Editing Lysine (section)

==Catabolism==
[[File:Saccharopine Pathway Final.tiff|thumb|upright=0.8|'''Saccharopine lysine catabolism pathway.''' The saccharopine pathway is the most prominent pathway for the catabolism of lysine.]]

As with all amino acids, [[catabolism]] of lysine is initiated from the uptake of dietary lysine or from the breakdown of [[intracellular]] protein. Catabolism is also used as a means to control the intracellular concentration of free lysine and maintain a [[Steady state|steady-state]] to prevent the toxic effects of excessive free lysine.<ref name="Zhu_2004">{{cite journal | vauthors = Zhu X, Galili G | title = Lysine metabolism is concurrently regulated by synthesis and catabolism in both reproductive and vegetative tissues | journal = Plant Physiology | volume = 135 | issue = 1 | pages = 129–136 | date = May 2004 | pmid = 15122025 | pmc = 429340 | doi = 10.1104/pp.103.037168 }}</ref> There are several pathways involved in lysine catabolism but the most commonly used is the saccharopine pathway, which primarily takes place in the [[liver]] (and equivalent organs) in animals, specifically within the [[Mitochondrion|mitochondria]].<ref name="Tomé_2007">{{cite journal | vauthors = Tomé D, Bos C | title = Lysine requirement through the human life cycle | journal = The Journal of Nutrition | volume = 137 | issue = 6 Suppl 2 | pages = 1642S–1645S | date = June 2007 | pmid = 17513440 | doi = 10.1093/jn/137.6.1642S | doi-access = free }}</ref><ref name="Zhu_2004" /><ref>{{cite journal | vauthors = Blemings KP, Crenshaw TD, Swick RW, Benevenga NJ | title = Lysine-alpha-ketoglutarate reductase and saccharopine dehydrogenase are located only in the mitochondrial matrix in rat liver | journal = The Journal of Nutrition | volume = 124 | issue = 8 | pages = 1215–1221 | date = August 1994 | pmid = 8064371 | doi = 10.1093/jn/124.8.1215 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Galili G, Tang G, Zhu X, Gakiere B | title = Lysine catabolism: a stress and development super-regulated metabolic pathway | journal = Current Opinion in Plant Biology | volume = 4 | issue = 3 | pages = 261–266 | date = June 2001 | pmid = 11312138 | doi = 10.1016/s1369-5266(00)00170-9 | bibcode = 2001COPB....4..261G }}</ref> This is the reverse of the previously described AAA pathway.<ref name="Tomé_2007" /><ref>{{cite journal | vauthors = Arruda P, Kemper EL, Papes F, Leite A | title = Regulation of lysine catabolism in higher plants | journal = Trends in Plant Science | volume = 5 | issue = 8 | pages = 324–330 | date = August 2000 | pmid = 10908876 | doi = 10.1016/s1360-1385(00)01688-5 }}</ref> In animals and plants, the first two steps of the saccharopine pathway are catalysed by the bifunctional enzyme, [[Alpha-aminoadipic semialdehyde synthase, mitochondrial|α-aminoadipic semialdehyde synthase (AASS)]], which possess both lysine-ketoglutarate reductase (LKR) (E.C 1.5.1.8) and SDH activities, whereas in other organisms, such as bacteria and fungi, both of these enzymes are encoded by separate [[gene]]s.<ref>{{cite journal | vauthors = Sacksteder KA, Biery BJ, Morrell JC, Goodman BK, Geisbrecht BV, Cox RP, Gould SJ, Geraghty MT | title = Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia | journal = American Journal of Human Genetics | volume = 66 | issue = 6 | pages = 1736–1743 | date = June 2000 | pmid = 10775527 | pmc = 1378037 | doi = 10.1086/302919 }}</ref><ref>{{cite journal | vauthors = Zhu X, Tang G, Galili G | title = The activity of the Arabidopsis bifunctional lysine-ketoglutarate reductase/saccharopine dehydrogenase enzyme of lysine catabolism is regulated by functional interaction between its two enzyme domains | journal = The Journal of Biological Chemistry | volume = 277 | issue = 51 | pages = 49655–49661 | date = December 2002 | pmid = 12393892 | doi = 10.1074/jbc.m205466200 | doi-access = free }}</ref> The first step involves the LKR catalysed reduction of <small>L</small>-lysine in the presence of α-ketoglutarate to produce saccharopine, with NAD(P)H acting as a proton donor.<ref name="Kiyota_2015">{{cite journal | vauthors = Kiyota E, Pena IA, Arruda P | title = The saccharopine pathway in seed development and stress response of maize | journal = Plant, Cell & Environment | volume = 38 | issue = 11 | pages = 2450–2461 | date = November 2015 | pmid = 25929294 | doi = 10.1111/pce.12563 | doi-access = free }}</ref> Saccharopine then undergoes a dehydration reaction, catalysed by SDH in the presence of [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]], to produce AAS and glutamate.<ref>{{cite journal | vauthors = Serrano GC, Rezende e Silva Figueira T, Kiyota E, Zanata N, Arruda P | title = Lysine degradation through the saccharopine pathway in bacteria: LKR and SDH in bacteria and its relationship to the plant and animal enzymes | journal = FEBS Letters | volume = 586 | issue = 6 | pages = 905–911 | date = March 2012 | pmid = 22449979 | doi = 10.1016/j.febslet.2012.02.023 | s2cid = 32385212 | doi-access = free | bibcode = 2012FEBSL.586..905D }}</ref> [[L-aminoadipate-semialdehyde dehydrogenase|AAS dehydrogenase (AASD)]] (E.C 1.2.1.31) then further dehydrates the molecule into AAA.<ref name="Kiyota_2015" /> Subsequently, PLP-AT catalyses the reverse reaction to that of the AAA biosynthesis pathway, resulting in AAA being converted to α-ketoadipate. The product, α‑ketoadipate, is decarboxylated in the presence of NAD<sup>+</sup> and coenzyme A to yield glutaryl-CoA, however the enzyme involved in this is yet to be fully elucidated.<ref name="Danhauser_2012">{{cite journal | vauthors = Danhauser K, Sauer SW, Haack TB, Wieland T, Staufner C, Graf E, Zschocke J, Strom TM, Traub T, Okun JG, Meitinger T, Hoffmann GF, Prokisch H, Kölker S | title = DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria | journal = American Journal of Human Genetics | volume = 91 | issue = 6 | pages = 1082–1087 | date = December 2012 | pmid = 23141293 | pmc = 3516599 | doi = 10.1016/j.ajhg.2012.10.006 }}</ref><ref>{{cite journal | vauthors = Sauer SW, Opp S, Hoffmann GF, Koeller DM, Okun JG, Kölker S | title = Therapeutic modulation of cerebral <small>L</small>-lysine metabolism in a mouse model for glutaric aciduria type I | journal = Brain | volume = 134 | issue = Pt 1 | pages = 157–170 | date = January 2011 | pmid = 20923787 | doi = 10.1093/brain/awq269 | doi-access = free }}</ref> Some evidence suggests that the 2-oxoadipate dehydrogenase complex (OADHc), which is structurally homologous to the E1 subunit of the [[Oxoglutarate dehydrogenase complex|oxoglutarate dehydrogenase complex (OGDHc)]] (E.C 1.2.4.2), is responsible for the decarboxylation reaction.<ref name="Danhauser_2012" /><ref>{{cite journal | vauthors = Goncalves RL, Bunik VI, Brand MD | title = Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex | journal = Free Radical Biology & Medicine | volume = 91 | pages = 247–255 | date = February 2016 | pmid = 26708453 | doi = 10.1016/j.freeradbiomed.2015.12.020 | doi-access = free }}</ref> Finally, glutaryl-CoA is oxidatively decarboxylated to crotonyl-CoA by [[glutaryl-CoA dehydrogenase]] (E.C 1.3.8.6), which goes on to be further processed through multiple enzymatic steps to yield acetyl-CoA; an essential carbon [[metabolite]] involved in the [[Citric acid cycle|tricarboxylic acid cycle (TCA)]].<ref name="Kiyota_2015" /><ref>{{cite journal | vauthors = Goh DL, Patel A, Thomas GH, Salomons GS, Schor DS, Jakobs C, Geraghty MT | title = Characterization of the human gene encoding alpha-aminoadipate aminotransferase (AADAT) | journal = Molecular Genetics and Metabolism | volume = 76 | issue = 3 | pages = 172–180 | date = July 2002 | pmid = 12126930 | doi = 10.1016/s1096-7192(02)00037-9 }}</ref><ref>{{cite journal | vauthors = Härtel U, Eckel E, Koch J, Fuchs G, Linder D, Buckel W | title = Purification of glutaryl-CoA dehydrogenase from Pseudomonas sp., an enzyme involved in the anaerobic degradation of benzoate | journal = Archives of Microbiology | volume = 159 | issue = 2 | pages = 174–181 | date = 1993-02-01 | pmid = 8439237 | doi = 10.1007/bf00250279 | bibcode = 1993ArMic.159..174H | s2cid = 2262592 }}</ref><ref>{{cite journal | vauthors = Sauer SW | title = Biochemistry and bioenergetics of glutaryl-CoA dehydrogenase deficiency | journal = Journal of Inherited Metabolic Disease | volume = 30 | issue = 5 | pages = 673–680 | date = October 2007 | pmid = 17879145 | doi = 10.1007/s10545-007-0678-8 | s2cid = 20609879}}</ref>