Pyruvate dehydrogenase activity

Where two enzymes compete for the same substrate, we expect to see some form of metabolic control and in this case the concentrations of NADH and acetyl-CoA are the key controlling factors (Figure 6.44). When glucose is not available as a fuel, metabolism switches to 3- oxidation of fatty acids, which generates more than sufficient quantities of both NADH and acetyl-CoA to drive the TCA cycle and to maintain oxidative phosphorylation. Pyruvate dehydrogenase activity is suppressed and pyruvate carboxylase is stimulated by ATP, NADH and acetyl-CoA (strictly speaking by low mitochondrial ratios of ADP/ATP, NAD+/NADH and coenzyme A/acetyl-CoA), so... 

Hoshi, M. Takashima, A. Noguchi, K. Murayama, M. Sato, M. Kondo, S. Saitoh, Y. Ishiguro, K. Hoshino, T. Imahori, K. Regulation of mitochondrial pyruvate dehydrogenase activity by r protein kinase I/glycogen synthase kinase 3/1 in brain. Proc. Natl. Acad. Sci. USA, 93, 2719-2723 (1996)... 

The negative effects of acetyl-CoA on pyruvate dehydrogenase activity are supplemented by ATP and NADH. These effects are in the correct direction to cause the rate of acetyl-CoA synthesis to vary with the need for electrons and for regeneration of NADH and ATP. 

Regulation of Pyruvate Dehydrogenase Activity Pyruvate dehydrogenase is the key enzyme that commits pyruvate (and hence the products of carbohydrate metabolism) to complete oxidation (via the tricarboxyUc acid cycle) or lipogenesis. It is subject to regulation by both product inhibition and a phosphorylation/dephosphorylation mechanism. Acetyl CoA and NADH are both inhibitors, competing with coenzyme A and NAD+. 

Kolobova E,Tuganova A, BoulatnikovI, and Popov KM (2001) Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites. Biochemical Journal 358, 69-77. 

Fig. 12a, b. Stimulation of electron transport in two metabolic pathways of D. gigas by ferredoxin. (a) Sulfite reductase activity dependence on Fd II (o) and Fd I ( ) concentration. The values of hydrogen comsumption represent the activity after 12 min and were corrected for the endogenous activity (adapted from Bruschi et al., 8>9))- (b) Pyruvate dehydrogenase activity dependence of Fd II and Fd I concentration. The values determined for hydrogen evolution represent the activity after 12 min (between 8—20 min for Fd I and between 28—40 min for Fd II, due to the existence of a lag period before which Fd II is not active 49h The values were corrected for the endogenous activity (our unpublished data)... 

Inhibition of glycolysis by products of fatty acid oxidation. Pyruvate dehydrogenase activity is inhibited by acetyl CoA, NADH, and ATP, all of which are elevated as fatty acid oxidation proceeds. As AMP levels drop, and ATP levels rise, PFK-1 activity is decreased (see Chapter 22). 

Zhou Q, Lam PY, Han D, Cadenas E (2007) c-Jun N-temiinal kinase regulates mitochondrial bioenergetics by modulating pyruvate dehydrogenase activity in primary cortical neurons. J Neurochem 104(2) 325-335... 

Data on the role of acetylcholine deficit in thiamine deficiency are conflicting, but most recent studies do not favor a significant decrease in the synthesis of this neurotransmitter (Hazell et al, 1998 Vorhees et al, 1977). This would be consistent with normal pyruvate dehydrogenase activity in experimental thiamine deficiency, which should not, therefore, result in a lower Acetyl CoA level as a precursor to acetylcholine. 

IMPLICATION OF ESSENTIAL FATTY ACIDS IN PYRUVATE DEHYDROGENASE ACTIVATION... 

Rutter GA, Burnett P, Rizzuto R et al (1996) SubceUular imaging of intramitochondrial Ca with recombinant targeted aequorin significance for the regulation of pyruvate dehydrogenase activity. Proceedings of the National Academy of Science, USA 93 5489-5494. 

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