Metabolic switching

In contrast, the fluorine atom at the peri-position of 12F-5-methylchrysene influences dihydrodiol formation in the adjacent angular ring. Whereas the ratio of 5-MeC-7,8-diol to 5-MeC-l,2-diol in mouse epidermis was 1 1, 2 hr after topical application of [%] 5-MeC, the ratio of 12F-5-methylchrysene-7,8-diol to 12F-5-methylchrysene-1,2-diol was 68 1. In contrast to 5-MeC, the metabolites formed from 12F-5-methylchrysene in mouse skin resulted almost exclusively from oxidation at the 7,8-bond (57). Thus, metabolic switching to the less tumorigenic 7,8-dihydrodiol appears to be the basis for the lower tumorigenicity of 12F-5-methylchrysene compared to 5-MeC. 

Figure 3.11 cAMP activates the metabolic switch from PFK-2 kinase to phosphatase 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... 

B. Crabtree, A metabolic switch produced by enzymatically interconvertible forms of an enzyme, FEBSLett., 187(2), 193-195 (1985). 

Unusual shapes of dose-response curves may contribute to the identification of specific mechanisms of genotoxicity. For example, extremely steep increases suggest an indirect mode of action or metabolic switching. 

Glucuronidation is normally a primary detoxification pathway. In cases where glucuronidation becomes saturated or inhibited, metabolic switching to form reactive metabolites (typically catalyzed by cytochrome P450 enzymes) can occur. 

Kalyanaraman N. Inhibition of naltrexone metabolism by NSAIDs leading to metabolic switching and reactive metabolite formation. In MS. thesis. Minneapolis University of Minnesota, 2004. 

An, D., Pulinilkunnil, T., Qi, D., Ghosh, S., Abrahani, A., and Rodrigues, B. 2005. The metabolic switch AMPK regulates cardiac heparin-releasable lipoprotein lipase. Am J Physiol Endocrinol Metab 288(1) E246-E253. 

AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Acta Physiol Scand 178 435—442. 

Ohman L, Ljunggren J, Haggstrom L (1995), Induction of a metabolic switch in insect cell by substrate-limited fed batch cultures, Appl. Microbiol. Biotechnol. 43 1006-1013. 

Besides pyruvate kinase, phosphoglyceromutase was already identified as a key regulatory element in the metabolic switch (Mazurek and Eigenbrodt, 2003). Therefore, it seemed to be worthwhile to evaluate the glycolytic complex and its susceptibility to dynamic change in general, and the process of glutaminolysis in... 

Fig. 1 Molecular and biochemical basis of Friedreich s ataxia (FRDA). (a) A GAA-repeat expansion in the first intron of the FRDA gene results in decreased levels of frataxin as a result of inhibition of transcriptional elongation, (b) Alterations in mitochondrial biochemistry that are associated with reduced frataxin levels. Proposed functions for frataxin include iron binding, protection and synthesis of Fe-S clusters, providing a binding partner for ferrochetalase in heme (haem) metabolism, and providing a metabolic switch between heme metabolism and Fe-S cluster biosynthesis. In FRDA, reduction of firataxin results in lowered levels of aconitase and respiratory complexes 1,11, and 111. Cytosolic proteins that contain Fe-S clusters may also be affected. Inability to form Fe-S clusters leads to an accumulation of iron, which leads to increased free radical formation (Fenton chemistry) in these organelles. Increased free radical formation may feed back to further decrease levels of Fe-S clusters, which are known to be sensitive to oxidative stress.

In contrast to metabolic stabilization, metabolic switching is a versatile means of deflecting metabolism away from toxic products to enhance the formation of therapeutically active metabolites and/or to obtain a suitable pharmacokinetic behavior. 

Atkins, W.M. and S.G. Sligar (1987). Metabolic switching in cytochrome P450cam Deuterium isotope effects on regiospecificity and the monooxygenase/oxidase ratio. J. Am. Chem. Soc. 109, 3754-3760. 

Osawa, Y., N. Yoshida, M. Fronckowiak, and J. Kitawaki (1987). Immunoaffinity purification of aromatase cytochrome P-450 from human placental microsomes, metabolic switching from aromatization at ip and 2p-monohydroxylation, and recognition of aromatase isozymes. Steroids 50, 11-28. 

Fixing a metabolic stability problem at one position can lead to a new problem somewhere else on the molecule, a second meaning (the other being a PGx-induced changes in metabolic pathways) of the term metabolic switching. 

King, J.R. et al. (2013) A shift in the dominant phenotype governs the pH-induced metabolic switch... 

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