Lysine (symbolLys orK)[2] is anα-amino acid that is aprecursor to manyproteins. Lysine contains an α-amino group (which is in theprotonated−NH+3 form when the lysine is dissolved in water atphysiological pH), an α-carboxylic acid group (which is in the deprotonated−COO− form when the lysine is dissolved in water at physiological pH), and a side chain(CH2)4NH2 (which is partially protonated when the lysine is dissolved in water at physiological pH), and so it is classified as abasic, charged (in water at physiological pH),aliphatic amino acid. It is encoded by thecodons AAA and AAG. Like almost all other amino acids, the α-carbon ischiral and lysine may refer to eitherenantiomer or aracemic mixture of both. For the purpose of this article, lysine will refer to the biologically active enantiomerL-lysine, where the α-carbon is in theS configuration.
Lysine plays several roles in humans, most importantlyproteinogenesis, but also in the crosslinking ofcollagen polypeptides, uptake of essential mineral nutrients, and in the production ofcarnitine, which is key infatty acid metabolism. Lysine is also often involved inhistone modifications, and thus, impacts theepigenome. The ε-amino group often participates in hydrogen bonding and as a general base incatalysis. The ε-ammonium group (−NH+3) is attached to the fourth carbon from the α-carbon, which is attached to thecarboxyl (−COOH) group.[3]
Due to its importance in several biological processes, a lack of lysine can lead to several disease states including defective connective tissues, impaired fatty acid metabolism, anaemia, and systemic protein-energy deficiency. In contrast, an overabundance of lysine, caused by ineffective catabolism, can cause severeneurological disorders.
Lysine was first isolated by the German biological chemist Ferdinand Heinrich Edmund Drechsel in 1889 from hydrolysis of the proteincasein,[4] and thus named it Lysin, from Greek λύσις (lysis)'loosening'.[5][6] In 1902, the German chemistsEmil Fischer andFritz Weigert determined lysine's chemical structure by synthesizing it.[7]
The one-letter symbol K was assigned to lysine for being alphabetically nearest, with L being assigned to the structurally simpler leucine, and M to methionine.[8]
Lysine biosynthesis pathways. Two pathways are responsible for thede novo biosynthesis ofL-lysine, namely the (A) diaminopimelate pathway and (B) α‑aminoadipate pathway.
The DAP pathway is found in bothprokaryotes and plants and begins with thedihydrodipicolinate synthase (DHDPS) (E.C 4.3.3.7)catalysedcondensation reaction between the aspartate derived,L-aspartate semialdehyde, andpyruvate to form (4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinic acid (HTPA).[13][14][15][16][17] The product is thenreduced bydihydrodipicolinate reductase (DHDPR) (E.C 1.3.1.26), withNAD(P)H as a proton donor, to yield 2,3,4,5-tetrahydrodipicolinate (THDP).[18] From this point on, four pathway variations have been found, namely the acetylase, aminotransferase, dehydrogenase, and succinylase pathways.[9][19] Both the acetylase and succinylase variant pathways use fourenzyme catalysed steps, the aminotransferase pathway uses two enzymes, and the dehydrogenase pathway uses a single enzyme.[20] These four variant pathways converge at the formation of the penultimate product,meso‑diaminopimelate, which is subsequently enzymaticallydecarboxylated in an irreversible reaction catalysed bydiaminopimelate decarboxylase (DAPDC) (E.C 4.1.1.20) to produceL-lysine.[21][22] 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.[22][23] Lysine imparts a strongnegative feedback loop on these enzymes and, subsequently, regulates the entire pathway.[23]
The AAA pathway involves the condensation ofα-ketoglutarate andacetyl-CoA via the intermediate AAA for the synthesis ofL-lysine. This pathway has been shown to be present in severalyeast species, as well as protists and higher fungi.[12][24][25][26][27][28][29] It has also been reported that an alternative variant of the AAA route has been found inThermus thermophilus andPyrococcus horikoshii, which could indicate that this pathway is more widely spread in prokaryotes than originally proposed.[30][31][32] The first andrate-limiting step in the AAA pathway is the condensation reaction between acetyl-CoA and α‑ketoglutarate catalysed byhomocitrate-synthase (HCS) (E.C 2.3.3.14) to give the intermediate homocitryl‑CoA, which ishydrolysed by the same enzyme to producehomocitrate.[33] Homocitrate is enzymaticallydehydrated byhomoaconitase (HAc) (E.C 4.2.1.36) to yieldcis-homoaconitate.[34] HAc then catalyses a second reaction in whichcis-homoaconitate undergoesrehydration to producehomoisocitrate.[12] The resulting product undergoes anoxidative decarboxylation byhomoisocitrate dehydrogenase (HIDH) (E.C 1.1.1.87) to yield α‑ketoadipate.[12] AAA is then formed via apyridoxal 5′-phosphate (PLP)-dependentaminotransferase(PLP-AT) (E.C 2.6.1.39), using glutamate as the amino donor.[33] 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 bothadenylation and reduction that is activated by aphosphopantetheinyl transferase (E.C 2.7.8.7).[12] Once the semialdehyde is formed,saccharopinereductase (E.C 1.5.1.10) catalyses a condensation reaction with glutamate and NAD(P)H, as a proton donor, and theimine is reduced to produce the penultimate product, saccharopine.[32] The final step of the pathway in fungi involves thesaccharopine dehydrogenase (SDH) (E.C 1.5.1.8) catalysed oxidativedeamination of saccharopine, resulting inL-lysine.[12] In a variant AAA pathway found in some prokaryotes, AAA is first converted toN‑acetyl-α-aminoadipate, which isphosphorylated and then reductivelydephosphorylated to the ε-aldehyde.[32][33] The aldehyde is thentransaminated toN‑acetyllysine, which is deacetylated to giveL-lysine.[32][33] However, the enzymes involved in this variant pathway need further validation.
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 ofintracellular protein. Catabolism is also used as a means to control the intracellular concentration of free lysine and maintain asteady-state to prevent the toxic effects of excessive free lysine.[35] There are several pathways involved in lysine catabolism but the most commonly used is the saccharopine pathway, which primarily takes place in theliver (and equivalent organs) in animals, specifically within themitochondria.[36][35][37][38] This is the reverse of the previously described AAA pathway.[36][39] In animals and plants, the first two steps of the saccharopine pathway are catalysed by the bifunctional enzyme,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 separategenes.[40][41] The first step involves the LKR catalysed reduction ofL-lysine in the presence of α-ketoglutarate to produce saccharopine, with NAD(P)H acting as a proton donor.[42] Saccharopine then undergoes a dehydration reaction, catalysed by SDH in the presence ofNAD+, to produce AAS and glutamate.[43]AAS dehydrogenase (AASD) (E.C 1.2.1.31) then further dehydrates the molecule into AAA.[42] 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+ and coenzyme A to yield glutaryl-CoA, however the enzyme involved in this is yet to be fully elucidated.[44][45] Some evidence suggests that the2-oxoadipate dehydrogenase complex (OADHc), which is structurally homologous to the E1 subunit of theoxoglutarate dehydrogenase complex (OGDHc) (E.C 1.2.4.2), is responsible for the decarboxylation reaction.[44][46] Finally, glutaryl-CoA is oxidatively decarboxylated to crotonyl-CoA byglutaryl-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 carbonmetabolite involved in thetricarboxylic acid cycle (TCA).[42][47][48][49]
Lysine is an essential amino acid in humans.[50] The human daily nutritional requirement varies from ~60 mg/kg in infancy to ~30 mg/kg in adults.[36] This requirement is commonly met in awestern society with the intake oflysine from meat and vegetable sources well in excess of the recommended requirement.[36] In vegetarian diets, the intake of lysine is less due to the limited quantity of lysine incereal crops compared to meat sources.[36]
Given the limiting concentration of lysine in cereal crops, it has long been speculated that the content of lysine can be increased throughgenetic modification practices.[51][52] Often these practices have involved the intentional dysregulation of the DAP pathway by means of introducing lysine feedback-insensitiveorthologues of the DHDPS enzyme.[51][52] These methods have met limited success likely due to thetoxic side effects of increased free lysine and indirect effects on the TCA cycle.[53] Plants accumulate lysine and other amino acids in the form of seedstorage proteins, found within the seeds of the plant, and this represents the edible component of cereal crops.[54] This highlights the need to not only increase free lysine, but also direct lysine towards the synthesis of stable seed storage proteins, and subsequently, increase the nutritional value of the consumable component of crops.[55][56] While genetic modification practices have met limited success, more traditionalselective breeding techniques have allowed for the isolation of "Quality Protein Maize", which has significantly increased levels of lysine andtryptophan, also an essential amino acid. This increase in lysine content is attributed to anopaque-2 mutation that reduced thetranscription of lysine-lackingzein-related seed storage proteins and, as a result, increased the abundance of other proteins that are rich in lysine.[56][57] Commonly, to overcome the limiting abundance of lysine inlivestock feed, industrially produced lysine is added.[58][59] The industrial process includes thefermentative culturing ofCorynebacterium glutamicum and the subsequent purification of lysine.[58]
Good sources of lysine are high-protein foods such as eggs, meat (specifically red meat, lamb, pork, and poultry),soy, beans and peas, cheese (particularly Parmesan), and certain fish (such ascod andsardines).[60] Lysine is thelimiting amino acid (the essential amino acid found in the smallest quantity in the particular foodstuff) in mostcereal grains, but is plentiful in mostpulses (legumes).[61] Beans contain the lysine thatmaize lacks, and in the human archeological record beans and maize often appear together, as in theThree Sisters: beans, maize, and squash.[62]
A food is considered to have sufficient lysine if it has at least 51 mg of lysine per gram of protein (so that the protein is 5.1% lysine).[63]L-lysine HCl is used as adietary supplement, providing 80.03%L-lysine.[64] As such, 1 g ofL-lysine is contained in 1.25 g ofL-lysine HCl.
The most common role for lysine is proteinogenesis. Lysine frequently plays an important role inprotein structure. Since its side chain contains a positively charged group on one end and a longhydrophobic carbon tail close to the backbone, lysine is considered somewhatamphipathic. For this reason, lysine can be found buried as well as more commonly in solvent channels and on the exterior of proteins, where it can interact with the aqueous environment.[65] Lysine can also contribute to protein stability as its ε-amino group often participates inhydrogen bonding,salt bridges andcovalent interactions to form aSchiff base.[65][66][67][68]
A second major role of lysine is inepigenetic regulation by means ofhistonemodification.[69][70] There are several types of covalent histone modifications, which commonly involve lysine residues found in the protruding tail of histones. Modifications often include the addition or removal of anacetyl (−CH3CO) formingacetyllysine or reverting to lysine, up to threemethyl (−CH3),ubiquitin or asumo protein group.[69][71][72][73][74] The various modifications have downstream effects ongene regulation, in which genes can be activated or repressed.
Lysine has also been implicated to play a key role in other biological processes including; structural proteins ofconnective tissues,calciumhomeostasis, andfatty acid metabolism.[75][76][77] Lysine has been shown to be involved in thecrosslinking between the threehelical polypeptides incollagen, resulting in its stability and tensile strength.[75][78] This mechanism is akin to the role of lysine inbacterial cell walls, in which lysine (andmeso-diaminopimelate) are critical to the formation of crosslinks, and therefore, stability of the cell wall.[79] This concept has previously been explored as a means to circumvent the unwanted release of potentiallypathogenic genetically modified bacteria. It was proposed that anauxotrophic strain ofEscherichia coli (X1776) could be used for all genetic modification practices, as the strain is unable to survive without the supplementation of DAP, and thus, cannot live outside of a laboratory environment.[80] Lysine has also been proposed to be involved in calcium intestinal absorption and renal retention, and thus, may play a role incalcium homeostasis.[76] Finally, lysine has been shown to be a precursor forcarnitine, which transports fatty acids to themitochondria, where they can be oxidised for the release of energy.[77][81] Carnitine is synthesised fromtrimethyllysine, which is a product of the degradation of certain proteins, as such lysine must first be incorporated into proteins and be methylated prior to being converted to carnitine.[77] However, in mammals the primary source of carnitine is through dietary sources, rather than through lysine conversion.[77]
There has been a long discussion that lysine, when administered intravenously or orally, can significantly increase the release ofgrowth hormones.[82] This has led to athletes using lysine as a means of promoting muscle growth while training, however, no significant evidence to support this application of lysine has been found to date.[82][83]
Becauseherpes simplex virus (HSV) proteins are richer in arginine and poorer in lysine than the cells they infect, lysine supplements have been tried as a treatment. Since the two amino acids are taken up in the intestine, reclaimed in the kidney, and moved into cells by the sameamino acid transporters, an abundance of lysine would, in theory, limit the amount of arginine available for viral replication.[84] Clinical studies do not provide good evidence for effectiveness as aprophylactic or in the treatment for HSV outbreaks.[85][86] In response to product claims that lysine could improve immune responses to HSV, a review by theEuropean Food Safety Authority found no evidence of a cause–effect relationship. The same review, published in 2011, found no evidence to support claims that lysine could lower cholesterol, increase appetite, contribute to protein synthesis in any role other than as an ordinary nutrient, or increase calcium absorption or retention.[87]
Diseases related to lysine are a result of the downstream processing of lysine, i.e., the incorporation into proteins or modification into alternative biomolecules. The role of lysine in collagen has been outlined above, however, a lack of lysine andhydroxylysine involved in the crosslinking of collagen peptides has been linked to a disease state of the connective tissue.[88] As carnitine is a key lysine-derived metabolite involved in fatty acid metabolism, a substandard diet lacking sufficient carnitine and lysine can lead to decreased carnitine levels, which can have significant cascading effects on an individual's health.[81][89] Lysine has also been shown to play a role inanaemia, as lysine is suspected to have an effect on the uptake ofiron and, subsequently, the concentration offerritin inblood plasma.[90] However, the exact mechanism of action is yet to be elucidated.[90] Most commonly, lysine deficiency is seen in non-western societies and manifests asprotein-energy malnutrition, which has profound and systemic effects on the health of the individual.[91][92] There is also ahereditary genetic disease that involvesmutations in the enzymes responsible for lysine catabolism, namely the bifunctional AASS enzyme of the saccharopine pathway.[93] Due to a lack of lysine catabolism, the amino acid accumulates in plasma and patients develophyperlysinaemia, which can present as asymptomatic to severeneurological disabilities, includingepilepsy,ataxia,spasticity, andpsychomotor impairment.[93][94] The clinical significance of hyperlysinemia is the subject of debate in the field with some studies finding no correlation between physical or mental disabilities and hyperlysinemia.[95] In addition to this, mutations in genes related to lysine metabolism have been implicated in several disease states, includingpyridoxine-dependent epilepsia (ALDH7A1 gene),α-ketoadipic and α-aminoadipic aciduria (DHTKD1 gene), andglutaric aciduria type 1 (GCDH gene).[44][96][97][98][99]
Hyperlysinuria is marked by high amounts of lysine in the urine.[100] It is often due to ametabolic disease in which aprotein involved in the breakdown of lysine is non functional due to a genetic mutation.[101] It may also occur due to a failure ofrenal tubular transport.[101]
Lysine production for animal feed is a major global industry, reaching in 2009 almost 700,000 tons for a market value of over €1.22 billion.[102] Lysine is an important additive to animal feed because it is a limiting amino acid when optimizing the growth of certain animals such as pigs and chickens for the production of meat. Lysine supplementation allows for the use of lower-cost plant protein (maize, for instance, rather thansoy) while maintaining high growth rates, and limiting the pollution from nitrogen excretion.[103] In turn, however, phosphate pollution is a major environmental cost when corn is used as feed for poultry and swine.[104]
Lysine is industrially produced by microbial fermentation, from a base mainly of sugar. Genetic engineering research is actively pursuing bacterial strains to improve the efficiency of production and allow lysine to be made from other substrates.[102] The most common bacteria used isCorynebacterium glutamicum specially mutagenized or gene-engineered to produce lysine, but analogous strains ofEscherichia coli are also employed.
The 1993 filmJurassic Park, which is based on the 1990 novelJurassic Park byMichael Crichton, featuresdinosaurs that weregenetically altered so that they could not produce lysine, an example of engineeredauxotrophy.[105] This was known as the "lysine contingency" and was supposed to prevent thecloned dinosaurs from surviving outside the park, forcing them to depend on lysine supplements provided by the park's veterinary staff. In reality, no animal can produce lysine; it is anessential amino acid.[106]
In 1996, lysine became the focus of aprice-fixing case, the largest in United States history. TheArcher Daniels Midland Company paid a fine of US$100 million, and three of its executives were convicted and served prison time. Also found guilty in the price-fixing case were two Japanese firms (Ajinomoto, Kyowa Hakko) and a South Korean firm (Sewon).[107] Secret video recordings of the conspirators fixing lysine's price can be found online or by requesting the video from theU.S. Department of Justice, Antitrust Division. This case gave the basis for the bookThe Informant: A True Story,[108] and the movieThe Informant!.
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^Drechsel E (1891). "Der Abbau der Eiweissstoffe" [The disassembly of proteins].Archiv für Anatomie und Physiologie (in German):248–278.;Fischer E (1891)."Ueber neue Spaltungsproducte des Leimes" [On new cleavage products of gelatin].Archiv für Anatomie und Physiologie (in German):465–469.From p. 469:]" … die Base C6H14N2O2, welche mit dem Namen Lysin bezeichnet werden mag, … " ( … the base C6H14N2O2, which may be designated with the name "lysine", … ) [Note: Ernst Fischer was a graduate student of Drechsel.]
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