Mechanism-based inhibition of proline dehydrogenase by proline analogues.
The inactivation of proline dehydrogenase by several L-Pro analogues was investigated with the aim to block the essential metabolic pathway of tsetse flies allowing the degradation of L-Pro to L-Glu. In vitro studies on rat liver mitochondria showed that only 4-methylene-L-proline was able to inactivate proline dehydrogenase. The inactivation kinetics agreed with a mechanism-based inhibition. The other tested analogues E- and Z-4-fluoromethylene-L-proline, and cis and trans-5-ethynyl-D,L-proline were neither substrate nor inactivator of the enzyme. In vivo 4-methylene-L-proline showed no toxicity against Drosophila flies, but was lethal for Glossina pallidipes flies. This result allows the consideration of 4-methylene-L-proline as an attractive compound molecule in the struggle against tsetse flies.
Laboratoire de Chimie Organique Biologique, URA CNRS 31, Faculté de Chimie, Université Louis Pasteur, Strasbourg, France.
D
D
Tritsch
H
H
Mawlawi
J F
JF
Biellmann
D000818:Animals; D004331:Drosophila melanogaster / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D008930:Mitochondria, Liver / Q000201:enzymology; D011392:Proline / Q000031:analogs & derivatives* / Q000633:toxicity; D011394:Proline Oxidase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D014370:Tsetse Flies / Q000187:drug effects*
C083252:4-methyleneproline; D011392:Proline; D011394:Proline Oxidase