Inhibition of GABA shunt enzymes' activity by 4-hydroxybenzaldehyde derivatives.
4-Hydroxybenzaldehyde (HBA) derivatives were examined as inhibitors for GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). Investigation of structure-activity relation revealed that a carbonyl group or an amino group as well as a hydroxy group at the para position of the benzene ring are important for both enzymes' inhibition. HBA was shown to give competitive inhibition of GABA-T with respect to alpha-ketoglutarate and competitive inhibition of SSADH. 4-Hydroxybenzylamine (HBM) also showed the competitive inhibition on GABA-T with respect to GABA. In conclusion, the inhibitory effects of HBA and HBM on both enzymes could result from the similarity between both molecules and the two enzymes' substrates in structure, as well as the conjugative effect of the benzene ring. This suggested that the presence of the benzene ring may be accepted by the active site of both enzymes, HBA and HBM may be considered as lead compounds to design novel GABA-T inhibitors.
Tao
Yun-Hai
YH
Institute of Materia Medica, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, China.
Yuan
Zheng
Z
Tang
Xiao-Qiao
XQ
Xu
Hui-Bi
HB
Yang
Xiang-Liang
XL
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D001547:Benzaldehydes / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D013329:Structure-Activity Relationship; D050644:Succinate-Semialdehyde Dehydrogenase / Q000037:antagonists & inhibitors*
D001547:Benzaldehydes; D004791:Enzyme Inhibitors; D050644:Succinate-Semialdehyde Dehydrogenase; D000612:4-Aminobutyrate Transaminase; C011483:4-hydroxybenzaldehyde