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Mitochondrial and peroxisomal disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Fumarase deficiency is a rare disorder of the Kreb’s cycle (also known as the citric acid cycle), a metabolic pathway that is central to the breakdown of carbohydrates, fats and proteins to carbon dioxide and water in order to generate energy. Individuals afected by this disorder develop postnatal neurological problems. Patients who have a more severe form of fumarase deiciency usually develop respiratory diiculties, and this results in their life expectancy not extending beyond early childhood, whereas patients who are less severely afected develop non-progressive brain problems and survive into adolescence or adulthood.
Historical Background
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
The enzymes involved in this pathway are: (a) pyruvate kinase, (b) malic enzyme, (c) malate dehydrogenase, and (d) phosphoenolpyruvate (PEP) carboxykinase. The equilibrium between malate and fumarate (e) is catalyzed by fumarase.
Metabolism, pharmacokinetics and excretion of [14C]dimethyl fumarate in healthy volunteers: an example of xenobiotic biotransformation following endogenous metabolic pathways
Published in Xenobiotica, 2023
Lin Xu, Chi-Chi Peng, Kate Dawson, Scott Stecher, James Woodworth, Chandra Prakash
[14C]DMF was rapidly metabolised to [14C]MMF in LM incubation, and this rapid biotransformation appears to be NADPH-independent (data not shown), suggestive of a hydrolytic reaction. In comparison to liver microsomal incubation, DMF is converted to more diverse metabolites in hepatocytes. Besides the predominant formation of MMF (93%), consistent with what was observed in the LMs, DMF was also converted to other minor metabolites (see Supplement Figure 1) after 10-min incubation with hepatocytes. In general, the minor metabolites appear to be formed via glutathione (GSH) conjugation (3.3%, M10 and M11) or were identified as endogenous components such as fumaric acid (M1). In fumarase incubation, only fumaric acid was rapidly hydrated to form malic acid, and its mono- and di-methyl esters (MMF and DMF) remained unchanged.
The evolution and competitive strategies of Akkermansia muciniphila in gut
Published in Gut Microbes, 2022
Ji-Sun Kim, Se Won Kang, Ju Huck Lee, Seung-Hwan Park, Jung-Sook Lee
Multiple genome alignments were performed to identify the structural differences in the genome. Genome synteny also showed no significant differences between the KGMB strains. However, it was found that there are length variations in the homopolymeric polyguanine (poly G) region in the promoter of fumarate hydratase between type strain KCTC 15667 T and KGMB strains (Figure S1). KGMB strains had a greater number of homopolymeric guanosine repeats, 22–29 mer Gs, compared to the type strain with 18-mer Gs. Fumarate hydratase, also known as fumarase, converts fumaric acid to L-malic acid in the tricarboxylic acid (TCA) cycle, and is a conserved protein in all organisms, from bacteria to humans, with respect to its sequence, structure, and enzymatic activity.37,38 Although the intergenic region (297 bp) of fumarase was identical between the type strain KCTC 15667 T and KGMB strains, differences in the number of poly G repeats in the promoter may cause physiological differences between them.
Coupling of oxidative stress responses to tricarboxylic acid cycle and prostaglandin E2 alterations in Caenorhabditis elegans under extremely low-frequency electromagnetic field
Published in International Journal of Radiation Biology, 2018
Yongyan Sun, Zhenhua Shi, Yahong Wang, Chao Tang, Yanyan Liao, Chuanjun Yang, Peng Cai
Decreased fumarase expression, both in transcription and translation level in ELF-EMF exposed worms were identified in this study (Figure 1). Fumarase depression can affect hydrolysis of fumarate to malate and result in accumulation of fumarate which is indicated in our previous results (Shi et al. 2015). In recent researches, the fumarase has been regarded as a tumor suppressor gene whose heterozygous mutations predispose to hereditary leiomyomatosis and renal cell cancer (Lorenzato et al. 2008; Wang et al. 2016). Similar inhibitory regulation of fumarase has been reported to cause Mycobacterium tuberculosis hypersusceptible to oxidative stress (Ruecker et al. 2017). Induced oxidative stress by ELF-EMF exposure has been demonstrated in numerous organisms, including in human cells (Garip and Akan 2010) and rats (Bułdak et al. 2012), etc. Similar results of ROS elevation and depressed T-AOC were demonstrated in the following results of this study. Fumarate accumulation and fumarase deficiency can act as a response to oxidative stress induced by ELF-EMF exposure.