EFFECTS ON OXIDATIVE PHOSPHOEYLATION 479 



rylation in irradiated preparations, but introduces an uncoupling activity 

 (Brodie and Russell, 1963). The 6-chromanol-P derivative of vitamin K^, 

 when added to a mycobacterial extract, cytochrome c, and a P-acceptor, 

 causes the anaerobic reduction of cytochrome c, the formation of vitamin 

 Ki, and the appearance of ATP (Asano et al., 1962), and such chromanol 

 derivatives have been detected during oxidative phosphorylation, including 

 the 6-chromenol of ubiquinone. The detailed sequence of phosphate transfer 

 has not been elucidated but possibly cyclization is necessary for the proc- 

 ess and the retention of energy in the phosphate bonds. In any event, 

 the effects of quinones on oxidative phosphorylation must be considered 

 against a background of the widespread participation of various naturally 

 occurring quinones and their derivatives in the transphosphorylation reac- 

 tions. 



Inhibition of Oxidative Phosphorylation 



Four general mechanisms for the interference by exogenous quinones in 

 phosphorylations may be readily suggested: (1) a competitive displacement 

 of the endogenous quinones from their loci in the electron transport chain 

 or their interaction sides, (2) a competitive acceptance of phosphate without 

 the ability to transfer the phosphate to ADP, (3) a shunting of electron 

 flow through nonphosphorylating pathways, and (4) a reaction with SH 

 groups somehow involved in the transphosphorylations since other SH 

 reagents have occasionally been shown to uncouple oxidative phosphoryla- 

 tion. We shall first discuss briefly some of the results obtained and then 

 return to the problem of the mechanisms which may be involved. 



Martins and Nitz-Litzow (1953) found phthiocol to be a very potent 

 depressant of /?-hydroxybutyrate oxidation by liver mitochondria, 0.0048 

 m.M inhibiting oxygen uptake 61%; however, phosphorylation is reduced 

 100%, so that a degree of uncoupling was observed. Menadione acts similarly 

 but is much less potent. A true uncoupling by menadione was noted in a 

 particulate fraction from Micrococcus lysodeiliticus oxidizing NADH, the 

 P:0 ratio being reduced from 0.27 to 0.04, oxygen uptake being slightly 

 increased (Ishikawa and Lehninger, 1962), and an even more striking un- 

 coupling was reported in a preparation from E. coli, lapachol lowering the 

 P:0 ratio from 1.1 to 0.2 and stimulating the respiration with malate as 

 the substrate (Kashket and Brodie, 1963 a). Coenzyme Q analogs are 

 occasionally efficient uncouplers. Jacobs and Crane (1960) divided these 

 analogs into three groups on the basis of their action on liver mitochondria 

 oxidizing succinate: 



(I) Qi and methyl-Q„: neither uncouple nor inhibit respiration 



(II) Qo, 6-Cl-Qo, and 6-Br-Q„: uncouple and inhibit respiration 



(III) Qa and Q3: uncouple and slightly stimulate respiration 



