Endogenous Metabolite from Microbe and Human

L-lysine is an L-alpha-amino acid; the L-isomer of lysine. It has a role as a micronutrient, a nutraceutical, an anticonvulsant, an Escherichia coli metabolite, a Saccharomyces cerevisiae metabolite, a plant metabolite, a human metabolite, an algal metabolite and a mouse metabolite. It is an aspartate family amino acid, a proteinogenic amino acid, a lysine and a L-alpha-amino acid. It is a conjugate base of a L-lysinium(1+). It is a conjugate acid of a L-lysinate. It is an enantiomer of a D-lysine. It is a tautomer of a L-lysine zwitterion and a L-Lysine zwitterion.
Lysine (abbreviated as Lys or K) is an α-amino acid with the chemical formula HO2CCH(NH2)(CH2)4NH2. This amino acid is an essential amino acid, which means that humans cannot synthesize it. Its codons are AAA and AAG. Lysine is a base, as are arginine and histidine. The ε-amino group acts as a site for hydrogen binding and a general base in catalysis. Common posttranslational modifications include methylation of the ε-amino group, giving methyl-, dimethyl-, and trimethyllysine. The latter occurs in calmodulin. Other posttranslational modifications include acetylation. Collagen contains hydroxylysine which is derived from lysine by lysyl hydroxylase. O-Glycosylation of lysine residues in the endoplasmic reticulum or Golgi apparatus is used to mark certain proteins for secretion from the cell.

Pre- or post-treatment with L-lysine led to significant decreases in the levels of malondialdehyde and nitric oxide, while significant enhancement was observed in the activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and glutathione (p < 0.001). However, the treatment potential of L-lysine was better as a protective agent than a therapeutic agent. Conclusions: L-lysine treatment attenuates pancreatic tissue injury induced by L-arginine by inhibiting the release of the inflammatory cytokine IL-6 and enhance antioxidant activity. These effects may involve upregulation of anti-inflammatory factors and subsequent downregulation of IL6.[1]

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On histopathology with hematoxylin and eosin, mild to moderate hyperplasia transitional was observed in at the site of anastomosis in all animals submitted to cystoplasty (Groups A and B), but "transitional metaplasia" of the intestinal glandular epithelium was more accentuated in Group A (p=0.045). No inflammatory cells, dysplasia or abnormalities were observed. Staining with Alcian blue revealed a substantial reduction of goblet cells and mucins in the colon segment (Groups A and B). Conclusion:: The administration of L-lysine to rats accelerated the development of transitional metaplasia in the epithelium of the colon segment in cystoplasty.[2]

Four groups of mice (10 in each group) were assessed. Group I was the control. Animals in groups II-IV were injected intraperitoneally with L-arginine hydrochloride (400 mg/kg body weight [bw]) for 3 days. Group III animals were orally pre-treated with L-lysine (10 mg/kg bw), whereas group IV animals were orally post-treated with L-lysine (10 mg/kg bw). Serum samples were subjected to amylase, lipase, transaminase, and interleukin-6 (IL-6) assays. The pancreas was excised to measure the levels of malondialdehyde, nitric oxide, catalase, superoxide dismutase, reduced glutathione, and glutathione peroxidase.[1]

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Twenty-eight 9-week-old rats were assigned to 4 groups: Group A (n=8) cystoplasty followed by administration of L-lysine (150 mg/kg body weight by gavage) for 30 weeks; Group B (n=8) cystoplasty + water for 30 weeks; Group C (n=6) L-lysine for 30 weeks; Group D (n=6) water for 30 weeks.[2]

Absorption, Distribution and Excretion
Amino acids are absorbed into intestinal cells from the small intestine via active transport. Although free amino acids dissolved in body fluids constitute only a small fraction of the total amino acids in the body, they are essential for maintaining protein nutrition and metabolism. …While plasma is the easiest site for sampling, most amino acids are found in higher concentrations in intracellular pools. Typically, large neutral amino acids like leucine and phenylalanine are in near-equilibrium with their plasma concentrations. However, some other amino acids, particularly glutamine, glutamate, and glycine, are 10 to 50 times more concentrated in intracellular pools than in plasma. Dietary changes or pathological conditions can lead to significant variations in the concentrations of various free amino acids in plasma and tissue pools. /Amino Acids/ After ingestion, proteins are denatured by gastric acid and cleaved into smaller peptides by pepsin. Pepsin activity increases with the increase in gastric acid after eating. Proteins and peptides then enter the small intestine, where peptide bonds are hydrolyzed by various enzymes. These specific enzymes originate from the pancreas and include trypsin, chymotrypsin, elastase, and carboxypeptidase. The resulting mixture of free amino acids and small peptides is then transported to mucosal cells via various carrier systems. These carrier systems target specific amino acids, dipeptides, and tripeptides, with each system targeting only a limited range of peptide substrates. After the absorbed peptides are hydrolyzed intracellularly, the free amino acids are either secreted into the portal bloodstream via other specific carrier systems within the mucosal cells or further metabolized intracellularly. The absorbed amino acids enter the liver, where some are absorbed and utilized; the remainder enters systemic circulation and is utilized by peripheral tissues. /Amino Acids/
Even on a protein-free diet, protein is still secreted into the intestine, and fecal nitrogen loss (i.e., nitrogen lost in feces as bacteria) can account for up to 25% of essential nitrogen loss. Under these dietary conditions, amino acids secreted into the intestine as components of proteolytic enzymes and those from shed mucosal cells are the only amino acid sources for maintaining intestinal bacterial biomass. …Other pathways of intact amino acid loss include urinary excretion and shedding of skin and hair. These losses are smaller compared to the pathways described above, but can still significantly impact the estimation of requirements, especially in disease states. /Amino Acids/
A healthy adult ingests 70 to 100 grams of protein daily, and excretes approximately 11 to 15 grams of nitrogen in urine, primarily as urea, with smaller amounts excreted as ammonia, uric acid, creatinine, and some free amino acids. These are the final products of protein metabolism, with urea and ammonia originating from the partial oxidation of amino acids. Uric acid and creatinine also indirectly originate from amino acids. Removing nitrogen from amino acids and converting it into a form that can be excreted through the kidneys can be viewed as a two-step process. The first step is typically accomplished through one of two enzymatic reactions: transamination or deamination. Transamination is a reversible reaction that utilizes ketoacid intermediates from glucose metabolism (such as pyruvate, oxaloacetate, and α-ketoglutarate) as acceptors of amino nitrogen. Most amino acids can participate in these reactions, resulting in the transfer of amino nitrogen to only three amino acids: pyruvate to alanine, oxaloacetate to aspartic acid, and α-ketoglutarate to glutamate. Unlike many amino acids, transamination of branched-chain amino acids occurs throughout the body, particularly in skeletal muscle. Here, the main acceptors of amino nitrogen are alanine and glutamine (derived from pyruvate and glutamate, respectively), which then enter the bloodstream. These amino acids act as important carriers, transporting nitrogen from the periphery (skeletal muscle) to the intestines and liver. In the small intestine, glutamine is extracted and metabolized into ammonia, alanine, and citrulline, which are then transported to the liver via the portal vein circulation. Nitrogen can also be removed from amino acids via deamination, a reaction that generates ammonia. Many amino acids can undergo deamination, including direct deamination (histidine), dehydration deamination (serine, threonine), deamination via the purine nucleotide cycle (aspartate), and oxidative deamination (glutamate). ...Glutamate is also a product of specific degradation pathways of arginine and lysine. Therefore, nitrogen in any amino acid can be converted into two precursors for urea synthesis—ammonia and aspartate. /Amino Acids/
For more complete data on the absorption, distribution, and excretion of L-lysine (7 types), please visit the HSDB record page.

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Metabolism/Metabolites
Liver
Like other amino acids, the metabolism of free lysine mainly follows two pathways: protein synthesis and oxidative catabolism. It is essential for the biosynthesis of substances such as carnitine, collagen, and elastin.
Oxidative deamination or transamination of L-lysine produces α-keto-ε-aminocaproic acid; decarboxylation of L-lysine produces cadaverine. (Data from table)
Once the deamination products of amino acids enter the tricarboxylic acid cycle (TCA cycle, also known as the citric acid cycle or Krebs cycle) or glycolysis, their carbon skeletons are available for biosynthetic pathways, particularly the synthesis of glucose and fats. Whether the carbon skeleton of an amino acid ultimately produces glucose or fat depends on the route it enters through these two pathways. If it enters in the form of acetyl-CoA, only fat or ketone bodies can be produced. However, the carbon skeletons of other amino acids can enter these pathways in some way, making their carbon atoms available for gluconeogenesis. This is the basis of the classical nutritional description of amino acids, which classifies amino acids into ketogenic amino acids and glucogenic amino acids (i.e., those capable of producing ketone bodies [or fats] or glucose). Some amino acids produce both ketogenic and glucogenic products during degradation and are therefore considered ketogenic and glucogenic amino acids. To explain the adaptive response of protein metabolism to low blood glucose concentrations, we compared the rate of lysine metabolism in fetal sheep during chronic hypoglycemia and after blood glucose normalization with that in normal, age-matched, blood glucose-normal control fetal sheep. Restricting maternal glucose supply to the fetus reduced the net uptake of fetal (umbilical cord) glucose (42%) and lactate (36%), leading to compensatory changes in fetal lysine metabolism. Plasma lysine concentrations in hypoglycemic fetal sheep were 1.9 times higher than in control fetal sheep, but there was no difference in fetal (umbilical cord) lysine uptake. Lysine clearance was also higher in hypoglycemic fetuses than in control fetuses, due to a higher rate of lysine reflux to the placenta and fetal tissues. The rate of carbon dioxide expulsion from lysine decarboxylation in hypoglycemic fetuses was 2.4 times higher than in control fetuses, indicating a higher rate of lysine oxidative metabolism during chronic hypoglycemia. Although the rate of protein breakdown was significantly increased in hypoglycemic fetuses (p < 0.05), no difference was observed in the rates of fetal protein accumulation or synthesis between the hypoglycemic and control groups, indicating minimal variation in these rates. Elevated levels of muscle-specific ubiquitin ligases and increased 4E-BP1 concentrations further supported this finding. Following chronic hypoglycemia, blood glucose returned to normal, all metabolic fluxes normalized, and the rate of lysine decarboxylation was actually reduced compared to the control group (p < 0.05). These results suggest that chronic hypoglycemia increases net protein breakdown and lysine oxidation metabolism, both of which contribute to a slowing of fetal growth over time. Furthermore, lysine flux returned to normal 5 days after normoglycemic correction, but this resulted in excessive correction of lysine oxidation.
Liver

Toxicity Summary
Herpes simplex virus (HSV) proteins are rich in L-arginine. Tissue culture studies have shown that viral replication is enhanced when the amino acid ratio of L-arginine to L-lysine in the tissue culture medium is high. A higher L-lysine to L-arginine ratio inhibits both HSV replication and cytopathic effects. L-lysine may promote calcium absorption in the small intestine.

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Health Effects
Long-term high levels of lysine are associated with at least five innate metabolic disorders, including: D-2-hydroxyglutarateuria, familial hyperlysinemia type I, hyperlysinemia type II, pyruvate carboxylase deficiency, and saccharinuria.

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Exposed Routes
Absorbed into intestinal cells via active transport from the small intestine.

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Interactions
Administration of 10 mmol/kg lysine to mice for 1 to 10 days significantly prolonged the latency of clonic and tonic seizures induced by 60 mg/kg pentylenetetrazole (PTZ). On day 1, the latency of clonic and tonic seizures increased from 160.4 ± 26.3 seconds and 828.6 ± 230.8 seconds to 286.1 ± 103.3 seconds and 982.3 ± 98.6 seconds, respectively. With increasing L-lysine treatment dose, the latency of both clonic and tonic seizures continued to prolong, but survival rates did not change significantly. On day 10, the anticonvulsant effect reached its peak, with tonic seizures completely blocked, a survival rate of 100%, and no tolerance developed. Acute L-lysine treatment significantly prolonged the mean latency of clonic seizures (from 85.8 ± 5.24 seconds to 128.2 ± 9.0 seconds) and the mean latency of tonic seizures (from 287.2 ± 58.7 seconds to 313.5 ± 42.2 seconds), concurrently with 80 mg/kg pentylenetetrazol. On day 10 of treatment, L-lysine exhibited the strongest anticonvulsant effect, with the latency of clonic and tonic seizures significantly prolonged by 155% and 184%, respectively, compared to the control group. After 15 and 20 days of treatment, the latency of clonic seizures, the latency of tonic seizures, and the survival rate all decreased, suggesting the development of tolerance...PMID:8385623
Acute intake of high doses of lysine interferes with dietary protein metabolism and competes with arginine for transport, suggesting that if protein intake or dietary arginine intake is low, high doses of lysine are more likely to produce adverse reactions.

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Rat intraperitoneal injection LD50: 11400 mg/kgt, Monthly Pharmacy, 23(1253), 1981
Rat intraperitoneal injection LD50: 3700 mg/kgt, Monthly Pharmacy, 23(1253), 1981, Medical Monthly, 23(1253), 1981
Rat subcutaneous injection LD50: 4 g/kg. Medical Research, 12(933), 1981
Rat intravenous injection LD50: 2850 mg/kg. Monthly Journal of Medicine, 23(1253), 1981
Oral LD50 in mice: 13400 mg/kg. Monthly Journal of Medicine, 23(1253), 1981
Interaction

Administration of 10 mmol/kg lysine to mice for 1 to 10 days significantly prolonged the latency of clonic and tonic seizures induced by 60 mg/kg pentylenetetrazole (PTZ). On day 1, the latency of clonic and tonic seizures increased from 160.4 ± 26.3 seconds and 828.6 ± 230.8 seconds to 286.1 ± 103.3 seconds and 982.3 ± 98.6 seconds, respectively. With increasing L-lysine treatment dose, the latency of both clonic and tonic seizures continued to prolong, but survival rate did not change significantly. On day 10, the anticonvulsant effect reached its peak, with tonic seizures completely blocked, a survival rate of 100%, and no tolerance observed. Acute L-lysine treatment significantly prolonged the mean latency of clonic seizures (from 85.8 ± 5.24 seconds to 128.2 ± 9.0 seconds) and the mean latency of tonic seizures (from 287.2 ± 58.7 seconds to 313.5 ± 42.2 seconds), concurrently with 80 mg/kg pentylenetetrazole. On day 10 of treatment, L-lysine exhibited the strongest anticonvulsant effect, with the latency of clonic and tonic seizures significantly prolonged by 155% and 184%, respectively, compared to the control group. After 15 and 20 days of treatment, the latency of clonic seizures, the latency of tonic seizures, and survival rates all decreased, suggesting the development of tolerance…
Acute intake of high-dose lysine interferes with dietary protein metabolism and competes with arginine for transport, suggesting that adverse effects of high-dose lysine are more likely to occur if protein intake or dietary arginine intake is low.
Intravenous injection of L-lysine (16.5 to 41.3 g daily in young men) has been shown to inhibit renal tubular protein reabsorption. L-lysine shares an intestinal transport system with L-arginine and competes with L-arginine for renal tubular reabsorption.
Feeding rats with 5% L-lysine and 15% casein for two weeks increased the concentrations of total lipids, triglycerides, and cholesterol in the liver, while arginine supplementation reversed this effect.
…This study aimed to investigate the effects of acute and repeated administration of L-lysine to inhibit L-arginine transport on phencyclidine (PCP)-induced PPI disorders in mice. Results: Subchronic (and to some extent acute) L-lysine pretreatment blocked PCP-induced PPI deficiency without affecting basal PPI. Conclusion: In vitro experiments showed that L-lysine can block L-arginine transport, likely through competitive blocking and downregulation of cationic amino acid transporters. However, the importance of L-arginine transport as a regulatory mechanism for NO production in vivo remains unclear. These results further support the view that some roles of PCP in the central nervous system are mediated by NO, and that L-arginine transport may play a role in the regulation of NO production in the brain.

[1].Suppression of acute pancreatitis by L-lysine in mice. BMC Complement Altern Med. 2015 Jun 23;15:193.

[2].Transitional metaplasia in intestinal epithelium of rats submitted to intestinal cystoplasty and treatment with L -lysine. Acta Cir Bras. 2017 Apr;32(4):297-306.

Therapeutic Uses
Lysine appears to have antiviral, anti-osteoporosis, cardiovascular, and lipid-lowering effects, but more controlled human studies are needed. Unproven Uses: The most common use of lysine supplementation is for the prevention and treatment of herpes simplex virus infection. Lysine has been used in combination with calcium for the prevention and treatment of osteoporosis. It has also been used to treat pain, mouth ulcers, migraines, rheumatoid arthritis, and opioid withdrawal symptoms. Many bodybuilding formulas contain lysine to aid muscle repair. /Experimental Therapy/ A major cause of mobility impairment in older adults is the gradual and persistent loss of lean body mass… A double-blind, controlled study recruited 39 older women (76 ± 1.6 years) and 38 older men. Study participants were randomly assigned to either an isonitrogenous control supplement group (n = 37) or a therapeutic supplement group (HMB/Arg/Lys, consisting of β-hydroxy-β-methylbutyrate, L-arginine, and L-lysine, n = 40) for a one-year study… In subjects taking the HMB/Arg/Lys supplement, lean tissue increased during the one-year study period, while no change was observed in the control group… A one-year study suggests that ingestion of a simple amino acid mixture can increase protein turnover and lean tissue in older adults. In 27 Finnish patients with lysine-induced proteinuria (LPI), dietary supplementation with low-dose oral lysine improved fasting plasma lysine concentrations without causing hyperammonemia or other identifiable side effects during a 12-month follow-up period. In conclusion, low-dose oral lysine supplementation may be beneficial for patients with LPI and can be safely started early. Drug Warning: Patients with hypercholesterolemia should be aware that animal studies have shown an association between lysine supplementation and elevated cholesterol levels. However, other studies have shown that lysine can also lower cholesterol levels. Adverse reactions: There have been reports of renal impairment (including Fanconi syndrome and renal failure). A premature infant with respiratory distress was given L-lysine ibuprofen to induce patent ductus arteriosus closure, resulting in pulmonary hypertension. Previously, only three cases of pulmonary hypertension due to early use of tromethorphan-buffered ibuprofen solution had been reported. However, this serious side effect has never been observed in multicenter, randomized, double-blind controlled trials or in recent reviews or meta-analyses on the use of lysine ibuprofen. Pharmacodynamics: Ensures adequate calcium absorption; helps form collagen (which makes up bones, cartilage, and connective tissue); assists in the production of antibodies, hormones, and enzymes. Recent studies suggest that lysine may be effective against herpes by improving nutritional balance that reduces viral growth. Lysine deficiency may lead to fatigue, poor concentration, irritability, conjunctivitis, growth retardation, hair loss, anemia, and reproductive problems.

C6H14N2O2

146.1876

146.105

56-87-1

L-Lysine-13C6 dihydrochloride;201740-81-0;L-Lysine hydrochloride;657-27-2;L-Lysine hydrate;39665-12-8;L-Lysine orotate;28003-86-3;L-Lysine-d3 hydrochloride;2330878-43-6;L-Lysine-15N-1 dihydrochloride;L-Lysine acetate;57282-49-2

5962

Off-white to yellow solid powder

1.1±0.1 g/cm3

311.5±32.0 °C at 760 mmHg

215 °C (dec.)(lit.)

142.2±25.1 °C

0.0±1.4 mmHg at 25°C

1.503

-1.04

3

4

5

10

106

1

C(CCN)C[C@@H](C(=O)O)N

KDXKERNSBIXSRK-YFKPBYRVSA-N

InChI=1S/C6H14N2O2/c7-4-2-1-3-5(8)6(9)10/h5H,1-4,7-8H2,(H,9,10)/t5-/m0/s1

(2S)-2,6-diaminohexanoic acid

L-lysine; lysine; 56-87-1; h-Lys-oh; lysine acid; (S)-Lysine; (2S)-2,6-diaminohexanoic acid; Aminutrin;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~100 mg/mL (~684.04 mM)
DMSO :< 1 mg/mL

Solubility in Formulation 1: ≥ 100 mg/mL (684.04 mM) (saturation unknown) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)