Editing Lysine (section)

==Biosynthesis==
[[File:AAA DAP pathways.tif|thumb|left|'''Lysine biosynthesis pathways.''' Two pathways are responsible for the ''de novo'' biosynthesis of <small>L</small>-lysine, namely the (A) diaminopimelate pathway and (B) α‑aminoadipate pathway.]]

Two pathways have been identified in nature for the synthesis of lysine. The [[diaminopimelate]] (DAP) pathway belongs to the [[Aspartic acid|aspartate]] derived biosynthetic family, which is also involved in the synthesis of [[threonine]], [[methionine]] and [[isoleucine]],<ref name="Hudson_2005">{{cite journal | vauthors = Hudson AO, Bless C, Macedo P, Chatterjee SP, Singh BK, Gilvarg C, Leustek T | title = Biosynthesis of lysine in plants: evidence for a variant of the known bacterial pathways | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1721 | issue = 1–3 | pages = 27–36 | date = January 2005 | pmid = 15652176 | doi = 10.1016/j.bbagen.2004.09.008 }}</ref><ref name="Velasco_2002">{{cite journal | vauthors = Velasco AM, Leguina JI, Lazcano A | title = Molecular evolution of the lysine biosynthetic pathways | journal = Journal of Molecular Evolution | volume = 55 | issue = 4 | pages = 445–459 | date = October 2002 | pmid = 12355264 | doi = 10.1007/s00239-002-2340-2 | bibcode = 2002JMolE..55..445V | s2cid = 19460256 }}</ref> whereas the [[α-aminoadipate]] (AAA) pathway is part of the [[Glutamic acid|glutamate]] biosynthetic family.<ref name="Miyazaki_2004">{{cite journal | vauthors = Miyazaki T, Miyazaki J, Yamane H, Nishiyama M | title = alpha-Aminoadipate aminotransferase from an extremely thermophilic bacterium, Thermus thermophilus | journal = Microbiology | volume = 150 | issue = Pt 7 | pages = 2327–2334 | date = July 2004 | pmid = 15256574 | doi = 10.1099/mic.0.27037-0 | doi-access = free | s2cid = 25416966 }}</ref><ref name="Xu_2006">{{cite journal | vauthors = Xu H, Andi B, Qian J, West AH, Cook PF | title = The alpha-aminoadipate pathway for lysine biosynthesis in fungi | journal = [[Cell Biochemistry and Biophysics]] | volume = 46 | issue = 1 | pages = 43–64 | date = 2006 | pmid = 16943623 | doi = 10.1385/CBB:46:1:43 | s2cid = 22370361 }}</ref>

=== DAP pathway ===
The DAP pathway is found in both [[prokaryote]]s and plants and begins with the [[dihydrodipicolinate synthase]] (DHDPS) (E.C 4.3.3.7) [[Catalysis|catalysed]] [[condensation reaction]] between the aspartate derived, <small>L</small>-aspartate semialdehyde, and [[Pyruvic acid|pyruvate]] to form (4''S'')-4-hydroxy-2,3,4,5-tetrahydro-(2''S'')-dipicolinic acid (HTPA).<ref name="Atkinson_2013">{{cite journal | vauthors = Atkinson SC, Dogovski C, Downton MT, Czabotar PE, Dobson RC, Gerrard JA, Wagner J, Perugini MA | title = Structural, kinetic and computational investigation of Vitis vinifera DHDPS reveals new insight into the mechanism of lysine-mediated allosteric inhibition | journal = Plant Molecular Biology | volume = 81 | issue = 4–5 | pages = 431–446 | date = March 2013 | pmid = 23354837 | doi = 10.1007/s11103-013-0014-7 | hdl = 11343/282680 | s2cid = 17129774 | hdl-access = free }}</ref><ref name="Griffin_2012">{{cite journal | vauthors = Griffin MD, Billakanti JM, Wason A, Keller S, Mertens HD, Atkinson SC, Dobson RC, Perugini MA, Gerrard JA, Pearce FG | title = Characterisation of the first enzymes committed to lysine biosynthesis in Arabidopsis thaliana | journal = PLOS ONE | volume = 7 | issue = 7 | pages = e40318 | date = 2012 | pmid = 22792278 | pmc = 3390394 | doi = 10.1371/journal.pone.0040318 | bibcode = 2012PLoSO...740318G | doi-access = free }}</ref><ref name="Soares_da_Costa_2010">{{cite journal | vauthors = Soares da Costa TP, Muscroft-Taylor AC, Dobson RC, Devenish SR, Jameson GB, Gerrard JA | title = How essential is the 'essential' active-site lysine in dihydrodipicolinate synthase? | journal = Biochimie | volume = 92 | issue = 7 | pages = 837–845 | date = July 2010 | pmid = 20353808 | doi = 10.1016/j.biochi.2010.03.004 }}</ref><ref name="Soares_da_Costa_2015">{{cite book | vauthors = Soares da Costa TP, Christensen JB, Desbois S, Gordon SE, Gupta R, Hogan CJ, Nelson TG, Downton MT, Gardhi CK, Abbott BM, Wagner J, Panjikar S, Perugini MA | chapter = Quaternary Structure Analyses of an Essential Oligomeric Enzyme | volume = 562 | pages = 205–223 | date = 2015 | pmid = 26412653 | doi = 10.1016/bs.mie.2015.06.020 | series = Methods in Enzymology | isbn = 9780128029084 | title = Analytical Ultracentrifugation }}</ref><ref>{{cite journal | vauthors = Muscroft-Taylor AC, Soares da Costa TP, Gerrard JA | title = New insights into the mechanism of dihydrodipicolinate synthase using isothermal titration calorimetry | journal = Biochimie | volume = 92 | issue = 3 | pages = 254–262 | date = March 2010 | pmid = 20025926 | doi = 10.1016/j.biochi.2009.12.004 }}</ref> The product is then [[Redox|reduced]] by [[4-hydroxy-tetrahydrodipicolinate reductase|dihydrodipicolinate reductase (DHDPR)]] (E.C 1.3.1.26), with [[Nicotinamide adenine dinucleotide phosphate|NAD(P)H]] as a proton donor, to yield 2,3,4,5-tetrahydrodipicolinate (THDP).<ref>{{cite journal | vauthors = Christensen JB, Soares da Costa TP, Faou P, Pearce FG, Panjikar S, Perugini MA | title = Structure and Function of Cyanobacterial DHDPS and DHDPR | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 37111 | date = November 2016 | pmid = 27845445 | pmc = 5109050 | doi = 10.1038/srep37111 | bibcode = 2016NatSR...637111C }}</ref> From this point on, four pathway variations have been found, namely the acetylase, aminotransferase, dehydrogenase, and succinylase pathways.<ref name="Hudson_2005" /><ref>{{cite journal | vauthors = McCoy AJ, Adams NE, Hudson AO, Gilvarg C, Leustek T, Maurelli AT | title = <small>L</small>,<small>L</small>-diaminopimelate aminotransferase, a trans-kingdom enzyme shared by Chlamydia and plants for synthesis of diaminopimelate/lysine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 47 | pages = 17909–17914 | date = November 2006 | pmid = 17093042 | pmc = 1693846 | doi = 10.1073/pnas.0608643103 | bibcode = 2006PNAS..10317909M | doi-access = free }}</ref> Both the acetylase and succinylase variant pathways use four [[enzyme]] catalysed steps, the aminotransferase pathway uses two enzymes, and the dehydrogenase pathway uses a single enzyme.<ref>{{cite journal | vauthors = Hudson AO, Gilvarg C, Leustek T | title = Biochemical and phylogenetic characterization of a novel diaminopimelate biosynthesis pathway in prokaryotes identifies a diverged form of <small>LL</small>-diaminopimelate aminotransferase | journal = Journal of Bacteriology | volume = 190 | issue = 9 | pages = 3256–3263 | date = May 2008 | pmid = 18310350 | pmc = 2347407 | doi = 10.1128/jb.01381-07 }}</ref> These four variant pathways converge at the formation of the penultimate product,  ''meso''‑diaminopimelate, which is subsequently enzymatically [[Decarboxylation|decarboxylated]] in an irreversible reaction catalysed by [[Diaminopimelate decarboxylase|diaminopimelate decarboxylase (DAPDC)]] (E.C 4.1.1.20) to produce <small>L</small>-lysine.<ref>{{cite journal | vauthors = Peverelli MG, Perugini MA | title = An optimized coupled assay for quantifying diaminopimelate decarboxylase activity | journal = Biochimie | volume = 115 | pages = 78–85 | date = August 2015 | pmid = 25986217 | doi = 10.1016/j.biochi.2015.05.004 }}</ref><ref name="Soares_da_Costa_2016">{{cite journal | vauthors = Soares da Costa TP, Desbois S, Dogovski C, Gorman MA, Ketaren NE, Paxman JJ, Siddiqui T, Zammit LM, Abbott BM, Robins-Browne RM, Parker MW, Jameson GB, Hall NE, Panjikar S, Perugini MA | title = Structural Determinants Defining the Allosteric Inhibition of an Essential Antibiotic Target | journal = Structure | volume = 24 | issue = 8 | pages = 1282–1291 | date = August 2016 | pmid = 27427481 | doi = 10.1016/j.str.2016.05.019 | doi-access = free }}</ref> The DAP pathway is regulated at multiple levels, including upstream at the enzymes involved in aspartate processing as well as at the initial DHDPS catalysed condensation step.<ref name="Soares_da_Costa_2016" /><ref name="Jander_2009">{{cite journal | vauthors = Jander G, Joshi V | title = Aspartate-Derived Amino Acid Biosynthesis in Arabidopsis thaliana | journal = The Arabidopsis Book | volume = 7 | pages = e0121 | date = 2009-01-01 | pmid = 22303247 | pmc = 3243338 | doi = 10.1199/tab.0121 }}</ref> Lysine imparts a strong [[negative feedback]] loop on these enzymes and, subsequently, regulates the entire pathway.<ref name="Jander_2009" />

=== 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.