Metabolism of an alkyl polyamine analog by a polyamine oxidase from the microsporidian Encephalitozoon cuniculi.
Encephalitozoon cuniculi is a microsporidium responsible for systemic illness in mammals. In the course of developing leads to new therapy for microsporidiosis, we found that a bis(phenylbenzyl)3-7-3 analog of spermine, 1,15-bis{N-[o-(phenyl)benzylamino}-4,12-diazapentadecane (BW-1), was a substrate for an E. cuniculi amine oxidase activity. The primary natural substrate for this oxidase activity was N'-acetylspermine, but BW-1 had activity comparable to that of the substrate. As the sole substrate, BW-1 gave linear reaction rates over 15 min and K(m) of 2 microM. In the presence of N'-acetylspermine, BW-1 acted as a competitive inhibitor of oxidase activity and may be a subversive substrate, resulting in increased peroxide production. By use of (13)C-labeled BW-1 as a substrate and nuclear magnetic resonance analysis, two products were determined to be oxidative metabolites, a hydrated aldehyde or dicarboxylate and 2(phenyl)benzylamine. These products were detected after exposure of (13)C-labeled BW-1 to E. cuniculi preemergent spore preparations and to uninfected host cells. In previous studies, BW-1 was curative in a rodent model of infection with E. cuniculi. The results in this study demonstrate competitive inhibition of oxidase activity by BW-1 and support further studies of this oxidase activity by the parasite and host.
Bacchi
Cyrus J
CJ
Haskins Laboratories, Pace University, 41 Park Row, New York, NY 10038, USA. cbacchi@pace.edu
Yarlett
Nigel
N
Faciane
Evangeline
E
Bi
Xiangdong
X
Rattendi
Donna
D
Weiss
Louis M
LM
Woster
Patrick M
PM
D000818:Animals; D009670:Encephalitozoon cuniculi / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000502:physiology*; D011073:Polyamines / Q000378:metabolism*; D011817:Rabbits; D000097667:Polyamine Oxidase
D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D000097667:Polyamine Oxidase; C541530:1,15-bis(N-(o-phenyl)benzylamino)-4,12-diazapentadecane