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Amino Acids and Vitamin Production
Published in Debabrata Das, Soumya Pandit, Industrial Biotechnology, 2021
The isocitrate dehydrogenase produces α-ketoglutarate from isocitrate by decarboxylation and dehydrogenation reaction in the citric acid cycle, which is a key precursor in catalysing the amination reaction for the production of L-glutamic acid by glutamate dehydrogenase. In generalized citric acid cycles, there is an association of α-ketoglutarate dehydrogenase complex for the production of α-ketoglutarate but the commercially utilized strains in the glutamic acid production usually lack α-ketoglutarate dehydrogenase activity. However, this interruption, caused due to lack of α-ketoglutarate dehydrogenase activity, is compensated by the synthesis of oxaloacetate which in combination with acetyl co-enzyme produces isocitrate which in turn is utilized for the production of glutamic acid. GAB does not secrete glutamate out of the cell due to the rigid cell wall under normal growth conditions. The permeability of the bacterial cell membrane could be improved through a set of approaches: i. Limiting the development of normal phospholipids using biotin deprived media; ii. Constraining glycerol with glycerol auxotrophs; iii. Reducing oleic acid in oleic acid auxotrophs (for microbes requiring oleic acid for growth); iv. Adding surfactants e.g. Tween-60; v. The addition of penicillin to biotin-rich media (Enei et al., 1989).
Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
TCA cycle plays a central metabolic pathway that connects glucose, glutamine and fatty acids metabolism. In recent years, emerging studies have demonstrated that several TCA cycle enzymes are driver mutations in certain cancer subtypes. These include mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) in gliomas and acute myeloid leukemia (AML) (Yan et al., 2009; Paschka et al., 2010); succinate dehydrogenase (SDH) in paragangliomas and gastrointestinal stromal tumors (GISTs) (Astuti et al., 2001; Janeway et al., 2011); and fumarate hydratase (FH) in renal cancer (Toro et al., 2003). These genetic mutations revolve a unifying theme-the disruption of TCA cycle, which either results in the biosynthesis of oncometabolites, such as 2-hydroxylglutarate, or abnormal accumulation of TCA cycle metabolites succinate and fumarate. An altered balance of TCA cycle metabolites play an important role in epigenetic regulation by virtue of their effects on DNA/histone demethylases. DNA demethylases (Ten-Eleven Translocation; TET) and histone demethylases (Jumonji domain-containing proteins JMJD) are both dioxygenases, which require a-ketoglutarate as a cofactor and are competitively inhibited by succinate, fumarate or 2-hydroxylglutarate (Xiao etal., 2012). Consequently, the accumulation of 2-hydroxylglutarate, succinate or fumarate in these cancers inhibited the demethylation of DNA/histones, leading to DNA/ histone hypermethylation and aberrant gene expression.
Emerging Biomedical Analysis
Published in Lawrence S. Chan, William C. Tang, Engineering-Medicine, 2019
As one can see, one of the key elements allowing for the development of this diagnostic method was the discovery of a tumor-specific metabolite. A recent finding revealed that there was a mutation of the isocitrate dehydrogenase-1 (IDH1) gene present in a large majority of the common brain tumor glioma, with elevated levels up to 100-fold compared to wild type IDH1. This mutation and resulting gain-of-function leads to the production of the tumor-specific metabolite, 2-hydroxyglutarate (2-HG), which is not present in normal tissue. Besides glioma, the IDH1 mutation is also found in acute myeloid leukemia, cholangiocarcinoma, chondrosarcoma, and T cell lymphoma. These findings gave a substantial advantage for the development of tumor margin detection using MS (Pope 2014). Alternatively, other chemicals, if substantially different in quantity between tumor and normal tissues, can also be used for this identification purpose.
Proteomics investigation of molecular mechanisms affected by EnBase culture system in anti-VEGF fab fragment producing E. coli BL21 (DE3)
Published in Preparative Biochemistry and Biotechnology, 2019
Bahareh Azarian, Amin Azimi, Mahboubeh Sepehri, Vahideh Samimi Fam, Faegheh Rezaie, Yeganeh Talebkhan, Vahid Khalaj, Fatemeh Davami
Metabolism of isocitrate for continuing the TCA cycle or entering glyoxylate cycle is determined by regulation of two enzymes: isocitrate lyase and isocitrate dehydrogenase. Isocitrate lyase leads isocitrate to glyoxylate cycle and cleaves it to glyoxylate and succinate. Glyoxylate is finally converted to oxaloacetate to start a new glyoxylate cycle. The succinate may be converted into oxaloacetate through malate and be used for biosynthetic purposes. Several studies have reported up-regulation of isocitrate lyase and other glyoxylate cycle enzymes in cells cultivated in glucose-limited condition.[29–31] Fischer reports the PEP-glyoxylate cycle in E. coli and its higher rate of activity in glucose-limited cells.[29] The three enzymes of this cycle are isocitrate lyase and malate synthase from glyoxylate cycle and phosphoenolpyruvate carboxykinase (Pck). This cycle results in higher production of oxaloacetate, and the activity of Pck converts oxaloacetate to PEP which can be further metabolized for gluconeogenesis or as a precursor of amino acid biosynthesis. Isocitrate lyase and Pck, two enzymes of PEP-glyoxylate cycle, are up-regulated in EnBase-mode-cultured cells in the 6 hr phase, which is consistent with their higher biosynthetic activity and protein expression of cells in this phase. By continuing the culture for 24 hr, only the Pck was found to be up-regulated. EnBase-mode-cultured cells have elevated catabolic activity for degradation of aggregated plasmid-encoded protein in low growth-rate phase.[9] This catabolic activity leads to elevated gluconeogenesis of PEP as a product of the Pck.