Absorption, Distribution and Excretion
Although free amino acids dissolved in body fluids constitute only a tiny fraction of the total amino acids in the body, they are crucial for the nutritional and metabolic regulation of proteins. …While plasma is the easiest site for sampling, most amino acids are found 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 more concentrated in the 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, each targeting specific amino acids, dipeptides, and tripeptides, specifically transporting a limited range of peptide substrates. After intracellular hydrolysis of the absorbed peptides, 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/ In healthy adults, after consuming 70 to 100 grams of protein daily, approximately 11 to 15 grams of nitrogen are excreted in the 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 derived from the partial oxidation of amino acids. Uric acid and creatinine also indirectly originate from amino acids. The removal of nitrogen from amino acids and its conversion into a form 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, particularly in skeletal muscle. Here, the main acceptors of amino nitrogen are alanine and glutamine (derived from pyruvate and glutamate, respectively), which subsequently 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 produces ammonia. Many amino acids can be deaminated in multiple ways, including direct deamination (histidine), dehydration deamination (serine, threonine), deamination via the purine nucleotide cycle (aspartic acid), and oxidative deamination (glutamate). Glutamate is also present in specific degradation pathways of arginine and lysine. Therefore, nitrogen in any amino acid can be converted into two precursors for urea synthesis—ammonia and aspartic acid. Although the digestibility of dietary protein (i.e., the efficiency of amino acid removal from the small intestinal lumen) appears high, there is ample evidence that visceral tissues, including intestinal mucosal cells, also metabolize large amounts of nutritionally valuable essential amino acids. Therefore, less than 100% of the amino acids cleared from the intestinal lumen enter the peripheral circulation, and the amount of amino acids metabolized in the visceral circulation varies, with the intestine being particularly active in the metabolism of threonine. For more complete data on the absorption, distribution, and excretion of L-threonine (one of 12 amino acids), please visit the HSDB record page.

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Metabolism / Metabolites
Liver evidence suggests that excess threonine is converted into carbohydrates, liver fat, and carbon dioxide. L-threonine is an important neutral amino acid and is indispensable. …L-threonine does not participate in transamination reactions. 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 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 for the classical nutritional classification of amino acids into ketogenic and glucogenic amino acids (i.e., those capable of producing ketone bodies [or fats] or glucose). Some amino acids degrade to produce both ketogenic and glucogenic products, and are therefore considered to have both ketogenic and glucogenic effects. The threonine dehydrogenase (TDG) pathway is an important pathway for threonine degradation, producing glycine in experimental animals, but its precise quantification in humans has not yet been achieved. Therefore, this study investigated the effects of dietary threonine (in the form of free amino acids (+Thr) or protein components (+P-Thr)) on the catabolism of threonine to CO₂ and glycine in six healthy adult men using a 4-hour continuous infusion of L-[1-(13)C]threonine and [(15)N]glycine. The [(13)C]glycine produced from labeled threonine was determined using gas chromatography-combustion isotope ratio mass spectrometry. Compared with the control group, the +Thr and +P-Thr diet groups had significantly higher threonine intakes (126, 126, and 50 μmol·kg⁻¹·h⁻¹, respectively, SD 8, P < 0.0001). The amount of threonine oxidized to CO₂ in the +Thr and +P-Thr diet groups was three times that of the control group (49, 45, and 15 μmol·kg⁻¹·h⁻¹, respectively, SD 6, P < 0.0001). The amount of threonine converted to glycine in the +Thr and +P-Thr diet groups also tended to be higher than in the control group (3.5, 3.4, and 1.6 μmol·kg⁻¹·h⁻¹, respectively, SD 1.3, P = 0.06). The TDG pathway accounts for only 7–11% of total threonine catabolism and is therefore a minor pathway in adults. For more complete metabolite/metabolite data on L-threonine (8 metabolites in total), please visit the HSDB record page. Liver

Toxicity Summary
It is safe at the current usage and concentration. Ingredient, concentration, and usage information can be found at: https://cir-reports.cir-safety.org
L-Threonine is a precursor to the amino acids glycine and serine. It has lipophilic properties and can control fat accumulation in the liver. It may help combat mental illness and is very beneficial for indigestion and intestinal dysfunction. Furthermore, threonine can prevent excessive liver fat. Nutrients are more easily absorbed when threonine is present in the body.

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Interactions
In rats with nephritis but without severe protein malnutrition, a low-casein (8.5%) diet supplemented with methionine-threonine (8.5CMT) alleviated symptoms such as proteinuria. This study aimed to investigate whether adding L-arginine to an 8.5CMT diet exacerbated proteinuria and other symptoms in rats with nephritis. Male Wistar rats were induced to develop glomerulonephritis by a single intravenous injection of nephrotoxic serum, and subsequently fed a 20% casein diet (control group), an 8.5% casein diet, an 8.5CMT diet, or an 8.5CMT diet supplemented with L-arginine (8.5CMTA) for 16 days. Compared to the 8.5CMT diet, the 8.5CMTA diet exacerbated proteinuria and glomerulonephritis. Adding the nitric oxide synthase inhibitor LN(G)-nitroarginine methyl ester to the drinking water of rats fed 8.5CMTA for 14 days eliminated the adverse effects of L-arginine on proteinuria and glomerular histopathological damage. These results indicate that L-arginine supplementation exacerbates glomerulonephritis by promoting nitric oxide production. Rats fed a low-protein diet and orally administered 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione (NTBC) at a dose of 30 μmol/kg/day (i.e., 10 mg/kg/day) or a low-protein diet containing 5 ppm NTBC developed corneal lesions within 3–8 days post-exposure, with an incidence of approximately 80%. This therapy also significantly inhibited 4-hydroxyphenylpyruvate dioxygenase (HPPD) activity in the liver and kidneys, induced tyrosine aminotransferase activity in the liver but not the kidneys, and caused significant tyrosinemia in plasma and aqueous humor. The degree of tyrosinemia and changes in tyrosine catabolic enzyme activity were similar to those reported in rats fed a normal protein diet and orally administered NTBC at a dose of 30 μmol/kg/day. However, corneal damage appeared earlier in rats fed a low-protein diet. Supplementing a low-protein diet with 1% (w/w) threonine can alleviate the adverse ocular effects of NTBC. The protective effect provided by dietary threonine supplementation is not due to improved hepatic HPPD activity inhibition or a decrease in tyrosinemia measured 8 days after treatment. In rats on a low-protein diet supplemented with 5% (w/w) L-tyrosine, corneal damage rapidly develops, accompanied by significant tyrosinemia, elevated hepatic tyrosine aminotransferase activity, and approximately 50% reduction in hepatic HPPD activity. Supplementing a low-protein diet with 1% (w/w) threonine can delay the onset of corneal damage induced by a high-tyrosine diet, but cannot completely prevent it. The mechanism by which dietary threonine supplementation alleviates NTBC-induced corneal damage remains unclear. However, our results suggest that protein deficiency limits the rats' ability to respond to HPPD-induced tyrosine overload.

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Non-Human Toxicity Values
The intraperitoneal LD50 in rats was 3098 mg/kg.

[1]. Increasing L-threonine production in Escherichia coli by engineering the glyoxylate shunt and the L-threonine biosynthesis pathway. Appl Microbiol Biotechnol. 2018 Jul;102(13):5505-5518.

L-Threonine is an optically active form of threonine, possessing the L-configuration. It is a micronutrient, a nutritional supplement, and a metabolite found in mice, Saccharomyces cerevisiae, plants, Escherichia coli, humans, and algae. It is an L-α-amino acid, belonging to the aspartic acid family, and is a protein-synthesizing amino acid. It is the conjugate base of L-threonium, the conjugate acid of L-threonine, an enantiomer of D-threonine, and a zwitterion of L-threonine. It is an essential amino acid, naturally occurring in its L-form, which is its active form. It is found in eggs, milk, gelatin, and other proteins. L-Threonine is a metabolite discovered or produced by Escherichia coli (K12 strain, MG1655 strain). L-Threonine has also been reported in Euphorbia, Angelica sinensis, and other organisms with relevant data. Threonine is an essential amino acid for the human body (primarily obtained through food) and a crucial component of many proteins, such as tooth enamel, collagen, and elastin. It is also an important amino acid for the nervous system, plays a vital role in porphyrin and lipid metabolism, and helps prevent fat accumulation in the liver. Threonine has been used to treat intestinal disorders and indigestion, and has also been used to alleviate anxiety and mild depression. (NCI04) Threonine is an essential amino acid abundant in human plasma, especially in newborns. Severe threonine deficiency in laboratory animals can lead to neurological dysfunction and lameness. Threonine is an immunostimulant that promotes thymus growth and may enhance cellular immune defense. This amino acid has shown significant efficacy in treating hereditary spastic disorders and multiple sclerosis, with a daily dose of 1 gram. It is abundant in meat products, cheese, and wheat germ. Most commercially available infant formulas currently contain approximately 20% more threonine than breast milk. Due to this high threonine content, premature infants fed these formulas have nearly twice the threonine concentration in their plasma compared to breastfed infants. The whey protein used in infant formula is sweet whey protein, a byproduct of cheese production. In mammals, the catabolism of threonine is primarily (70-80%) attributed to the activity of threonine dehydrogenase (EC 1.1.1.103), which oxidizes threonine to 2-amino-3-oxobutyrate, which produces glycine and acetyl-CoA; while threonine dehydratase (EC 4.2.1.16) breaks down threonine into 2-oxobutyrate and ammonia, but its activity is significantly lower. Elevated plasma threonine concentrations lead to the accumulation of threonine and glycine in the brain. This accumulation can affect neurotransmitter balance, potentially impacting early postnatal brain development. Therefore, excessive threonine intake should be avoided during infant feeding. (A3450) L-threonine is a metabolite found or produced in Saccharomyces cerevisiae. It is an essential amino acid, naturally occurring, in its L-form (active form). It is found in eggs, milk, gelatin, and other proteins. See also: D,L-threonine (note moved here).

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Drug Indication
L-Threonine is a component of collagen, elastin, and enamel. It helps the liver metabolize fat normally, aids in the smooth functioning of the digestive tract and intestines, and assists in metabolism and absorption.

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Mechanism of Action
L-Threonine is a precursor to the amino acids glycine and serine. As a lipophile, it can control fat accumulation in the liver. It may help combat mental illness and is very beneficial for indigestion and bowel disorders. Furthermore, threonine can prevent excessive liver fat. Nutrients are more easily absorbed when threonine is present in the body. Amino acids are selected for protein synthesis by binding to transfer RNA (tRNA) in the cytoplasm. The amino acid sequence information of each protein is contained in the nucleotide sequence of messenger RNA (mRNA) molecules, which are synthesized from DNA fragments in the cell nucleus through transcription. The mRNA molecules then interact with various tRNA molecules attached to specific amino acids in the cytoplasm, synthesizing specific proteins by linking individual amino acids together; this process is called translation and is regulated by amino acids (such as leucine) and hormones. Which specific proteins are expressed in a particular cell and the rate of synthesis of different cellular proteins depends on the relative abundance of different mRNAs and the availability of specific tRNA-amino acid combinations, which in turn depends on the transcription rate and the stability of the mRNA. From a nutritional and metabolic perspective, it is important to recognize that protein synthesis is a continuous process that occurs in most cells of the body. At steady state, when there is neither net growth nor net loss, protein synthesis and an equal amount of protein degradation are in equilibrium. Insufficient protein intake, or a diet with low or absent levels of certain essential amino acids (often called limiting amino acids) relative to others, primarily disrupts this equilibrium, leading to a decrease in the rate of synthesis of certain proteins while protein degradation continues to provide an endogenous source for the most needed amino acids. /Protein Synthesis/
The mechanism of intracellular protein degradation, the process of hydrolyzing proteins into free amino acids, is more complex than that of protein synthesis, and its mechanisms have been relatively less studied. Cells contain a variety of enzymes capable of hydrolyzing peptide bonds. However, most intracellular protein hydrolysis appears to be accomplished by two multi-enzyme systems: the lysosomal system and the proteasome system. Lysosomes are membrane-bound vesicles within the cell containing various proteolytic enzymes, primarily functioning under acidic pH conditions. Large amounts of cytoplasm are phagocytosed by lysosomes (autophagy) and then acted upon by proteases at high concentrations. This system is generally considered to have low selectivity, although it can also degrade certain intracellular proteins. This system is tightly regulated by hormones such as insulin and glucocorticoids, as well as amino acids. The second system is the ATP-dependent ubiquitin-proteasome system, located in the cytoplasm. The first step involves linking ubiquitin molecules (basic peptides composed of 76 amino acids) to lysine residues of the target protein. Multiple enzymes participate in this process, selectively targeting the protein for degradation by the second component—the proteasome. /Protein Degradation/

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Therapeutic Uses
L-Threonine has been used clinically to increase glycine concentration in the cerebrospinal fluid of patients with spasticity. No adverse clinical reactions were observed when 4.5 to 6.0 grams were administered daily for 14 days. To determine whether the natural amino acid threonine (a potential precursor for glycine biosynthesis in the spinal cord) affects spasticity in multiple sclerosis, researchers conducted a randomized crossover trial involving 26 independently walking patients. A total daily dose of 7.5 grams of threonine reduced signs of spasticity on clinical examination, but neither the examining physician nor the patient noticed any improvement in symptoms. Unlike the sedative and motor function-impairing side effects of antispasmodic drugs commonly used to treat multiple sclerosis, no side effects or toxicities were observed with threonine… According to a double-blind crossover trial protocol, 18 patients with familial spastic paraplegia (FSP) were given 4.5 grams and 6.0 grams of L-threonine daily, respectively. …Although the efficacy of L-threonine was not clinically significant, it significantly suppressed spasticity symptoms.
/Experimental Therapy/ A randomized, double-blind, placebo-controlled trial enrolled 22 patients with edematous leg ulcers. Patients received topical treatment with either a cream containing the amino acids L-cysteine, glycine, and DL-threonine, or a cream base only (placebo). Most patients received treatment and dressing changes three times a week for 12 weeks. …The group receiving the amino acid combination therapy showed significantly better wound healing and pain reduction than the other groups. This study demonstrates the value of the combination of L-cysteine, glycine, and DL-threonine in promoting the healing of edematous leg ulcers.

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Drug Warnings
In this placebo-controlled crossover study, we investigated the effect of oral threonine (THR) supplementation on plasma amino acid concentrations in 12 patients with hyperphenylalaninemia. Prior to the first treatment period of this crossover study, patients were randomly assigned to two groups, receiving either approximately 50 mg/kg/day of THR or an equivalent amount of maltodextrin (as a placebo). After an 8-week feeding period and an 8-week washout period, the two groups were crossovered and THR supplementation continued for another 8 weeks. Blood samples were collected at the beginning and end of each supplementation period. Results showed that daily THR supplementation of approximately 50 mg/kg significantly reduced plasma phenylalanine (PHE) levels (P = 0.0234). A significant positive correlation was found between plasma and urinary PHE concentrations (P < 0.001), indicating that the reduction in plasma PHE levels in patients receiving THR supplementation was not due to increased urinary PHE excretion. Conclusion: The data from this study suggest that oral THR supplementation has a significant effect on reducing plasma PHE levels, but the mechanism of action remains unclear. Although THR supplementation appears attractive for patients with hyperphenylalaninemia based on existing data, its mechanism of action needs to be elucidated before this therapy can be administered to these patients. A six-month, two-center, double-blind, placebo-controlled trial investigated the efficacy of oral branched-chain amino acids (BCAAs) (12 g L-leucine, 8 g L-isoleucine, and 6.4 g L-valine daily) or L-threonine (4 g daily) in combination with pyridoxal phosphate (160 mg daily) in patients with amyotrophic lateral sclerosis (ALS). …The amino acids were well tolerated. Our results did not show any benefit of six months of BCAA or L-threonine treatment on the progression of ALS. The higher rate of decreased lung function in patients receiving BCAA or L-threonine treatment may be due to chance, but adverse effects of these amino acids cannot be ruled out. Currently, most commercially available infant formula contains approximately 20% more threonine than breast milk. Due to the high threonine content in these formulas, preterm infants have nearly twice the plasma threonine concentration compared to breastfed infants. Elevated threonine levels in blood plasma can lead to elevated glycine levels in the brain, thus affecting the balance of neurotransmitters in the brain. This may impact early brain development after birth. Therefore, excessive threonine intake should be avoided during infant feeding.

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Pharmacodynamics
L-Threonine is an essential amino acid that helps maintain proper protein balance in the body. It is crucial for the formation of collagen, elastin, and tooth enamel, and when combined with aspartic acid and methionine, it aids in liver and fat metabolism.

C4H9NO3

119.1192

119.058

72-19-5

82822-12-6

6288

White to off-white solid powder

1.3±0.1 g/cm3

345.8±32.0 °C at 760 mmHg

256 °C (decomposes) ; MP: 228-229 °C with decomposition (dl-threonine); 255-275 °C with decomposition (l(-)-threonine) (naturally occurring); 250-252 °C (dl-allo-threonine) ; 256 °C

162.9±25.1 °C

0.0±1.7 mmHg at 25°C

1.507

-1.23

3

2

8

93.3

2

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

AYFVYJQAPQTCCC-GBXIJSLDSA-N

InChI=1S/C4H9NO3/c1-2(6)3(5)4(7)8/h2-3,6H,5H2,1H3,(H,7,8)/t2-,3+/m1/s1

(2S,3R)-2-amino-3-hydroxybutanoic acid

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 : ~33.33 mg/mL (~279.80 mM)
DMSO :< 1 mg/mL

Solubility in Formulation 1: 50 mg/mL (419.74 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.)