Succinylpurinemic autism: increased sensitivity of defective adenylosuccinate lyase towards 4-hydroxy-2-nonenal.
We studied the effect of trans-4-hydroxy-2-nonenal on the wild-type human adenylosuccinate lyase and on the enzyme from a patient compound-heterozygous for two missense mutations (P75A/D397Y; McKusick 103050.0003/103050.0004). Both the enzymes were inhibited by 10-50 microM trans-4-hydroxy-2-nonenal in a concentration-dependent manner by means of a mixed-type co-operative mechanism. A significantly stronger inhibition was noticed in the presence of the defective enzyme. Nonanal and trans-2,3-nonenal inhibited the enzymes to a less extent and at about 10-times higher concentrations. Hydroxylamine reversed the inhibition by trans-4-hydroxy-2-nonenal, trans-2,3-nonenal or nonanal in the case of the wild-type enzyme, but it was ineffective to reverse the inhibition by trans-4-hydroxy-2-nonenal on the defective enzyme. Dithiothreitol slightly decreased the inhibition exerted by trans-4-hydroxy-2-nonenal on both the wild-type and the defective adenylosuccinate lyase, while it did not produce practically any change in the presence of trans-2,3-nonenal or nonanal.
Salerno
C
C
Department of Biochemical Sciences and Clinical Biochemistry Laboratory, University of Roma La Sapienza, I-00185, Rome, Italy.
Siems
W G
WG
Crifò
C
C
D000264:Adenylosuccinate Lyase / Q000037:antagonists & inhibitors*; D000447:Aldehydes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001321:Autistic Disorder / Q000097:blood / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019811:Hydroxylamine / Q000494:pharmacology; D007700:Kinetics; D011687:Purines / Q000097:blood*
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D011687:Purines; D019811:Hydroxylamine; C008664:nonanal; D000264:Adenylosuccinate Lyase; C027576:4-hydroxy-2-nonenal; D004229:Dithiothreitol