MOLECULE

Succinic acid

Succinic acid is a four-carbon acyclic dicarboxylic acid. It is a white, odorless solid with a highly acidic taste. It is used as a flavoring agent, contributing a sour and astringent component characteristic of the umami taste (PMID:21932253). The anion, succinate, is a key component of the citric acid or TCA cycle and is capable of donating electrons to the electron transfer chain. Succinate dehydrogenase (SDH) plays an important role in mitochondrial function, being both part of the respiratory chain and the Krebs cycle. SDH, with a covalently attached FAD prosthetic group, is able to bind several different enzyme substrates (succinate and fumarate) and physiological regulators (oxaloacetate and ATP). Oxidizing succinate links SDH to the fast-cycling Krebs cycle portion where it participates in the breakdown of acetyl-CoA throughout the entire Krebs cycle. Succinate can readily be imported into the mitochondrial matrix by the n-butyl malonate- (or phenyl succinate-) sensitive dicarboxylate carrier in exchange with inorganic phosphate or another organic acid, e. g. malate (PMID:16143825). Human mutations in the four genes encoding the subunits of the mitochondrial succinate dehydrogenase are associated with a wide spectrum of clinical presentations, i.e.: Huntington’s disease (PMID:11803021). Moreover, succinic acid is found to be associated with D-2-hydroxyglutaric aciduria, which is an inborn error of metabolism. Additionally, succinic acid has been identified as an oncometabolite or an endogenous cancer-causing metabolite. Oncoetabolites are metabolic intermediates whose accumulation causes a metabolic and non-metabolic dysregulation leading to tumorigenesis. (PMID:23999438, PMID:27117029). High levels of succinic acid can be found in tumors or biofluids surrounding tumors. Its oncogenic action appears due to its ability to inhibit prolyl hydroxylase domain-containing enzymes. In many tumours, oxygen availability becomes limited (hypoxia) very quickly due to rapid cell proliferation and limited blood vessel growth. The major regulator of the response to hypoxia is the HIF transcription factor (HIF-alpha). Under normal oxygen levels, protein levels of HIF-alpha are very low due to constant degradation, mediated by a series of post-translational modification events catalyzed by the prolyl hydroxylase domain-containing enzymes PHD1, 2 and 3, (also known as EglN2, 1 and 3) that hydroxylate HIF-alpha and lead to its degradation. All three of the PHD enzymes are inhibited by succinate. Succinic acid has been found to be associated with D-2-hydroxyglutaric aciduria, which is an inborn error of metabolism. Succinic acid is also a microbial metabolite. Indeed, urinary succinic acid is produced by Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Enterobacter sp., Acinetobacter sp., Proteus mirabilis, Citrobactes frundii, Enterococcus faecalis (PMID: 22292465). Succinic acid is also found in Actinobacillus, Anaerobiospirillum, Mannheimia, Corynebacterium and Basfia (PMID: 22292465; PMID: 18191255; PMID: 26360870). Succinic acid, or its anion succinate, is used as an excipient in pharmaceutical products to control acidity or as a counter ion. Drugs involving succinate include metoprolol succinate, sumatriptan succinate, Doxylamine succinate or solifenacin succinate. In 2004, succinic acid was identified by the Department of Energy of the United States of America as one of twelve molecules that can be produced from plant sugars through biological or chemical processes and that have a potential to subsequently be converted to a number of high-value bio-based chemicals or materials. In this regard, industrial hemp (Cannabis sativa L.) has been identified as a source of succinic acid after several chemical and biological treatments (PMID:25682224), suggessting it could serve as a promising source of building blocks for green chemistry products.