Disease relevance of Substrate Cycling

• To assess the "futile cycle" fructose-6-P leads to fructose-1,6-P2 leads to fructose-6-P in Escherichia coli we have grown the cells on [6-14C]glucose and determined label in the 1-position of glucose obtained from glycogen [1].
• A current model ascribes O6-methylguanine toxicity to unsuccessful attempts at repair of this lesion by mismatch-repair proteins, resulting in a futile cycle of incision and synthesis, leading ultimately to lethal DNA-strand breaks [2].
• The mode of action of metronidazole in Helicobacter pylori: futile cycling or reduction [3]?
• Novel phosphoenolpyruvate-dependent futile cycle in Streptococcus lactis: 2-deoxy-D-glucose uncouples energy production from growth [4].
• Regulation of proline utilization in Salmonella typhimurium: how do cells avoid a futile cycle [5]?

High impact information on Substrate Cycling

• Effect of severe burn injury on substrate cycling by glucose and fatty acids [6].
• This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and resynthesis from glycerol and FFAs [7].
• We show here that the nuclear import of NF-ATs is not sufficient to activate NF-AT target genes, as NF-ATs are subject to a futile cycling across the nuclear envelope owing to engagement with the exportin protein Crm1 [8].
• The results provide no evidence of significant dephosphorylation of glucose-6-phosphate and do not support the hypothesis of a futile cycle involving glucose-6-phosphatase activity in the brain [9].
• In summary, it appears that liver LPL shunts circulating triglycerides to the liver, which results in a futile cycle of enhanced VLDL production and increased ketone production, and subsequently spares glucose [10].

Chemical compound and disease context of Substrate Cycling

• Here, we demonstrate that cysteine sulfinic acid is also a partial substrate for E. coli asparagine synthetase, acting as a nucleophile to form the sulfur analogue of beta-aspartyl-AMP, which is subsequently hydrolyzed back to cysteine sulfinic acid and AMP in a futile cycle [11].
• How folate and/or vitamin B12 deficiency influence carcinogenesis remains to be established, but it is currently believed that they may act to decrease DNA methylation, resulting in proto-oncogene activation, and/or to induce instability in the DNA molecule via a futile cycle of uracil misincorporation and removal [12].
• The futile cycle of the fructose phosphates also controls the transition from physiological aerobiosis to hypoxia [13].
• UL30, the herpes simplex virus type-1 DNA polymerase, stalls at the base preceding a cisplatin crosslinked 1,2 d(GpG) dinucleotide and engages in a futile cycle of incorporation and excision by virtue of its 3'-5' exonuclease [14].

Biological context of Substrate Cycling

• One function of this process might be to prevent a futile cycle of formation and hydrolysis of fructose 1,6-bisphosphate [15].
• The human erythrocyte actively phosphorylates and dephosphorylates phosphatidylinositol present in the membrane in an apparent "futile cycle." Recent reports have proposed that this phosphorylation/dephosphorylation cycle is a significant consumer of adenosine-5'-triphosphate (ATP) in the erythrocyte [16].
• The progressive loss of these enzymes under anaesthesia could contribute to the mechanism of heat production by diverting fructose 1,6 diphosphate into a futile cycle [17].
• Metabolic effects of caffeine in humans: lipid oxidation or futile cycling [18]?
• Only in developing siliques of the tag1 mutant, deficient in the accumulation of triacylglycerols and shown to have a substantial futile cycling of fatty acids toward beta-oxidation, have some changes in gene expression been detected, notably the induction of the isocitrate lyase gene [19].

Anatomical context of Substrate Cycling

• Obese subjects are limited in their ability to produce heat, either in a cold environment or after food, because of a reduced activity in skeletal muscle of a "futile" cycle in glucose metabolism [20].
• It is concluded that yeast mitochondria contain a previously unrecognized Ca(2+):2H(+) antiporter that is highly active in the presence of free fatty acids and leads to a futile cycle of Ca(2+) accumulation and release when exogenous Ca(2+) and ETH 129 are available [21].
• On this basis, although enterocyte hexokinase activity is much higher than in other 'glycolytic' cells (for example, brain), potentially high rates of glucose utilisation are modulated by substrate cycling of glucose 6-phosphate back to glucose through glucose 6-phosphatase [22].
• OBJECTIVES: Our objectives were to determine whether the lipolytic effect of caffeine is associated with increased lipid oxidation or futile cycling between triacylglycerol and free fatty acids (FFAs) and whether the effects of caffeine are mediated via the sympathetic nervous system [18].
• Measurement of the rates of acetyl-CoA hydrolysis and synthesis from acetate in rat hepatocytes and the role of these fluxes in substrate cycling [23].

Associations of Substrate Cycling with chemical compounds

• We have therefore investigated the acute response of glucose/glucose-6P-glucose (glucose) and triglyceride/fatty acid (TG/FA) substrate cycling to the infusion of epinephrine (0.03 microgram/kg.min) and glucagon [24].
• The phosphoenolpyruvate/pyruvate futile cycle was followed in situ by comparing the concentration of 13C at the scrambled alanine C2 position with that at glucose C5 [25].
• Existence and role of substrate cycling between AMP and adenosine in isolated rabbit cardiomyocytes under control conditions and in ATP depletion [26].
• This futile cycle between AMP and adenosine amounts to at least 20 nmol/min per g of liver and, thus, exceeds the basic rate of allantoin formation [27].
• This study details two independent techniques for quantitating the ATP consumed by this phosphoinositide futile cycle [16].

Gene context of Substrate Cycling

• Activation of UCP1 enhances respiration, and the uncoupling process results in a futile cycle and dissipation of oxidation energy as heat [28].
• However, overexpression of PYK2 during growth on ethanol did not cause any of the deleterious effects expected from a futile cycling between pyruvate and phosphoenolpyruvate [29].
• A proposed mechanism of cell death is via activation of a futile cycling of the drug by the cytoplasmic two-electron reductase NAD(P) H: quinone oxidoreductase, also known as NQO1, DT-diaphorase and Xip3 [30].
• We conclude that 1) the loss of PPAR alpha results in lower expression levels and diminished response to meal regulation for gluconeogenic/glycolytic enzyme expression; and 2) consequently, substrate/futile cycling of glucose is decreased when PPAR alpha is absent despite increased gluconeogenesis [31].
• Experiments using cycloheximide, a general inhibitor of translation, allow to exclude the possibility of a futile cycle of Pde1 synthesis and degradation [32].

Analytical, diagnostic and therapeutic context of Substrate Cycling

• The application of substrate cycling for alpha-ketoglutarate (AKG) through enzymatic amplification has been demonstrated in conjunction with capillary electrophoresis [33].

References