Endogenous Metabolite from Microbe and Human

L-lysine acetate (VSMCs) prevents apoptosis and mineral precipitation by suppressing plasma iPTH and raising plasma alanine, proline, plasma arginine, and homoarginine [1].

L-lysine acetate (40 μg/kg; oral) improves arterial calcification in adenine rats and protects femurs against osteoporotic alterations in adenine rats [1]. L-lysine acetate (10 and 400 mg/kg; ig and po; male mice) prevents pancreatic tissue damage [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.[1]

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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.
Results: 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.[2]

Animal/Disease Models: Male mice [2]
Doses: 10 and 400 mg/kg
Route of Administration: intraperitoneal (ip) injection and oral administration; 15 days.
Experimental Results: Inhibited the release of inflammatory cytokine IL-6 and enhanced antioxidant activity.

Absorption, Distribution and Excretion
Absorption
Absorbed from the lumen of the small intestine into the enterocytes by an active transport process

Although the free amino acids dissolved in the body fluids are only a very small proportion of the body's total mass of amino acids, they are very important for the nutritional and metabolic control of the body's proteins. ... Although the plasma compartment is most easily sampled, the concentration of most amino acids is higher in tissue intracellular pools. Typically, large neutral amino acids, such as leucine and phenylalanine, are essentially in equilibrium with the plasma. Others, notably glutamine, glutamic acid, and glycine, are 10- to 50-fold more concentrated in the intracellular pool. Dietary variations or pathological conditions can result in substantial changes in the concentrations of the individual free amino acids in both the plasma and tissue pools. /Amino acids/

After ingestion, proteins are denatured by the acid in the stomach, where they are also cleaved into smaller peptides by the enzyme pepsin, which is activated by the increase in stomach acidity that occurs on feeding. The proteins and peptides then pass into the small intestine, where the peptide bonds are hydrolyzed by a variety of enzymes. These bond-specific enzymes originate in the pancreas and include trypsin, chymotrypsins, elastase, and carboxypeptidases. The resultant mixture of free amino acids and small peptides is then transported into the mucosal cells by a number of carrier systems for specific amino acids and for di- and tri-peptides, each specific for a limited range of peptide substrates. After intracellular hydrolysis of the absorbed peptides, the free amino acids are then secreted into the portal blood by other specific carrier systems in the mucosal cell or are further metabolized within the cell itself. Absorbed amino acids pass into the liver, where a portion of the amino acids are taken up and used; the remainder pass through into the systemic circulation and are utilized by the peripheral tissues. /Amino acids/

Protein secretion into the intestine continues even under conditions of protein-free feeding, and fecal nitrogen losses (ie, nitrogen lost as bacteria in the feces) may account for 25% of the obligatory loss of nitrogen. Under this dietary circumstance, the amino acids secreted into the intestine as components of proteolytic enzymes and from sloughed mucosal cells are the only sources of amino acids for the maintenance of the intestinal bacterial biomass. ... Other routes of loss of intact amino acids are via the urine and through skin and hair loss. These losses are small by comparison with those described above, but nonetheless may have a significant impact on estimates of requirements, especially in disease states. /Amino acids/

About 11 to 15 g of nitrogen are excreted each day in the urine of a healthy adult consuming 70 to 100 g of protein, mostly in the form of urea, with smaller contributions from ammonia, uric acid, creatinine, and some free amino acids. These are the end products of protein metabolism, with urea and ammonia arising from the partial oxidation of amino acids. Uric acid and creatinine are indirectly derived from amino acids as well. The removal of nitrogen from the individual amino acids and its conversion to a form that can be excreted by the kidney can be considered as a two-part process. The first step usually takes place by one of two types of enzymatic reactions: transamination or deamination. Transamination is a reversible reaction that uses ketoacid intermediates of glucose metabolism (e.g., pyruvate, oxaloacetate, and alpha-ketoglutarate) as recipients of the amino nitrogen. Most amino acids can take part in these reactions, with the result that their amino nitrogen is transferred to just three amino acids: alanine from pyruvate, aspartate from oxaloacetate, and glutamate from alpha-ketoglutarate. Unlike many amino acids, branched-chain amino acid transamination occurs throughout the body, particularly in skeletal muscle. Here the main recipients of amino nitrogen are alanine and glutamine (from pyruvate and glutamate, respectively), which then pass into the circulation. These serve as important carriers of nitrogen from the periphery (skeletal muscle) to the intestine and liver. In the small intestine, glutamine is extracted and metabolized to ammonia, alanine, and citrulline, which are then conveyed to the liver via the portal circulation. Nitrogen is also removed from amino acids by deamination reactions, which result in the formation of ammonia. A number of amino acids can be deaminated, either directly (histidine), by dehydration (serine, threonine), by way of the purine nucleotide cycle (aspartate), or by oxidative deamination (glutamate). ... Glutamate is also formed in the specific degradation pathways of arginine and lysine. Thus, nitrogen from any amino acid can be funneled into the two precursors of urea synthesis, ammonia and aspartate. /Amino acids/

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Metabolism / Metabolites
Hepatic
Like other amino acids, the metabolism of free lysine follows two principal paths: protein synthesis and oxidative catabolism. It is required for biosynthesis of such substances as carnitine, collage, and elastin.

Oxidative deamination or transamination of l-lysine /yields/ alpha-keto-epsilon-aminocaproic acid; decarboxylation of l-lysine /yields/ cadaverine. /From table/

Once the amino acid deamination products enter the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle) or the glycolytic pathway, their carbon skeletons are also available for use in biosynthetic pathways, particularly for glucose and fat. Whether glucose or fat is formed from the carbon skeleton of an amino acid depends on its point of entry into these two pathways. If they enter as acetyl-CoA, then only fat or ketone bodies can be formed. The carbon skeletons of other amino acids can, however, enter the pathways in such a way that their carbons can be used for gluconeogenesis. This is the basis for the classical nutritional description of amino acids as either ketogenic or glucogenic (ie, able to give rise to either ketones [or fat] or glucose). Some amino acids produce both products upon degradation and so are considered both ketogenic and glucogenic. /Amino acids/

... Rates of lysine metabolism in fetal sheep during chronic hypoglycemia and following euglycemic recovery /were compared with/ results with normal, age-matched euglycemic control fetuses to explain the adaptive response of protein metabolism to low glucose concentrations. Restriction of the maternal glucose supply to the fetus lowered the net rates of fetal (umbilical) glucose (42%) and lactate (36%) uptake, causing compensatory alterations in fetal lysine metabolism. The plasma lysine concentration was 1.9-fold greater in hypoglycemic compared with control fetuses, but the rate of fetal (umbilical) lysine uptake was not different. In the hypoglycemic fetuses, the lysine disposal rate also was higher than in control fetuses due to greater rates of lysine flux back into the placenta and into fetal tissue. The rate of CO2 excretion from lysine decarboxylation was 2.4-fold higher in hypoglycemic than control fetuses, indicating greater rates of lysine oxidative metabolism during chronic hypoglycemia. No differences were detected for rates of fetal protein accretion or synthesis between hypoglycemic and control groups, although there was a significant increase in the rate of protein breakdown (p < 0.05) in the hypoglycemic fetuses, indicating small changes in each rate. This was supported by elevated muscle specific ubiquitin ligases and greater concentrations of 4E-BP1. Euglycemic recovery after chronic hypoglycemia normalized all fluxes and actually lowered the rate of lysine decarboxylation compared with control fetuses (p < 0.05). These results indicate that chronic hypoglycemia increases net protein breakdown and lysine oxidative metabolism, both of which contribute to slower rates of fetal growth over time. Furthermore, euglycemic correction for 5 days returns lysine fluxes to normal and causes an overcorrection of lysine oxidation.

Toxicity Summary
Proteins of the herpes simplex virus are rich in L-arginine, and tissue culture studies indicate an enhancing effect on viral replication when the amino acid ratio of L-arginine to L-lysine is high in the tissue culture media. When the ratio of L-lysine to L-arginine is high, viral replication and the cytopathogenicity of herpes simplex virus have been found to be inhibited. L-lysine may facilitate the absorption of calcium from the small intestine.

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Health Effects
Chronically high levels of lysine are associated with at least 5 inborn errors of metabolism including: D-2-Hydroxyglutaric Aciduria, Familial Hyperlysinemia I, Hyperlysinemia II, Pyruvate carboxylase deficiency and Saccharopinuria.

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Exposure Routes
Absorbed from the lumen of the small intestine into the enterocytes by an active transport process

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Interactions
Lysine 10 mmol/kq given to mice for 1 to 10 days significantly increased clonic and tonic seizure latencies caused by 60 mg/kg pentylenetetrazol (PTZ). On day 1 the clonic and tonic seizure latencies were increased from 160.4 +/- 26.3 and 828.6 +/- 230.8 s to 286.1 +/- 103.3 and 982.3 +/- 98.6 respectively. Both clonic and tonic seizure latencies increased steadily with additional L-lysine treatment without significant change in survival rate. On day 10, the anticonvulsant effect reached its highest level with a block of tonic seizures and survival rate of 100% without tolerance developing. Acute L-lysine significantly increased the mean clonic latency from 85.8 +/- 5.24 to 128.2 +/- 9.0 s and the mean tonic seizure from 287.2 +/- 58.7 to 313.5 +/- 42.2 s with 80 mg/kg of PTZ. On day 10 of treatment, the anticonvulsant effect of L-lysine was highest, with a significant incr of 155 and 184% in clonic and tonic latencies over control, respectively. After 15 and 20 day treatment, clonic and tonic seizure latencies and survival rate decreased, suggesting development of tolerance ... PMID:8385623

Acute intake of high levels of lysine interferes with dietary protein metabolism and competes with the transport of arginine, suggesting that adverse effects from high levels of lysine are more likely to occur if protein intake or dietary arginine intake is low.

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rat LD50 oral 11400 mg/kg Gekkan Yakuji. Pharmaceuticals Monthly., 23(1253), 1981
rat LD50 intraperitoneal 3700 mg/kg Gekkan Yakuji. Pharmaceuticals Monthly., 23(1253), 1981
rat LD50 subcutaneous 4 gm/kg Iyakuhin Kenkyu. Study of Medical Supplies., 12(933), 1981
rat LD50 intravenous 2850 mg/kg Gekkan Yakuji. Pharmaceuticals Monthly., 23(1253), 1981
mouse LD50 oral 13400 mg/kg Gekkan Yakuji. Pharmaceuticals Monthly., 23(1253), 1981

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

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

An essential amino acid. It is often added to animal feed.

C8H18N2O4

206.2395

206.126

C, 46.59; H, 8.80; N, 13.58; O, 31.03

57282-49-2

L-Lysine;56-87-1;L-Lysine hydrochloride;657-27-2;L-Lysine hydrate;39665-12-8

104152

White to off-white solid powder

441ºC at 760 mmHg

224ºC, decomposes

220.5ºC

1.018

4

6

5

14

137

1

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

RRNJROHIFSLGRA-JEDNCBNOSA-N

InChI=1S/C6H14N2O2.C2H4O2/c7-4-2-1-3-5(8)6(9)10;1-2(3)4/h5H,1-4,7-8H2,(H,9,10);1H3,(H,3,4)/t5-;/m0./s1

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

L-Lysine acetate; 57282-49-2; Lysine acetate; L-LYSINE ACETATE SALT; L-Lysine monoacetate; Lysine monoacetate; 52315-76-1; L-Lysine, acetate (1:1);

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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