2-Oxoglutarate inhibition

The reactions of Eq. 15-19 occur nonenzymatically only under the influence of strong base but dehydrogenases often catalyze similar condensations relatively rapidly and reversibly. Pyruvate inhibits lactate dehydrogenase, 2-oxoglutarate inhibits glutamate dehydrogenase, and ketones inhibit a short-chain alcohol dehydrogenase in this manner.133,693... 

The storage role of (Cu,Zn)-SOD in seeds e.g. seems plausible, when the Cu-carrier function of ceruloplasmin is considered The lipophilic anti-inflammatory and anti-ulcer Cu-chelates could also raise the Cu concentration in certain tissues and thus enhance their lysyl oxidase activity. But especially Cu(acetylsalicylate)2 inhibited protine,2-oxoglutarate dioxygenase (EC 1.14.11.2) and lysine,2-oxoglutarate dioxygenase (EC 1.14.1.4), which are also important enzymes in the processing of collagen... 

Fluorocitrate is therefore a pseudosubstrate. As well as inhibiting cellular respiration, inhibition of the TCA cycle will also reduce the supply of 2-oxoglutarate. This may decrease the removal of ammonia via formation of glutamic acid and glutamine, and this might account for the convulsions seen in some species after exposure to fluoroacetate. The toxicity is manifested as a malfunction of the CNS and heart, giving rise to nausea, apprehension, convulsions, and defects of cardiac rhythm, leading to ventricular fibrillation. Fluoroacetate and fluorocitrate do not appear to inhibit other enzymes involved in intermediary metabolism, and the di- and trifluoroacetic acids are not similarly incorporated and therefore do not produce the same toxic effects. 

Glutamate dehydrogenase 770, 775 inhibition by 2-oxoglutarate 780 Glutamate mutase 871... 

The third control step in the citric acid cycle is catalyzed by 2-oxoglutarate dehydrogenase. This multienzyme complex is subject to product inhibition by both NADH and succinyl-CoA. Yet again,... 

Fluoroacetic acid has been identifled as the toxic component of the South African plant gijblaar (Dichapetalum cymosum) [34]. Its mechanism of action is based on inhibition of the citric acid cycle, the main source of metabolic energy in all animals [35]. In this cyde, fluoroacetate can replace acetate as a substrate of aconi-tase, an enzyme complex which usually forms dtrate by addition of acetate to a-oxoglutarate. The resulting fluorocitrate is binds tightly to the enzyme, but cannot be further converted to ds-aconitate and isocitrate [36], thus inhibiting aconitase. 

Figure 3-9 (a) Structures of PdTCPP and PdTAPP (b) purification of porphyrin-binding proteins using SG beads (c) inhibition of 2-oxoglutarate mitochondrial uptake by porphyrin derivatives (PP IX, protoporphyrin IX CP III, coproporphyrin IE) (d) model of mitochondrial accumulation of porphyrins. (Continued)... 

To assess the effect of PdTCPP on the transporter activity of OGC, we analyzed the incorporation activity of the OGC substrate 2-oxoglutarate using mitochondria fractions isolated from rat liver (Fig. 3-9c). PdTCPP inhibited... 

Important sites of inhibition are the pyruvate dehydrogenase complex, which converts pyruvate into acetyl-CoA isocitrate dehydrogenase, which converts isocitrate into 2-oxoglutarate and 2-oxoglutarate dehydrogenase. The enzyme citrate synthase, which catalyzes the first reaction of the cycle, is also inhibited by ATP. ... 

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