Lysine
Lysine is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group, an α-carboxylic acid group, and a side chain , and so it is classified as a basic, charged, aliphatic amino acid. It is encoded by the codons AAA and AAG. Like almost all other amino acids, the α-carbon is chiral and lysine may refer to either enantiomer or a racemic mixture of both. For the purpose of this article, lysine will refer to the biologically active enantiomer L-lysine, where the α-carbon is in the S configuration.
The human body cannot synthesize lysine. It is essential in humans and must therefore be obtained from the diet. In organisms that synthesise lysine, two main biosynthetic pathways exist, the diaminopimelate and α-aminoadipate pathways, which employ distinct enzymes and substrates and are found in diverse organisms. Lysine catabolism occurs through one of several pathways, the most common of which is the saccharopine pathway.
Lysine plays several roles in humans, most importantly proteinogenesis, but also in the crosslinking of collagen polypeptides, uptake of essential mineral nutrients, and in the production of carnitine, which is key in fatty acid metabolism. Lysine is also often involved in histone modifications, and thus, impacts the epigenome. The ε-amino group often participates in hydrogen bonding and as a general base in catalysis. The ε-ammonium group is attached to the fourth carbon from the α-carbon, which is attached to the carboxyl group.
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 severe neurological disorders.
Lysine was first isolated by the German biological chemist Ferdinand Heinrich Edmund Drechsel in 1889 from hydrolysis of the protein casein, and thus named it Lysin,. In 1902, the German chemists Emil Fischer and Fritz Weigert determined lysine's chemical structure by synthesizing it.
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.
Biosynthesis
Two pathways have been identified in nature for the synthesis of lysine. The diaminopimelate pathway belongs to the aspartate derived biosynthetic family, which is also involved in the synthesis of threonine, methionine and isoleucine, whereas the α-aminoadipate pathway is part of the glutamate biosynthetic family.DAP pathway
The DAP pathway is found in both prokaryotes and plants and begins with the dihydrodipicolinate synthase catalysed condensation reaction between the aspartate derived, L-aspartate semialdehyde, and pyruvate to form -4-hydroxy-2,3,4,5-tetrahydro--dipicolinic acid. The product is then reduced by dihydrodipicolinate reductase , with NADH as a proton donor, to yield 2,3,4,5-tetrahydrodipicolinate. From this point on, four pathway variations have been found, namely the acetylase, aminotransferase, dehydrogenase, and succinylase pathways. 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. These four variant pathways converge at the formation of the penultimate product, meso‑diaminopimelate, which is subsequently enzymatically decarboxylated in an irreversible reaction catalysed by diaminopimelate decarboxylase to produce L-lysine. 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. Lysine imparts a strong negative feedback loop on these enzymes and, subsequently, regulates the entire pathway.AAA pathway
The AAA pathway involves the condensation of α-ketoglutarate and acetyl-CoA via the intermediate AAA for the synthesis of L-lysine. This pathway has been shown to be present in several yeast species, as well as protists and higher fungi. 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. The first and rate-limiting step in the AAA pathway is the condensation reaction between acetyl-CoA and α‑ketoglutarate catalysed by homocitrate-synthase to give the intermediate homocitryl‑CoA, which is hydrolysed by the same enzyme to produce homocitrate. Homocitrate is enzymatically dehydrated by homoaconitase to yield cis-homoaconitate. HAc then catalyses a second reaction in which cis-homoaconitate undergoes rehydration to produce homoisocitrate. The resulting product undergoes an oxidative decarboxylation by homoisocitrate dehydrogenase to yield α‑ketoadipate. AAA is then formed via a pyridoxal 5′-phosphate -dependent aminotransferase , using glutamate as the amino donor. From this point on, the AAA pathway varies with on the kingdom. In fungi, AAA is reduced to α‑aminoadipate-semialdehyde via AAA reductase in a unique process involving both adenylation and reduction that is activated by a phosphopantetheinyl transferase. Once the semialdehyde is formed, saccharopine reductase catalyses a condensation reaction with glutamate and NADH, as a proton donor, and the imine is reduced to produce the penultimate product, saccharopine. The final step of the pathway in fungi involves the saccharopine dehydrogenase catalysed oxidative deamination of saccharopine, resulting in L-lysine. In a variant AAA pathway found in some prokaryotes, AAA is first converted to N‑acetyl-α-aminoadipate, which is phosphorylated and then reductively dephosphorylated to the ε-aldehyde. The aldehyde is then transaminated to N‑acetyllysine, which is deacetylated to give L-lysine. However, the enzymes involved in this variant pathway need further validation.Catabolism
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 to prevent the toxic effects of excessive free lysine. There are several pathways involved in lysine catabolism but the most commonly used is the saccharopine pathway, which primarily takes place in the liver in animals, specifically within the mitochondria. This is the reverse of the previously described AAA pathway. In animals and plants, the first two steps of the saccharopine pathway are catalysed by the bifunctional enzyme, α-aminoadipic semialdehyde synthase, which possess both lysine-ketoglutarate reductase and SDH activities, whereas in other organisms, such as bacteria and fungi, both of these enzymes are encoded by separate genes. The first step involves the LKR catalysed reduction of L-lysine in the presence of α-ketoglutarate to produce saccharopine, with NADH acting as a proton donor. Saccharopine then undergoes a dehydration reaction, catalysed by SDH in the presence of NAD+, to produce AAS and glutamate. AAS dehydrogenase then further dehydrates the molecule into AAA. 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. Some evidence suggests that the 2-oxoadipate dehydrogenase complex, which is structurally homologous to the E1 subunit of the oxoglutarate dehydrogenase complex , is responsible for the decarboxylation reaction. Finally, glutaryl-CoA is oxidatively decarboxylated to crotonyl-CoA by glutaryl-CoA dehydrogenase, which goes on to be further processed through multiple enzymatic steps to yield acetyl-CoA; an essential carbon metabolite involved in the tricarboxylic acid cycle.Nutritional value
Lysine is an essential amino acid in humans. The human daily nutritional requirement varies from ~60 mg/kg in infancy to ~30 mg/kg in adults. This requirement is commonly met in a western society with the intake of [|lysine from meat and vegetable sources] well in excess of the recommended requirement. In vegetarian diets, the intake of lysine is less due to the limited quantity of lysine in cereal crops compared to meat sources.Given the limiting concentration of lysine in cereal crops, it has long been speculated that the content of lysine can be increased through genetic modification practices. Often these practices have involved the intentional dysregulation of the DAP pathway by means of introducing lysine feedback-insensitive orthologues of the DHDPS enzyme. These methods have met limited success likely due to the toxic side effects of increased free lysine and indirect effects on the TCA cycle. Plants accumulate lysine and other amino acids in the form of seed storage proteins, found within the seeds of the plant, and this represents the edible component of cereal crops. 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. While genetic modification practices have met limited success, more traditional selective breeding techniques have allowed for the isolation of "Quality Protein Maize", which has significantly increased levels of lysine and tryptophan, also an essential amino acid. This increase in lysine content is attributed to an opaque-2 mutation that reduced the transcription of lysine-lacking zein-related seed storage proteins and, as a result, increased the abundance of other proteins that are rich in lysine. Commonly, to overcome the limiting abundance of lysine in livestock feed, industrially produced lysine is added. The industrial process includes the fermentative culturing of Corynebacterium glutamicum and the subsequent purification of lysine.