Editing Lysine (section)

=== AAA pathway ===
{{Main|α-Aminoadipate pathway}}
The AAA pathway involves the condensation of [[Alpha-Ketoglutaric acid|α-ketoglutarate]] and [[acetyl-CoA]] via the intermediate AAA for the synthesis of <small>L</small>-lysine. This pathway has been shown to be present in several [[yeast]] species, as well as protists and higher fungi.<ref name="Xu_2006" /><ref>{{cite journal | vauthors = Andi B, West AH, Cook PF | title = Kinetic mechanism of histidine-tagged homocitrate synthase from Saccharomyces cerevisiae | journal = Biochemistry | volume = 43 | issue = 37 | pages = 11790–11795 | date = September 2004 | pmid = 15362863 | doi = 10.1021/bi048766p }}</ref><ref>{{cite journal | vauthors = Bhattacharjee JK | title = alpha-Aminoadipate pathway for the biosynthesis of lysine in lower eukaryotes | journal = Critical Reviews in Microbiology | volume = 12 | issue = 2 | pages = 131–151 | date = 1985 | pmid = 3928261 | doi = 10.3109/10408418509104427 }}</ref><ref>{{cite journal | vauthors = Bhattacharjee JK, Strassman M | title = Accumulation of tricarboxylic acids related to lysine biosynthesis in a yeast mutant | journal = The Journal of Biological Chemistry | volume = 242 | issue = 10 | pages = 2542–2546 | date = May 1967 | doi = 10.1016/S0021-9258(18)95997-1 | pmid = 6026248 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gaillardin CM, Ribet AM, Heslot H | title = Wild-type and mutant forms of homoisocitric dehydrogenase in the yeast Saccharomycopsis lipolytica | journal = European Journal of Biochemistry | volume = 128 | issue = 2–3 | pages = 489–494 | date = November 1982 | pmid = 6759120 | doi = 10.1111/j.1432-1033.1982.tb06991.x | doi-access = free}}</ref><ref>{{cite journal | vauthors = Jaklitsch WM, Kubicek CP | title = Homocitrate synthase from Penicillium chrysogenum. Localization, purification of the cytosolic isoenzyme, and sensitivity to lysine | journal = The Biochemical Journal | volume = 269 | issue = 1 | pages = 247–253 | date = July 1990 | pmid = 2115771 | pmc = 1131560 | doi = 10.1042/bj2690247 }}</ref><ref>{{cite journal | vauthors = Ye ZH, Bhattacharjee JK | title = Lysine biosynthesis pathway and biochemical blocks of lysine auxotrophs of Schizosaccharomyces pombe | journal = Journal of Bacteriology | volume = 170 | issue = 12 | pages = 5968–5970 | date = December 1988 | pmid = 3142867 | pmc = 211717 | doi = 10.1128/jb.170.12.5968-5970.1988 }}</ref> It has also been reported that an alternative variant of the AAA route has been found in ''[[Thermus thermophilus]]'' and ''[[Pyrococcus horikoshii]]'', which could indicate that this pathway is more widely spread in prokaryotes than originally proposed.<ref>{{cite journal | vauthors = Kobashi N, Nishiyama M, Tanokura M | title = Aspartate kinase-independent lysine synthesis in an extremely thermophilic bacterium, Thermus thermophilus: lysine is synthesized via alpha-aminoadipic acid not via diaminopimelic acid | journal = Journal of Bacteriology | volume = 181 | issue = 6 | pages = 1713–1718 | date = March 1999 | doi = 10.1128/JB.181.6.1713-1718.1999 | pmid = 10074061 | pmc = 93567 }}</ref><ref>{{cite journal | vauthors = Kosuge T, Hoshino T | title = The alpha-aminoadipate pathway for lysine biosynthesis is widely distributed among Thermus strains | journal = Journal of Bioscience and Bioengineering | volume = 88 | issue = 6 | pages = 672–675 | date = 1999 | pmid = 16232683 | doi = 10.1016/S1389-1723(00)87099-1 }}</ref><ref name="Nishida_1999">{{cite journal | vauthors = Nishida H, Nishiyama M, Kobashi N, Kosuge T, Hoshino T, Yamane H | title = A prokaryotic gene cluster involved in synthesis of lysine through the amino adipate pathway: a key to the evolution of amino acid biosynthesis | journal = Genome Research | volume = 9 | issue = 12 | pages = 1175–1183 | date = December 1999 | pmid = 10613839 | doi = 10.1101/gr.9.12.1175 | doi-access = free }}</ref> The first and [[Rate-determining step|rate-limiting step]] in the AAA pathway is the condensation reaction between acetyl-CoA and α‑ketoglutarate catalysed by [[Homocitrate synthase|homocitrate-synthase (HCS)]] (E.C 2.3.3.14) to give the intermediate homocitryl‑CoA, which is [[Hydrolysis|hydrolysed]] by the same enzyme to produce [[Homocitric acid|homocitrate]].<ref name="Nishida_2000">{{cite journal | vauthors = Nishida H, Nishiyama M | title = What is characteristic of fungal lysine synthesis through the alpha-aminoadipate pathway? | journal = Journal of Molecular Evolution | volume = 51 | issue = 3 | pages = 299–302 | date = September 2000 | pmid = 11029074 | doi = 10.1007/s002390010091 | bibcode = 2000JMolE..51..299N | s2cid = 1265909 }}</ref> Homocitrate is enzymatically [[Dehydration reaction|dehydrated]] by [[Homoaconitate hydratase|homoaconitase (HAc)]] (E.C 4.2.1.36) to yield [[Homoaconitic acid|''cis''-homoaconitate]].<ref>{{cite journal | vauthors = Zabriskie TM, Jackson MD | title = Lysine biosynthesis and metabolism in fungi | journal = Natural Product Reports | volume = 17 | issue = 1 | pages = 85–97 | date = February 2000 | pmid = 10714900 | doi = 10.1039/a801345d }}</ref> HAc then catalyses a second reaction in which ''cis''-homoaconitate undergoes [[Hydration reaction|rehydration]] to produce [[Homoisocitric acid|homoisocitrate]].<ref name="Xu_2006" /> The resulting product undergoes an [[Redox|oxidative]] decarboxylation by [[Homoisocitrate dehydrogenase|homoisocitrate dehydrogenase (HIDH)]] (E.C 1.1.1.87) to yield α‑ketoadipate.<ref name="Xu_2006" /> AAA is then formed via a [[Pyridoxal phosphate|pyridoxal 5′-phosphate (PLP)]]-dependent [[Transaminase|aminotransferase]] [[2-aminoadipate transaminase|(PLP-AT)]] (E.C 2.6.1.39), using glutamate as the amino donor.<ref name="Nishida_2000" /> From this point on, the AAA pathway varies with [something is missing here ? -> at the very least, section header! ] on the kingdom. In fungi, AAA is reduced to α‑aminoadipate-semialdehyde via AAA reductase (E.C 1.2.1.95) in a unique process involving both [[Adenylylation|adenylation]] and reduction that is activated by a [[Holo-(acyl-carrier-protein) synthase|phosphopantetheinyl transferase]] (E.C 2.7.8.7).<ref name="Xu_2006" /> Once the semialdehyde is formed, [[saccharopine]] [[Saccharopine dehydrogenase (NADP+, L-glutamate-forming)|reductase]] (E.C 1.5.1.10) catalyses a condensation reaction with glutamate and NAD(P)H, as a proton donor, and the [[imine]] is reduced to produce the penultimate product, saccharopine.<ref name="Nishida_1999" /> The final step of the pathway in fungi involves the [[Saccharopine dehydrogenase (NADP+, L-lysine-forming)|saccharopine dehydrogenase (SDH)]] (E.C 1.5.1.8) catalysed oxidative [[deamination]] of saccharopine, resulting in <small>L</small>-lysine.<ref name="Xu_2006" /> In a variant AAA pathway found in some prokaryotes, AAA is first converted to ''N''‑acetyl-α-aminoadipate, which is [[Phosphorylation|phosphorylated]] and then reductively [[Dephosphorylation|dephosphorylated]] to the ε-aldehyde.<ref name="Nishida_1999" /><ref name="Nishida_2000" /> The aldehyde is then [[Transamination|transaminated]] to ''N''‑acetyllysine, which is deacetylated to give <small>L</small>-lysine.<ref name="Nishida_1999" /><ref name="Nishida_2000" /> However, the enzymes involved in this variant pathway need further validation.