caa a22 4500 37885318X CHVBK 20180305123328.0 cr unu---uuuuu 161128e20030820xx s 000 0 eng 10.1515/BC.2003.132 doi (NATIONALLICENCE)gruyter-10.1515/BC.2003.132 The Activator-Binding Site of Onchocerca volvulus S-Adenosylmethionine Decarboxylase, a Potential Drug Target [Elektronische Daten] [D. Ndjonka, Y. Zou, X. Bi, P. Woster, R. D. Walter, K. Lüersen] 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 uM 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. Copyright © 2003 by Walter de Gruyter GmbH & Co. KG Biochemistry nationallicence Molecular biology nationallicence Cellular biology nationallicence Ndjonka D. aut Zou Y. aut Bi X. aut Woster P. aut Walter R. D. aut Lüersen K. aut Biological Chemistry Walter de Gruyter 384/8(2003-08-20), 1195-1201 1431-6730 384:8<1195 2003 384 bchm https://doi.org/10.1515/BC.2003.132 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1515/BC.2003.132 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ndjonka D. aut NATIONALLICENCE 700 1- Zou Y. aut NATIONALLICENCE 700 1- Bi X. aut NATIONALLICENCE 700 1- Woster P. aut NATIONALLICENCE 700 1- Walter R. D. aut NATIONALLICENCE 700 1- Lüersen K. aut NATIONALLICENCE 773 0- Biological Chemistry Walter de Gruyter 384/8(2003-08-20), 1195-1201 1431-6730 384:8<1195 2003 384 bchm CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter