Editing Succinic acid (section)

== Biosynthesis ==

=== Tricarboxylic acid (TCA) cycle ===
{{see also|Tricarboxylic acid cycle|Succinate dehydrogenase}}
Succinate is a key intermediate in the [[Citric acid cycle|tricarboxylic acid cycle]], a primary metabolic pathway used to produce chemical energy in the presence of O<sub>2</sub>. Succinate is generated from [[succinyl-CoA]] by the enzyme [[Succinyl coenzyme A synthetase|succinyl-CoA synthetase]] in a [[Guanosine triphosphate|GTP]]/[[Adenosine triphosphate|ATP]]-producing step:<ref name=BiochemText5th/>{{rp|Section 17.1}}

Succinyl-CoA + NDP + Pi → Succinate + CoA + NTP

Catalyzed by the enzyme [[succinate dehydrogenase]] (SDH), succinate is subsequently oxidized to [[Fumaric acid|fumarate]]:<ref name=BiochemText5th/>{{rp|Section 17.1}}

Succinate + FAD → Fumarate + FADH<sub>2</sub>

SDH also participates in the mitochondrial [[electron transport chain]], where it is known as [[respiratory complex II]]. This enzyme complex is a 4 subunit membrane-bound lipoprotein which couples the oxidation of succinate to the reduction of [[Coenzyme Q10|ubiquinone]] via the intermediate electron carriers [[Flavin adenine dinucleotide|FAD]] and three 2Fe-2S clusters. Succinate thus serves as a direct electron donor to the electron transport chain, and itself is converted into fumarate.<ref name=Drose2013rev>{{Cite journal|last=Dröse|first=Stefan|date=2013-05-01|title=Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning|journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics|series=Respiratory complex II: Role in cellular physiology and disease|volume=1827|issue=5|pages=578–587|doi=10.1016/j.bbabio.2013.01.004|pmid=23333272 |doi-access=}}</ref>

{{TCACycle WP78|highlight=Succinic_acid}}

=== Reductive branch of the TCA cycle ===
{{See also|Succinic acid fermentation}}
Succinate can alternatively be formed by reverse activity of SDH. Under anaerobic conditions certain bacteria such as ''A. succinogenes'', ''A. succiniciproducens'' and ''M. succiniciproducens'', run the TCA cycle in reverse and convert glucose to succinate through the intermediates of [[Oxaloacetic acid|oxaloacetate]], [[Malic acid|malate]] and [[Fumaric acid|fumarate]].<ref name=Cheng2013rev>{{Cite journal|last1=Cheng|first1=Ke-Ke|last2=Wang|first2=Gen-Yu|last3=Zeng|first3=Jing|last4=Zhang|first4=Jian-An|date=2013-04-18|title=Improved Succinate Production by Metabolic Engineering|journal=BioMed Research International|volume=2013|pages=538790|doi=10.1155/2013/538790|issn=2314-6133|pmc=3652112|pmid=23691505|doi-access=free}}</ref> This pathway is exploited in metabolic engineering to net generate succinate for human use.<ref name=Cheng2013rev/> Additionally, succinic acid produced during the fermentation of sugar provides a combination of saltiness, bitterness and acidity to fermented alcohols.<ref>{{Cite book|title=Knowing and Making Wine|last=Peynaud|first=Emile|date=1984}}</ref>

Accumulation of fumarate can drive the reverse activity of SDH, thus enhancing succinate generation. Under pathological and physiological conditions, the [[malate-aspartate shuttle]] or the [[Purine nucleotide cycle|purine nucleotide shuttle]] can increase mitochondrial fumarate, which is then readily converted to succinate.<ref name=Haas2016rev/>

=== Glyoxylate cycle ===
{{See also|Glyoxylate cycle}}
Succinate is also a product of the [[glyoxylate cycle]], which converts two two-carbon acetyl units into the four-carbon succinate. The glyoxylate cycle is utilized by many bacteria, plants and fungi and allows these organisms to subsist on acetate or acetyl CoA yielding compounds. The pathway avoids the [[decarboxylation]] steps of the TCA cycle via the enzyme [[isocitrate lyase]] which cleaves [[Isocitric acid|isocitrate]] into succinate and [[Glyoxylic acid|glyoxylate]]. Generated succinate is then available for either energy production or biosynthesis.<ref name=BiochemText5th>{{cite book|last1=Berg|first1=JM|last2=Tymoczko|first2=JL|last3=Stryer|first3=L|title=Biochemistry|date=2002|publisher=W H Freeman|location=New York|edition=5th|url=https://www.ncbi.nlm.nih.gov/books/NBK22383/}}</ref>{{rp|Section 17.4}}

=== GABA shunt ===
Succinate is the re-entry point for the [[Gamma-Aminobutyric acid|gamma-aminobutyric acid]] (GABA) shunt into the TCA cycle, a closed cycle which synthesizes and recycles GABA.<ref name=BasicNeurochemTextChapter>{{cite book|last1=Olsen|first1=Richard W|last2=DeLorey|first2=Timothy M|editor1-last=Siegel|editor1-first=GJ|editor2-last=Agranoff|editor2-first=BW|editor3-last=Albers|editor3-first=RW |display-editors=etal |title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects|date=1999|publisher=Lippincott-Raven|location=Philadelphia|edition=6th|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27979/|chapter=GABA Synthesis, Uptake and Release}}</ref> The GABA shunt serves as an alternate route to convert [[Alpha-Ketoglutaric acid|alpha-ketoglutarate]] into succinate, bypassing the TCA cycle intermediate succinyl-CoA and instead producing the intermediate GABA. Transamination and subsequent decarboxylation of alpha-ketoglutarate leads to the formation of GABA. GABA is then metabolized by [[GABA transaminase]] to [[succinic semialdehyde]]. Finally, succinic semialdehyde is oxidized by [[succinic semialdehyde dehydrogenase]] (SSADH) to form succinate, re-entering the TCA cycle and closing the loop. Enzymes required for the GABA shunt are expressed in neurons, glial cells, macrophages and pancreatic cells.<ref name=BasicNeurochemTextChapter/>
[[File:Integrated Diagram of Succinate Biofunctionality .png|thumb|540x540px|Biological roles of succinate. Inside the mitochondria, succinate serves as an intermediate in multiple metabolic pathways and contributes to the generation of ROS. Outside the mitochondria, succinate functions as both an intracellular and extracellular signaling molecule. OOA=oxaloacetate; a-KG=alpha ketoglutarate; GLUT= Glutamate; GABA = gamma-aminobutyric acid; SSA=Succinic semialdehyde; PHD= prolyl hydroxylase; HIF-1a=hypoxia inducible factor 1a; TET= Ten-eleven Translocation Enzymes; JMJD3= Histone demethylase Jumonji D3]]