NutrEval Plasma - Urine and Blood

1-methylhistidine is derived from the dipeptide anserine (which consists of the amino acids 1-methylhistidine and beta-alanine). Anserine and its derivatives are associated with the consumption of poultry and fish. Both 1-methylhistidine and 3-methylhistidine have been proposed as markers of meat intake. Note that confusion exists in the literature regarding the numbering of atoms in the imidazole ring of histidine – 1 versus 3 – and thus, there is caution with interpretation and clinical significance of these two markers.

Both 1-methylhistidine and 3-methylhistidine are histidine metabolites which have been proposed as markers of meat intake.

Note that some confusion exists in the literature regarding the numbering of atoms in the imidazole ring of histidine – 1 versus 3 – and thus, there is caution with interpretation and clinical significance of these two markers.

3-methylhistidine is a constituent of actin and myosin, the contractile proteins of skeletal muscles. Urinary excretion of 3-methylhistidine may be a result of muscle breakdown or consumption of meat fibers. Unlike 1-methylhistidine, 3-methylhistidine has been shown to increase in fasting states indicating catabolism of muscle tissue. Therefore, this marker is more variable with regards to animal protein consumption.

Alpha-Amino-N-butyric acid (α-ANB), also known as alphaaminobutyric acid, is a nonessential amino acid derived from the catabolism of methionine, threonine, and serine.

α-ANB is both formed and metabolized by reactions which require vitamin B6 as a cofactor.

Alpha-aminoadipic acid (also known as 2-aminoadipic acid) is an intermediary biomarker of lysine and tryptophan metabolism. The further metabolism of alpha-aminoadipic acid to alpha-ketoadipic acid requires vitamin B6.

Plasma alpha-aminoadipic acid is strongly associated with the risk of developing diabetes as seen in an assessment of the Framingham Heart Study data. Circulating levels were found to be elevated for many years prior to the onset of diabetes.

Preclinical data shows it may also play a role in oxidation and atherosclerotic plaque formation.

Alanine is a nonessential amino acid. It is the second most abundant amino acid in circulation, after glutamine.

It is found in many foods including eggs, meat, lentils, and fish.

Alanine is involved in sugar metabolism for energy and is important in immune system function, specifically T lymphocyte activation. Interestingly, alanine is an agonist that binds to the glycine site of N-methyl-d-aspartate (NMDA) receptors in the brain and improves the positive and cognitive symptoms of patients with schizophrenia.

Arginine is found in all protein foods and is very abundant in seeds and nuts. It is considered a semi-essential amino acid during early development, infection/inflammation, or renal and/or intestinal impairment. It has many functions in the body including:

- ammonia disposal in the urea cycle

- immune function

- stimulation of insulin release

- muscle metabolism (creatine/creatinine precursor)

- nitric oxide (NO) formation

- glutamic acid and proline formation

- glucose/glycogen conversion

- stimulation of the release of growth hormone, vasopressin, and prolactin

- wound healing

Because arginine is a precursor for nitric oxide synthesis, it is often used therapeutically in cardiovascular disease for its vasodilatory effects.

Asparagine is a non-essential protein amino acid that is present in many fruits and vegetables including asparagus, from which it gets its name.

Other dietary sources include meat, potatoes, eggs, nuts, and dairy. It can also be formed from aspartic acid and glutamine using the enzyme asparagine synthetase.

In addition to being a structural component of many proteins, asparagine is also useful to the urea cycle. It acts as a nontoxic carrier of residual ammonia to be eliminated from the body.

Aspartic acid is a nonessential amino acid that plays roles in many important metabolic processes, such as energy production (citric acid cycle), hormone metabolism, CNS activation, and the urea cycle. It is found in many protein sources such as oysters, meats, seeds, avocado, asparagus, and beets.

It is also an ingredient in artificial sweeteners.

Aspartic acid is a precursor to many amino acids and other molecules like asparagine, arginine, isoleucine, lysine, methionine, isoleucine, threonine, nucleotides, NAD, and pantothenate. Aspartate, like glutamine, can also be considered a neuroexcitatory neurotransmitter since it activates the N-methyl-D-aspartate receptor in the brain.

β-alanine is a breakdown product of carnosine and anserine, which are dipeptides from meat consumption. Although β-alanine’s properties are limited, its relationship to carnosine makes it important. Both have antioxidant properties. And carnosine is critical for pH buffering in skeletal muscle during exercise, but its formation can be limited by enzymatic factors. For this reason, supplementation with β-alanine is sometimes used to enhance carnitine and therefore improve athletic performance.

Beta-aminoisobutyric acid (also known as 3-aminoisobutyric acid) is a non-protein amino acid formed by the catabolism of valine and the nucleotide thymine. It is further catabolized to methylmalonic acid semialdehyde and propionyl-CoA.

Levels are controlled by a vitamin B6-dependent reaction in the liver and kidneys.

β-aminoisobutyric acid can also be produced by skeletal muscle during physical activity.

Citrulline is an intermediate, nonprotein-forming amino acid in the urea cycle serving as a precursor to arginine. It derives its name from the watermelon (Citrullus vulgaris), where it was first isolated and identified.

It is easily absorbed by the gut and bypasses the liver, making it an effective method for repleting arginine.

Other food sources of citrulline include muskmelons, bitter melons, squashes, gourds, cucumbers and pumpkins.

Citrulline can also be synthesized from arginine and glutamine in enterocytes, which can then be metabolized by the kidneys back into arginine.

Cysteine is a nonessential sulfur-containing amino acid. It is obtained from the diet and is also endogenously made from the intermediate amino acid cystathionine.

Dietary cysteine sources include poultry, eggs, beef, and whole grains.

This amino acid should not be confused with the oxidized derivative of cysteine called cystine. Cystine is formed by combining two cysteine molecules within a redox reaction.

The urinary FMV amino acid test reports cysteine and cystine separately.

The plasma amino acid test combines both cysteine and cystine as one biomarker called "Cyst(e)ine".

Cystathionine is an intermediate dipeptide within the process of transsulfuration.

Transsulfuration is the main route for irreversible homocysteine disposal, glutathione production, and energy. The initial step involves the enzyme cystathionine β-synthase enzyme (CBS). This reaction requires nutrient cofactors such as vitamin B6 and iron. Cystathionine is then converted to cysteine, and eventually goes on to either make glutathione or feed the Kreb’s cycle.

Ethanolamine is an intermediary metabolite in the serine-to-choline sequence. It can be used to synthesize phosphatidylethanolamine (PE), a very important membrane phospholipid. Ethanolamine is not only a precursor, but also a breakdown product of PE. Ethanolamine is abundant in both intestinal and bacterial cell membranes. It plays a significant role in the renewal and proliferation of intestinal cells and intestinal inflammation.

Also, since ethanolamine plays a structural role in skeletal muscle cell membranes, some evidence suggests it may be a marker of skeletal muscle turnover.

Gamma-aminobutyric acid (GABA) is an amino acid that functions as an inhibitory neurotransmitter. It serves one-third of brain neurons and is involved in depression and mania.

Although there are some dietary supplement and food sources for GABA (cruciferous vegetables, spinach, tomatoes, beans, and rice), the primary source may be endogenous prodution.

Nervous tissue, the gut microbiome, the liver, pancreas, and endothelial cells are important sources for production. Endogenous GABA is produced by the decarboxylation of the excitatory neurotransmitter glutamic acid. It can also be produced from the diamine putrescine using diamine oxidase (DAO).

Glutamic acid is a nonessential amino acid is derived from the diet and from the breakdown of gut proteins. Glutamate is a major excitatory neurotransmitter in the brain.

It plays a role in neuronal differentiation, migration, and survival in the developing brain. It is also involved in synaptic maintenance, neuroplasticity, learning, and memory.

Glutamate is present in many foods including cheese, seafood, meat, and spinach.

In spite of intake, the total pool of glutamic acid in the blood is small, due to its rapid uptake and utilization by tissues including muscle and the liver (which uses it to form glucose and lactate).

Glutamine is a nonessential amino acid and is the most abundant amino acid in the body. It is formed from glutamate using the enzyme glutamine synthetase.

Approximately 80% of glutamine is found in the skeletal muscle, and this concentration is 30 times higher than the amount of glutamine found in human plasma. Although glucose is used as fuel for many tissues in the body, glutamine is the main fuel source for a large number of cells including lymphocytes, neutrophils, macrophages, and enterocytes.

Glycine is a nonessential amino acid that is synthesized from choline, serine, hydroxyproline, and threonine.

It has many important physiologic functions. It is one of three amino acids that make up glutathione. Glycine’s dietary sources include meat, fish, legumes, and gelatins.

Glycine is a major collagen and elastin component, which are the most abundant proteins in the body.

Like taurine, it is an amino acid necessary for bile acid conjugation; therefore, it plays a key role in lipid digestion and absorption.

Glycine is the precursor to various important metabolites such as porphyrins, purines, heme, and creatine. It acts both as an inhibitory neurotransmitter in the CNS and as an excitatory neurotransmitter on N-methyl-D-aspartate (NMDA) receptors.

Histidine is a semi-essential amino acid which is formed in the breakdown of carnosine. Red meat is a common source of carnosine, and therefore histadine. 

Other food sources include poultry, fish, nuts, seeds, and grains. Histidine and histamine have a unique relationship. The amino acid histadine becomes histamine via a vitamin B6- dependent enzyme called histidine decarboxylase. 

With this, decreased amounts of histidine and insufficient vitamin B6 can subsequently lead to a decrease in histamine concentration. This may impair digestion, since histamine binds to H2 receptors located on the surface of parietal cells to stimulate gastric acid secretion, necessary for protein breakdown.

Histidine also inhibits the production of proinflammatory cytokines by monocytes and is therefore anti-inflammatory and antioxidant. 

With these beneficial effects, histidine supplementation has been shown to improve insulin resistance, reduce BMI, suppress inflammation, and lower oxidative stress in obese women with metabolic syndrome. 

Interestingly, histadine can also be broken down to form urocanic acid in the liver and skin. Urocanic acid absorbs UV light and is thought to act as a natural sunscreen.

Branched Chain Amino Acids (Isoleucine, Leucine, Valine) are the three branched chain amino acids (BCAAs).

Branched chain amino acids (BCAA) are essential amino acids and must be obtained from the diet (mainly meat, grains, and dairy). 

Not only do the BCAAs account for almost 50% of muscle protein, but they have many metabolic functions. 

BCAAs act as substrates for protein synthesis, energy production, neurotransmitter production, glucose metabolism, and the immune response. They are also involved in stimulation of albumin and glycogen synthesis, improvement of insulin resistance, inhibition of free radical production, and hepatocyte apoptosis with liver regeneration.

Branched Chain Amino Acids (Isoleucine, Leucine, Valine) Isoleucine, leucine and valine are the three branched chain amino acids (BCAAs).

Branched chain amino acids (BCAA) are essential amino acids and must be obtained from the diet (mainly meat, grains, and dairy). 

Not only do the BCAAs account for almost 50% of muscle protein, but they have many metabolic functions. 

BCAAs act as substrates for protein synthesis, energy production, neurotransmitter production, glucose metabolism, and the immune response. They are also involved in stimulation of albumin and glycogen synthesis, improvement of insulin resistance, inhibition of free radical production, and hepatocyte apoptosis with liver regeneration.

Lysine is a nutritionally essential amino acid abundant in meat, fish, fowl, and legumes and is needed for formation of body proteins and enzymes.

Lysine can be methylated using S-adenosylmethionine (SAM) to synthesize carnitine, which is needed for fatty acid oxidation. Lysine also generates Acetyl CoA for use in the citric acid cycle. Lysine, proline, hydroxyproline, and vitamin C are important in the synthesis of collagen for skin, bones, tendons and cartilage.

L-lysine supplementation has also been studied for herpes simplex treatment and prophylaxis and may be beneficial.

Methionine is an essential amino acid that plays an important role in the methylation cycle. Methionine is obtained from dietary intake or through homocysteine remethylation. Methionine’s dietary sources include eggs, fish, meats, Brazil nuts, and other plant seeds. 

Methionine is converted to the body’s main methyl donor, S-adenosylmethionine (SAM). This conversion requires the enzyme methionine adenosyltransferase (MAT).

Ornithine is an intermediate nonprotein-forming amino acid of the urea cycle.

Arginine is converted to ornithine via the arginase enzyme, with urea as a byproduct. Ornithine combined with carbamoyl phosphate is then converted into citrulline via the ornithine transcarbamylase (OTC) enzyme. The contribution of carbamoyl phosphate results from the metabolism of ammonia by the enzyme carbamoyl phosphate synthase, and if this magnesium-dependent process is impaired, ammonia buildup, or hyperammonemia can occur.

Ornithine can also form polyamines including putrescine via the ornithine decarboxylase (ODC) enzyme, which requires pyridoxal-5-phosphate (vitamin B6) as a cofactor.

Putrescine and other polyamines are crucial to the growth and proliferation of cells.

Phenylalanine is an essential amino acid found in most foods which contain protein such as meat, fish, lentils, vegetables, and dairy. 

Phenylalanine is the precursor to another amino acid, tyrosine. Because tyrosine is needed to form several neurotransmitters (dopamine, epinephrine, and norepinephrine), as well as thyroid hormone and melanin, phenylalanine intake is important.

Phosphoethanolamine is an intermediate in the serineto-choline sequence. It is both a precursor and byproduct of phospholipid biosynthesis and breakdown. As a precursor to the phospholipid phosphatidylethanolamine, phosphoethanolamine plays a key role in myelination.

Phosphoserine is the phosphorylated ester of the amino acid serine. The addition of a phosphoryl group to an amino acid, or its removal, plays a role in cell signaling and metabolism. Phosphoserine is a byproduct of glycolysis and subsequent intermediate to then become serine. The enzyme that catalyzes this step, phosphoserine phosphatase, is magnesium dependent.

This metabolite is not to be confused with a similar-sounding metabolite, phosphatidylserine; this is a common CNS supplement and essential for neuronal cell membranes.

Proline is a nonessential amino acid. It contains a secondary α-imino group and is sometimes called an α-imino acid.

Proline, and its metabolite hydroxyproline, constitute a third of the total amino acids found in collagen. Lysine, proline, hydroxyproline, and vitamin C are all important in the synthesis of collagen for skin, bones, tendons, and cartilage.

Proline is abundant in meat, bone meal, poultry, salmon, wheat, barley, and corn.

Sarcosine is an amino acid made within the methylation cycle when S-adenosylmethionine (SAM) is conjugated with glycine. It can also be made by catabolism of dimethylglycine (DMG).

There are many dietary sources of sarcosine including eggs, legumes, nuts, and meats.

Sarcosine is also available as an over-the-counter supplement, and it is widely used in cosmetic formulations (toothpaste, creams, and soaps) and detergents. In the methylation cycle, sarcosine is created by the GNMT enzyme, which functions to control SAM excess.

Serine is found in soybeans, nuts, eggs, lentils, shellfish, and meats.

Serine is a nonessential amino acid used in protein biosynthesis and can be derived from four possible sources: dietary intake, degradation of protein and phospholipids, biosynthesis from glycolysis intermediate 3-phosphoglycerate, or from glycine.

Serine is used to synthesize ethanolamine and choline for phospholipids. Serine is essential for the synthesis of sphingolipids and phosphatidylserine in CNS neurons.

In the folate cycle, glycine and serine are interconverted. These methyltransferase reactions and interconversions are readily reversible depending on the needs of the folate cycle. Dietary serine is not fully converted to glycine; therefore, serine supplementation has little value, though is not harmful.

Taurine differs from other amino acids because a sulfur group replaces the carboxyl group of what would be the nonessential amino acid, β-alanine. It takes part in biochemical reactions and is not fully incorporated into proteins.

In most tissues, it remains a free amino acid. Taurine’s highest concentration is in muscle, platelets, and the central nervous system.

Taurine is mainly obtained via dietary sources (dairy, shellfish, turkey, energy drinks), but can also come from sulfur amino acid metabolism (methionine and cysteine).

Threonine is a large neutral amino acid and a precursor for the amino acid glycine.

Foods that contain relatively high amounts of threonine include cheeses (especially Swiss), meat, fish, poultry, seeds, walnuts, cashews, almonds and peanuts. Threonine gets converted to glycine using a two-step biochemical pathway involving the enzymes threonine dehydrogenase and the vitamin B6-dependent glycine C-acetyltransferase.

Threonine has been studied clinically as a supplement to increase cerebrospinal fluid levels of glycine in patients with spasticity related to neurological conditions such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Threonine may also play a role in tissue healing and liver health.

Tryptophan is involved in serotonin production via vitamin B6-dependent pathways resulting in the intermediate 5-hydroxytryptophan (5-HTP). 5-HTP is often used as a supplement for serotonin formation instead of tryptophan, which can be quickly metabolized in other pathways.

Serotonin is further metabolized to melatonin via methylation.

Because of these downstream conversions, therapeutic administration of 5-HTP has been shown to be effective for depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.

Tyrosine is a conditionally essential amino acid which can come directly from the digestion of dietary protein.

Common food sources include dairy, beans, whole grains, meat, and nuts.

If intake is insufficient, tyrosine can be formed from the essential amino acid phenylalanine using a tetrahydrobiopterin reaction. Tyrosine itself is a precursor to several neurotransmitters including dopamine, epinephrine and norepinephrine. It is also needed to create thyroid hormone and melanin skin pigments.

Urea is a nontoxic byproduct of nitrogen (ammonia) detoxification. It is formed in the liver via the urea cycle and is the end product of protein metabolism. It is essentially a waste product with no physiological function.

Branched Chain Amino Acids (Isoleucine, Leucine, Valine) Isoleucine, leucine and valine are the three branched chain amino acids (BCAAs).

Branched chain amino acids (BCAA) are essential amino acids and must be obtained from the diet (mainly meat, grains, and dairy). 

Not only do the BCAAs account for almost 50% of muscle protein, but they have many metabolic functions. 

BCAAs act as substrates for protein synthesis, energy production, neurotransmitter production, glucose metabolism, and the immune response. They are also involved in stimulation of albumin and glycogen synthesis, improvement of insulin resistance, inhibition of free radical production, and hepatocyte apoptosis with liver regeneration.