Succinyl CoA becomes succinic acid using succinyl CoA synthetase. This reaction produces NADH which directly provides electrons for the electron transport chain or respiratory chain. Succinic acid requires the enzyme succinate dehydrogenase to become fumarate. This enzyme is ironbased and requires vitamin B2 to support flavin adenine dinucleotide (FAD) as a redox coenzyme. Succinate dehydrogenase plays a critical role in mitochondrial metabolism. Impairment of this enzyme’s activity has been linked to a variety of diseases such as cancer and neurodegenerative diseases.
- Tretter L, Adam-Vizi V. Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2335-2345.
- Rutter J, Winge DR, Schiffman JD. Succinate dehydrogenase - Assembly, regulation and role in human disease. Mitochondrion. 2010;10(4):393-401.
- Van Vranken JG, Na U, Winge DR, Rutter J. Protein-mediated assembly of succinate dehydrogenase and its cofactors. Crit Rev Biochem Molec Biol. 2015;50(2):168-180.
- Connors J, Dawe N, Van Limbergen J. The Role of Succinate in the Regulation of Intestinal Inflammation. Nutrients. 2018;11(1):25.
- Wentzel JF, Lewies A, Bronkhorst AJ, Van Dyk E, Du Plessis LH, Pretorius PJ. Exposure to high levels of fumarate and succinate leads to apoptotic cytotoxicity and altered global DNA methylation profiles in vitro. Biochimie. 2017;135:28-34.
- Harris RA, Joshi M, Jeoung NH, Obayashi M. Overview of the Molecular and Biochemical Basis of Branched-Chain Amino Acid Catabolism. J Nutr. 2005;135(6):1527S-1530S.
Low levels of succinic acid can be seen with poor dietary intake or absorption of branched-chain amino acids. Branched-chain amino acids are catabolized to acetyl-CoA or succinyl-CoA to feed the Citric Acid Cycle. Additionally, vitamin B12 deficiency can induce a defect in the conversion of methylmalonyl-CoA to succinyl-CoA at the distal end of the valine and isoleucine pathways which can then decrease succinyl-CoA.
Elevated levels of mitochondrial succinate are seen in nutritional cofactor insufficiencies of succinate dehydrogenase or primary enzymatic defects. Succinate can also be formed peripherally by microbes in the GI tract. The major producers of succinate in the gut are bacteria belonging to the Bacteroidetes phylum. However, it is typically detected at low rates in the gut lumen because it is rapidly converted to propionate, a major short chain fatty acid. Several studies indicate that elevations in both succinate and fumarate play a role in oncogenesis by causing DNA damage and hypermethylation.
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