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Distribution and Biological Functions of Pyruvate Carboxylase in Nature
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
Although as described in Chapter 1, pyruvate carboxylase was first sought and recognized as an enzyme of the gluconeogenic pathway in liver, its occurrence in many nongluconeogenic tissues as well (and even in microorganisms cultured in glucose-containing media) clearly indicates its wider biological roles. Thus, whenever intermediates of the tricarboxylic acid cycle are withdrawn for biosynthetic purposes, e.g., oxaloacetate for gluconeogenesis or glyceroneogenesis, citrate for fatty acid and cholesterol synthesis, citrate and 2-oxoglutarate for neurotransmitter synthesis, succinyl-CoA for porphyrin synthesis, or oxaloacetate and 2-oxoglutarate for amino acid synthesis, there is a need for regeneration of these by an anaplerotic reaction sequence.460
The Pleiotropic Effect of Physical Exercise on Mitochondrial Dynamics in Aging Skeletal Muscle
Published in Chad Cox, Clinical Nutrition and Aging, 2017
Elena Barbieri, Deborah Agostini, Emanuela Polidori, Lucia Potenza, Michele Guescini, Francesco Lucertini, Giosuè Annibalini, Laura Stocchi, Mauro De Santi, Vilberto Stocchi
In accordance, the enzyme phosphoenolpyruvate carboxykinase (PEPCK), mainly linked to gluconeogenesis, has been recently associated with a prolonged lifespan. Eukaryotes have a gene for both a mitochondrial (PEPCK-M) and cytosolic (PEPCK-C) form of the enzyme. Skeletal muscle has a small but significant level of PEPCK-C activity [66]. There have been several proposals regarding the metabolic role of this enzyme in muscle, among these we have the production of pyruvate for the synthesis of alanine by alanine aminotransferase; another possible metabolic role of PEPCK-C in skeletal muscle is glyceroneogenesis. In order to determine the metabolic role of PEPCK-C in skeletal muscle, transgenic mice were generated (PEPCK-Cmus mice) [67]. During exercise, the PEPCKCmus mice mainly use fatty acid as the primary fuel, the stimulation of the aerobic metabolism in the PEPCK-Cmus mice could be due to the increased number of mitochondria noted in their skeletal muscle [67]. Another interesting feature of the PEPCK-Cmus mice is that they lived almost two years longer than the controls and had normal litters of pups at 30 to 35 months of age [67]. This evidence is very interesting because these mice violate the idea that limiting food intake increases longevity, as a matter of fact, the PEPCK-Cmus mice eat almost twice as much as controls. Altogether, these data suggest that sustained activity could be a key element to extend lifespan and counteract sarcopenia.
Characterization of in vitro and in vivo metabolism of leelamine using liquid chromatography-tandem mass spectrometry
Published in Xenobiotica, 2019
Riya Shrestha, Jung Jae Jo, DooHyun Lee, Taeho Lee, Sangkyu Lee
Leelamine (Figure 1), a dehydroabietylamine derivative of dehydroabietic acid, is found in the resins of pine trees (Kovaleva et al., 2017). It is a pyruvate dehydrogenase kinase 4 (PDK4) inhibitor and has been found to exhibit hypoglycemic activity in ob/ob mice and inhibit glyceroneogenesis in isolated adipocytes by activating the pyruvate dehydrogenase complex (PDC) (Cadoudal et al., 2008; Jeoung & Harris, 2010). Leelamine as a drug has been of considerable interest recently because it has been effective in the treatment of melanoma by disrupting cholesterol homeostasis in cancer cells (Gowda et al., 2017; Kuzu et al., 2014). It exhibits a strong anticancer effect on human breast cancer cell lines by generating reactive oxygen species and inducing B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 homologous antagonist/killer (Bak)-dependent apoptosis (Sehrawat et al., 2017). Moreover, our previous study in mice showed that leelamine is a potent and selective inducer of CYP2B activity, but has a low oral bioavailability of 7.6% (Sim et al., 2015; Song et al., 2013).