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.

Treatment with L-lysine reduces pancreatic tissue damage caused by L-arginine and increases antioxidant activity by preventing the release of IL-6, an inflammatory cytokine. Malondialdehyde and nitric oxide levels were dramatically decreased by L-lysine either before or after treatment, while glutathione activity and antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) were significantly increased [1]. Vascular calcification was nearly entirely alleviated by L-lysine supplementation. In adenine rats, dietary L-lysine significantly suppresses plasma intact parathyroid hormone while promoting a healthy osteovascular axis. The Lys group's preserved orientation of femoral apatite further supports L-lysine's osteoprotective properties. In contrast to lysine, dietary L-lysine raises plasma levels of proline, arginine, homoarginine, and alanine [2]. With an enhanced gastric emptying half-life of 4 min/g L-lysine, the dose-dependent delay in gastric emptying seen in rats was also observed in people. Moreover, an increase in intestinal fluid buildup that was dose-dependent (0.4 mL/min/g L-lysine) was noted [3].

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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L-lysine doses from 0-800 mg in rats and 0.5-7.5 g in humans were analyzed for their effect on gastric emptying and GI secretion. Human GI function was assessed non-invasively using magnetic resonance imaging (MRI), rat data were acquired using standard lethal measurement methods. L-lysine dose dependently delayed gastric emptying and stimulated GI secretion in rats as reflected by residual phenol red content and increased gastric wet weight.[2]

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Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary l-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+l-lysine·HCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. l-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary l-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of l-lysine. Dietary l-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/phosphate solution. In conclusion, dietary supplementation of l-lysine ameliorated VC by modifying key pathways that exacerbate VC.[3]

Absorption, Distribution, and Excretion
Absorption
Absorbed by intestinal cells from the lumen of 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 the nutrition and metabolism of proteins. …Although plasma is the easiest to sample, most amino acids are in higher concentrations in the intracellular pools of tissue cells. 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 higher in the intracellular pools than in plasma. Dietary changes or pathological conditions can cause significant changes 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, as well as 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 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 the 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 amino acids from shed mucosal cells are the only amino acid sources for maintaining intestinal bacterial biomass. …Other pathways for the loss of intact amino acids include urinary excretion and shedding of skin and hair. Compared to the pathways described above, these losses are smaller, 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 as ammonia, uric acid, creatinine, and some free amino acids. These are the final products of protein metabolism, with urea and ammonia derived 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 by 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, especially 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, which produces ammonia. Many amino acids can be deaminated, 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/

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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. Lysine 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 can be used 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 pathway it enters. If it enters as 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 classification of amino acids, which divides them into ketogenic amino acids and glucogenic amino acids (i.e., those that can produce ketone bodies [or fats] or glucose). Some amino acids produce both products during degradation and are therefore considered ketogenic and glucogenic amino acids. /Amino Acids/
…To explain the adaptive response of protein metabolism to low blood glucose concentrations, we compared the lysine metabolism rate of fetal sheep during chronic hypoglycemia and after blood glucose returned to normal with that of normal-aged, age-matched control fetal sheep. Restriction of maternal glucose supply to the fetus reduced the net uptake of glucose (42%) and lactate (36%) by the fetus (umbilical cord), 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 fetal sheep than in control fetal sheep due to greater lysine reflux into the placenta and fetal tissues. The rate of carbon dioxide expulsion from lysine decarboxylation in hypoglycemic fetuses was 2.4 times that in the control group, 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), there was no difference in the rates of fetal protein accumulation or synthesis between the hypoglycemic and control groups, indicating minimal changes in these rates. Elevated levels of muscle-specific ubiquitin ligases and increased 4E-BP1 concentrations also support these findings. Following chronic hypoglycemia, blood glucose returned to normal, all metabolic fluxes normalized, and the rate of lysine decarboxylation was significantly lower in fetuses compared to the control group (p < 0.05). These results indicate that chronic hypoglycemia increases net protein breakdown and lysine oxidation metabolism, both of which contribute to a slowing of fetal growth rate over time. Furthermore, lysine flux returned to normal 5 days after normoglycemic correction, leading to excessive correction of lysine oxidation.

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

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

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Route of Exposure
Absorption into intestinal cells via active transport from the small intestinal lumen.

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Interactions
Administration of 10 mmol/kg lysine to mice for 1 to 10 days significantly prolonged the latency of pentylenetetrazole (PTZ, 60 mg/kg)-induced clonic and tonic seizures. On day 1, the clonic and tonic seizure latency periods increased from 160.4 ± 26.3 s and 828.6 ± 230.8 s to 286.1 ± 103.3 s and 982.3 ± 98.6 s, respectively. With increasing lysine dosage, the clonic and tonic seizure latency periods continued to prolong, while survival rates remained largely unchanged. On day 10, the anticonvulsant effect was optimal, tonic seizures were completely blocked, survival reached 100%, and no tolerance was observed. Acute L-lysine significantly prolonged the mean clonic latency period (from 85.8 ± 5.24 seconds to 128.2 ± 9.0 seconds) and the mean tonic seizure latency period (from 287.2 ± 58.7 seconds to 313.5 ± 42.2 seconds, compared to the 80 mg/kg pentylenetetrazole group). On day 10 of treatment, L-lysine showed the most significant anticonvulsant effect, with clonic latency and tonic seizure latency significantly prolonged by 155% and 184% respectively compared to the control group. After 15 and 20 days of treatment, the latency and survival rate of clonic and tonic epilepsy decreased, indicating the development of tolerance... PMID:8385623
Acute intake of high levels of lysine interferes with dietary protein metabolism and competes with arginine for transport, suggesting that adverse reactions to high levels of lysine are more likely to occur if protein intake or dietary arginine intake is low.

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Oral LD50 in rats: 11400 mg/kg, Monthly Pharmacy, 23(1253), 1981
Intraperitoneal LD50 in rats: 3700 mg/kg, Monthly Pharmacy, 23(1253), 1981
Subcutaneous LD50 in rats: 4 gm/kg, Drug Research. Medical Supplies Research, 12(933), 1981
Rat intravenous LD50 2850 mg/kg, Monthly Pharmacy, 23(1253), 1981
Mice oral LD50 13400 mg/kg, Monthly Pharmacy, 23(1253), 1981

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

[2]. L-lysine dose dependently delays gastric emptying and increases intestinal fluid volume in humans and rats. Neurogastroenterol Motil. 2014 Jul;26(7):999-1009.

[3]. Dietary L-lysineprevents arterial calcification in adenine-induced uremic rats. J Am Soc Nephrol. 2014 Sep;25(9):1954-65.

L-Lysine hydrochloride is the hydrochloride salt of L-lysine and contains L-lysine. L-lysine is an essential amino acid and is often added to animal feed. See also: Lysine (with active moiety)... See more...

C6H15CLN2O2

182.64

182.082

C, 39.46; H, 8.28; Cl, 19.41; N, 15.34; O, 17.52

657-27-2

L-Lysine;56-87-1;L-Lysine-15N2 hydrochloride;1217460-44-0;L-Lysine-13C6,15N2 hydrochloride;1200447-00-2;L-Lysine-d9 hydrochloride;2708343-64-8;L-Lysine-d4 hydrochloride;284664-96-6;L-Lysine hydrate;39665-12-8;L-Lysine-13C6,15N2,d9 dihydrochloride;1994268-57-3;L-Lysine-13C dihydrochloride;202190-50-9;L-Lysine-d8 hydrochloride;344298-93-7;L-Lysine-13C6 hydrochloride;1228077-86-8;L-Lysine acetate;57282-49-2

69568

White to off-white solid powder

311.5ºC at 760 mmHg

263 °C (dec.)(lit.)

142.2ºC

1.729

4

4

5

11

106

1

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

BVHLGVCQOALMSV-JEDNCBNOSA-N

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

(2S)-2,6-diaminohexanoic acid;hydrochloride

Lysine HCl; L-Lysine monohydrochloride; L-Lysine hydrochloride; 657-27-2; L-Lysine monohydrochloride; L-Lysine, monohydrochloride; lysine hydrochloride; Lyamine; 10098-89-2; H-Lys-OH.HCl; Lysine hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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 (~547.50 mM)
DMSO :< 1 mg/mL

Solubility in Formulation 1: 50 mg/mL (273.75 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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