Redoxal as a new lead structure for dihydroorotate dehydrogenase inhibitors: a kinetic study of the inhibition mechanism.

Abstract:

: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 IC(50) value for the inhibition of succinate-induced respiration by atovaquone was 6.1 microM and 27.4 microM for the DHO-induced respiration; for dichlorallyl-lawsone, the IC(50) values were 14.1 microM and 0.23 microM.

journal_name

FEBS Lett

journal_title

FEBS letters

authors

Knecht W,Löffler M

doi

10.1016/s0014-5793(00)01117-0

keywords:

subject

Has Abstract

pub_date

2000-02-04 00:00:00

pages

27-30

issue

1

eissn

0014-5793

issn

1873-3468

pii

S0014-5793(00)01117-0

journal_volume

467

pub_type

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