Temporary inactivation of plasma amine oxidase by alkylhydrazines. A combined enzyme/model study implicates cofactor reduction/reoxidation but cofactor deoxygenation and subsequent reoxygenation in the case of hydrazine itself
Y. Lee et al., Temporary inactivation of plasma amine oxidase by alkylhydrazines. A combined enzyme/model study implicates cofactor reduction/reoxidation but cofactor deoxygenation and subsequent reoxygenation in the case of hydrazine itself, J ORG CHEM, 66(6), 2001, pp. 1925-1937
It has been known for some time that hydrazine and its methyl and 1,1-dimet
hyl analogues induce inactivation of the copper-containing quinone-dependen
t plasma amine oxidase but that the activity recovers over time, suggesting
metabolism of all three inhibitors. However, the mechanism responsible for
loss and regain of activity has not been investigated. In this study a com
bination of enzyme studies under a controlled atmosphere along with model s
tudies using 5-tert-butyl-2-hydroxy-1,4-benzoquinone to mimic the 2,4,5-tri
hydroxyphenylalanine quinone (TPQ) cofactor of the enzyme suggest that rega
in of enzyme activity represents two different Os-dependent processes. In t
he case of methylhydrazine and 1,1-dimethylhydrazine, we propose that the i
nactive methyl hydrazone/azo form of the enzyme slowly rehydrates and elimi
nates MeN=NH to give the triol cofactor form, which instantly reoxidizes to
the catalytically active quinone form in the presence of O-2 Metabolism of
methylhydrazine represents its conversion to CH4 and N-2, and of 1,1-dimet
hylhydrazine to CH2=O, CH4, and N-2. In the case of hydrazine itself, howev
er, we propose that the inactive hydrazone/azo form of the enzyme instead u
ndergoes a slow decomposition, probably facilitated by the active-site copp
er, to give Nz and a novel 5-desoxy resorcinol form of the cofactor. The la
tter undergoes a rapid, but noninstantaneous reoxygenation at C5 to restore
the active cofactor form, also probably mediated by the active-site copper
.