined to be a competitive inhibitor with respect to AdoMet, having a Ki value of 310 microM for the putrescine-stimulated human AdoMetDC. Furthermore, we show for the O. volvulus and the human enzyme that the degree of inhibition by BW-1 depends on the actual putrescine concentration.
Ndjonka
Dieudonne
D
Department of Biochemical Parasitology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, D-20359 Hamburg, Germany.
Zou
Yu
Y
Bi
Xiangdong
X
Woster
Patrick
P
Walter
Rolf D
RD
Lüersen
Kai
K
D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D020536:Enzyme Activators; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D017181:Onchocerca volvulus / Q000201:enzymology*; D011073:Polyamines / Q000138:chemical synthesis / Q000494:pharmacology; D011700:Putrescine / Q000494:pharmacology
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D011073:Polyamines; D012437:Adenosylmethionine Decarboxylase; D011700:Putrescine