Redoxal as a new leadstructure for dihydroorotate dehydrogenase inhibitors: a kinetic study of the inhibition mechanism

FEBS Letters

Knecht, Wolfgang¹  Löffler, Monika¹ 

[1]Institute for Physiological Chemistry, Philipps-University, School of Medicine, Karl-von-Frisch-Str. 1, D-35033 Marburg, Germany

关键词: Dihydroorotate dehydrogenase;    Redoxal;    1;    4-Naphthoquinone;    Pyrimidine;    Mitochondrion;    DHOdehase;    dihydroorotate dehydrogenase (EC 1.3.99.11);    DCL;    dichloroallyl-lawsone;    QD;    decylubiquinone;    DHO;    L-dihydroorotate;   

DOI  :  10.1016/S0014-5793(00)01117-0

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Mitochondrial dihydroorotate dehydrogenase (DHOdehase; EC 1.3.99.11) is a target of anti-proliferative, immunosuppressive and anti-parasitic agents. Here, redoxal, (2,2′-[3,3′-dimethoxy[1,1′-biphenyl]-4,4′-diyl)diimino]bis-benzoic acid, was studied with isolated mitochondria and the purified recombinant human and rat enzyme to find out the mode of kinetic interaction with this target. Its pattern of enzyme inhibition was different from that of cinchoninic, isoxazol and naphthoquinone derivatives and was of a non-competitive type for the human (K _ic=402 nM; K _iu=506 nM) and the rat enzyme (K _ic=116 nM; K _iu=208 nM). The characteristic species-related inhibition of DHOdehase found with other compounds was less expressed with redoxal. In human and rat mitochondria, redoxal did not inhibit NADH-induced respiration, its effect on succinate-induced respiration was marginal. This was in contrast to the sound effect of atovaquone and dichloroallyl-lawsone, studied here for comparison. In human mitochondria, the IC₅₀ value for the inhibition of succinate-induced respiration by atovaquone was 6.1 μM and 27.4 μM for the DHO-induced respiration; for dichlorallyl-lawsone, the IC₅₀ values were 14.1 μM and 0.23 μM.

【 授权许可】

Unknown