Metabolimix+ (Genova Diagnostics)

When assessing fatty acids in RBCs, Genova measures a weighted percentage of fatty acids taken up into the erythrocyte wall. The total omega-3 percentage is a combined total weight percentage. It is calculated by adding up each of the measured omega-3s. Higher total percentages of omega-3 fatty acids are anti-inflammatory, cardioprotective, and considered beneficial.

It should be noted that when dealing with percentages, the amount of each fatty acid can influence the others. For example, fish oil supplementation may increase the overall omega-3 percentage. By default, this may then lower the omega-6 percentage.

When assessing fatty acids in RBCs, Genova measures a weighted percentage of fatty acids taken up into the erythrocyte wall. The total omega-6 percentage is a combined total weight percentage calculated by adding together each of the measured omega-6s.

Because some omega-6 fatty acids are less beneficial than others, each fatty acid abnormality should be addressed.

However, in general, assessing the total omega-6 percentage as it relates to the omega-3 percentage is helpful. A more balanced ratio may decrease risk of many chronic diseases. It should be noted that when dealing with percentages, the amount of each fatty acid can influence the others. For example, fish oil supplementation may increase the overall omega-3 percentage, which may ultimately lower the omega-6 percentage.

When assessing fatty acids in RBCs, Genova measures a weighted percentage of fatty acids taken up into the erythrocyte wall. The total omega-9 percentage is a combined total weight percentage calculated by adding up each of the measured omega-9s. In general, because the omega-9 fatty acids are beneficial, higher levels are preferred; though identifying root cause of elevations or deficiencies is important. It should be noted that when dealing with percentages, the amount of each fatty acid can influence the others. For example, fish oil supplementation may increase the overall omega-3 percentage. By default, this may then lower the omega-6 percentage.

When assessing fatty acids in RBCs, Genova measures a weighted percentage of fatty acids taken up into the erythrocyte wall. The total saturated fatty acid percentage is a combined total weight percentage calculated by adding up each of the measured saturated fatty acids. It should be noted that when dealing with percentages, the amount of each fatty acid can influence the others. For example, fish oil supplementation may increase the overall omega-3 percentage, which then lowers the omega-6 percentage. Because some saturated fatty acids are beneficial, it is important to look at the levels of those specifically as well.

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.

3-Hydroxyisovaleric Acid (3-HIA) is formed from the metabolism of the branched-chain amino acid leucine. Methylcrotonyl-CoA carboxylase catalyzes an essential step in this pathway and is biotin dependent. Reduced activity of this enzyme leads to an alternate pathway of metabolism resulting in 3-hydroxyisovaleric acid.

3-Hydroxyphenylacetic acid and 4-hydroxyphenylacetic acid are produced by the bacterial fermentation of amino acids, much like Indoleacetic acid (IAA).

3-Hydroxypropionic Acid (3-HPA) is a major urinary metabolite of propionic acid. Propionic acid is derived from dietary branched-chain amino acids, oddchain fatty acids, and can be produced in the gut by bacterial fermentation of fiber. The biotin-dependent enzyme propionyl CoA carboxylase is responsible for metabolizing propionic acid to methylmalonyl CoA, which is subsequently isomerized to succinyl CoA. Decreased activity of this enzyme shunts propionyl CoA into alternative pathways which form 3-HPA.

3-Methyl-4-OH-Phenylglycol (MHPG) is a byproduct of the central nervous system’s norepinephrine (NE) metabolism. MHPG metabolizes to vanilmandelic acid (VMA) in the liver using the enzymes alcohol dehydrogenase and aldehyde dehydrogenase. Urinary MHPG was originally thought to represent CNS sympathetic output, but is now known to be principally derived from peripheral neuronal NE metabolism.

MHPG has been widely studied as a marker to predict response to medications used in mood disorders or as a biomarker to monitor pharmacotherapies.

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.

3-Hydroxyphenylacetic acid and 4-hydroxyphenylacetic acid are produced by the bacterial fermentation of amino acids, much like Indoleacetic acid (IAA).

5-OH-indoleacetic Acid (5-HIAA) is a downstream metabolite of serotonin, which is formed from the essential amino acid tryptophan. Most blood serotonin and urinary 5-HIAA comes from serotonin formation outside of the CNS, primarily the liver and enterochromaffin cells in the gastrointestinal tract. Serotonin is further metabolized by monoamine oxidase to become 5-HIAA.

8-hydroxy- 2’-deoxyguanosine (8-OHdG) is a byproduct of oxidative damage to guanine bases in DNA. It is used as a biomarker for oxidative stress and carcinogenesis.

It has been studied to estimate DNA damage after exposure to carcinogens including tobacco smoke, asbestos fibers, heavy metals, and polycyclic aromatic hydrocarbons.

8-OHdG levels are positively associated with markers of inflammation and evening cortisol, indicating that increased physiological or psychosocial stress is associated with increased oxidative damage.

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.

α-hydroxybutyric acid (2-hydroxybuturic acid [2-HB]) is a marker that relates to oxidative stress. 2-HB is an organic acid produced from α-ketobutyrate via the enzymes lactate dehydrogenase (LDH) or α-hydroxybutyrate dehydrogenase (HBDH). These enzymes are catalyzed by NADH. Oxidative stress creates an imbalance in NADH/NAD ratios, which leads directly to the production of 2-HB. Being that 2-HB’s precursor α-ketobutyrate is a byproduct in the glutathione (GSH) synthesis pathway, an increased demand for GSH may ultimately result in increased 2-HB. Increased oxidative stress associated with insulin resistance increases the rate of hepatic glutathione synthesis. Plasma 2-HB is highly associated with insulin resistance and may be an effective biomarker for prediabetes. A study on type 2 diabetics showed that GSH infusion restored the NADH/NAD balance and resulted in improvement of insulin sensitivity and beta cell function.

α-Hydroxyisobutyric Acid is a major urinary metabolite of the industrial solvent methyl tert-butyl ether (MTBE).

MTBE was a gasoline additive discontinued in the early 2000’s used to reduce automobile emissions. Due to significant ground water leakage from storage tanks, ongoing exposure to MTBE exists in ground water. There is also data available on levels of MTBE in ambient air.

Urinary α-hydroxyisobutryic acid is a marker of recent MTBE exposure. Although, MTBE was initially designated as “noncarcinogenic”, recent studies suggest some interesting clinical associations. Exposure to MTBE has been linked to type 2 diabetes as a result of disrupted zinc homeostasis and glucose tolerance. There are also clinical associations with autism, DNA oxidative damage, and methylation defects. Studies on cancer, reproductive abnormalities, nonalcoholic fatty liver, and neurotoxicity have been either negative or inconclusive thus far.

Of the essential amino acids, there are three branchedchain amino acids (leucine, isoleucine, and valine).

Unlike most amino acids, the initial step of branchedchain amino acid (BCAA) metabolism does not take place in the liver. They increase rapidly in systemic circulation after protein intake and are readily available for use. Skeletal muscle is where most of the initial catabolism of BCAA takes place using branched-chain aminotransferase enzymes to form α-ketoacids, which are then released from muscles back into the blood to be further metabolized, mainly in the liver.

BCAA act as substrates for protein synthesis, energy production, neurotransmitter production, glucose metabolism, immune response, and many other beneficial metabolic processes.

α-Ketoisovaleric Acid (AKIV) is produced from the essential amino acid valine. It then metabolizes to become succinyl Co-A. AKIV is glucogenic.

α-Ketoisocaproic Acid (AKIC) is produced from leucine and further metabolizes to form acetyl-CoA and acetoacetate. AKIC is ketogenic.

α-Keto-β-Methylvaleric Acid (AKBM) comes from isoleucine, and further metabolizes to form acetylCoA and succinyl-CoA. AKBM is therefore both glycogenic and ketogenic.

These α-ketoacids then require an enzyme complex called branched-chain α-keto acid dehydrogenase (BCKD) for further metabolism.

This enzyme complex requires multiple vitamin cofactors, such as vitamin B1, B2, B3, B5, and lipoic acid.

α-Ketoadipic Acid (AKAA; 2-Oxoadipic acid, 2-Ketoadipic acid) is an organic acid formed from α-aminoadipic acid (which originates with lysine) and also from α-aminomuconic acid (derived from tryptophan).

AKAA metabolizes to form glutaryl-CoA via oxidative decarboxylation. The cofactors needed in this step are Coenzyme A, NAD, thiamine pyrophosphate (vitamin B1), lipoic acid, and vitamin B2.

Isocitric Acid is converted to α-ketoglutaric acid using the enzyme isocitrate dehydrogenase. Alphaketoglutarate is a rate-determining intermediate in the Citric Acid Cycle and provides an important source of glutamine and glutamate that stimulates protein synthesis and bone tissue formation, inhibits protein degradation in muscle, and constitutes an important metabolic fuel for cells of the gastrointestinal tract. Alpha-ketoglutaric acid is then converted to Succinyl CoA using the enzyme alpha-ketoglutarate dehydrogenase. This enzyme complex is very similar to the pyruvate dehydrogenase complex with similar nutrient cofactor needs.

Of the essential amino acids, there are three branchedchain amino acids (leucine, isoleucine, and valine).

Unlike most amino acids, the initial step of branchedchain amino acid (BCAA) metabolism does not take place in the liver. They increase rapidly in systemic circulation after protein intake and are readily available for use. Skeletal muscle is where most of the initial catabolism of BCAA takes place using branched-chain aminotransferase enzymes to form α-ketoacids, which are then released from muscles back into the blood to be further metabolized, mainly in the liver.

BCAA act as substrates for protein synthesis, energy production, neurotransmitter production, glucose metabolism, immune response, and many other beneficial metabolic processes.

α-Ketoisovaleric Acid (AKIV) is produced from the essential amino acid valine. It then metabolizes to become succinyl Co-A. AKIV is glucogenic.

α-Ketoisocaproic Acid (AKIC) is produced from leucine and further metabolizes to form acetyl-CoA and acetoacetate. AKIC is ketogenic.

α-Keto-β-Methylvaleric Acid (AKBM) comes from isoleucine, and further metabolizes to form acetylCoA and succinyl-CoA. AKBM is therefore both glycogenic and ketogenic.

These α-ketoacids then require an enzyme complex called branched-chain α-keto acid dehydrogenase (BCKD) for further metabolism.

This enzyme complex requires multiple vitamin cofactors, such as vitamin B1, B2, B3, B5, and lipoic acid.

Of the essential amino acids, there are three branchedchain amino acids (leucine, isoleucine, and valine).

Unlike most amino acids, the initial step of branchedchain amino acid (BCAA) metabolism does not take place in the liver. They increase rapidly in systemic circulation after protein intake and are readily available for use. Skeletal muscle is where most of the initial catabolism of BCAA takes place using branched-chain aminotransferase enzymes to form α-ketoacids, which are then released from muscles back into the blood to be further metabolized, mainly in the liver.

BCAA act as substrates for protein synthesis, energy production, neurotransmitter production, glucose metabolism, immune response, and many other beneficial metabolic processes.

α-Ketoisovaleric Acid (AKIV) is produced from the essential amino acid valine. It then metabolizes to become succinyl Co-A. AKIV is glucogenic.

α-Ketoisocaproic Acid (AKIC) is produced from leucine and further metabolizes to form acetyl-CoA and acetoacetate. AKIC is ketogenic.

α-Keto-β-Methylvaleric Acid (AKBM) comes from isoleucine, and further metabolizes to form acetylCoA and succinyl-CoA. AKBM is therefore both glycogenic and ketogenic.

These α-ketoacids then require an enzyme complex called branched-chain α-keto acid dehydrogenase (BCKD) for further metabolism.

This enzyme complex requires multiple vitamin cofactors, such as vitamin B1, B2, B3, B5, and lipoic acid.

α-Ketophenylacetic Acid, also known as phenylglyoxylic acid (PGA), is a urinary metabolite of styrene, toluene, xylenes, and ethylbenzene.

It acts as a urinary marker of recent exposure via inhalation, contact, oral, and others.

The biologic half-life of styrene in humans is fairly short and corresponds with the disappearance of PGA from the urine. Styrene is widely used for synthesis of polymers such as plastics, rubbers, and surface coating. It is also used in the pharmaceutical industry. Styrene is commonly applied in the manufacturing of paints, pigments, and glues. Coexposure to other solvents, like toluene and ethyl acetate is common in workplaces where styrene is a concern. Since toluene and xylene are components of unleaded gasoline, workers at gas stations are at potential risk of exposure, as well as the general population.

Styrene exposure may interfere with peripheral metabolism of thyroid hormones by inhibiting conversion of T4 to T3.

It may also affect DNA repair capacity and damage. There are also clinical associations with insulin resistance, oxidative stress, and inflammation.

Alpha-linolenic acid (ALA) is an essential n-3 fatty acid and must be obtained in the diet. Sources include green leafy vegetables, oily fish, flaxseed, soybean oil, canola oil, walnuts, and chia seeds. ALA has an 18-carbon backbone with 3 double bonds starting at the third carbon molecule (18:3n3). It is an important precursor to make eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), though these can also be obtained in the diet. Most dietary ALA is used to generate energy and only a small portion is converted to EPA and DHA.

EPA (n3) and AA (n6) both compete for use of the delta-5- desaturase enzyme to be synthesized. Increased dietary intake of animal fats alters fatty acid metabolism in favor of inflammation. There are many chronic diseases associated with elevations of this ratio including cardiovascular disease, mood disorders, and cancer. Increasing dietary intake of fish oils, or omega-3 fatty acid containing foods such as flax, chia, oily fish, or walnuts, can shift delta-5-desaturase activity toward the metabolism of the more beneficial n-3 metabolites.

Decreasing intake of animal fats is also recommended.

Dietary fatty acids are metabolized into fuel sources using beta-oxidation. Fatty acid conversion into Acetyl-CoA requires transport across the mitochondrial membrane via the carnitine shuttle. When beta-oxidation is impaired, fats are metabolized using an alternate pathway called omega-oxidation. Omega-oxidation results in elevated levels of dicarboxylic acids such as adipic acid and suberic acid. Impaired beta-oxidation occurs in carnitine deficiency or enzymatic dysfunction due to lack of nutrient cofactors. Vitamin B2 and magnesium play a role in optimizing beta-oxidation.

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.

SOURCES:

Found in virtually all food and food additives, water, air, and soil. Also found in antacids, antiperspirants, cosmetics, astringents, cans, pots, pans, siding, roofing, and foil.

Anserine (beta-alanyl-3-methyl-histidine) is a urinary biomarker from the consumption of poultry and fish. It is a dipeptide consisting of the amino acids 1-methylhistidine and beta-alanine. The enzyme carnosineN-methyl transferase catalyzes the transfer of a methyl group of S-adenosylmethionine (SAM) on carnosine to form anserine. Anserine acts as an antioxidant, free radical scavenger, and pH buffer. It can reduce blood sugar and affect renal sympathetic nerve activity and blood pressure. Anserine is measured in FMV urine only.

SOURCES:

Found naturally in the environment, air, soil, water.

Found in lead storage batteries, solder, sheet and pipe metal, pewter, bearings and castings, paints, ceramics, fireworks, plastic enamels, metal and glass.

Sometimes used medically to treat parasites.

Arachidic acid is very long, 20-carbon backbone saturated fatty acid (20:0). It is found in various nuts, soybeans, peanut oil, corn oil, and cocoa butter. In addition to dietary sources, it can be synthesized by the hydrogenation of the omega-6 fatty acid arachidonic acid or the elongation of stearic acid.

Arachidonic acid (AA) is a 20-carbon polyunsaturated n-6 fatty acid with 4 double bonds (20:4n6). Its double bonds contribute to cell membrane fluidity and predispose it to oxygenation. This can lead to several important metabolites which ensure a properly functioning immune system as well as regulate inflammation, brain activity, and other signaling cascades. AA’s metabolites are called eicosanoids which are signaling molecules. They can be produced via cyclooxygenases, lipoxygenase, cytochrome P450, and oxygen species-triggered reactions. These pathways yield molecules like prostaglandins, isoprostanes, thromboxane, leukotrienes, lipoxins, and epoxyeicosatrienoic acids. AA can be obtained in the diet from eggs, fish, and animal meats and fats – or produced directly from DGLA using the delta-5-desaturase enzyme. Although often vilified, adequate AA intake is needed to achieve an equilibrium between its inflammatory and resolution effects to support a healthy immune system. It is also fortified in infant formulas due to its importance in growth and development.

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.

Sources:

Found in water, air, soil, cigarettes, and cosmetics. Food grown in contaminated water sources, such as rice and vegetables, or fish, are a common source. Major sources of occupational exposureis the manufacture of pesticides, herbicides, and agricultural products.

90% of all arsenic produced is used as a preservative for wood to prevent rotting and decay. Copper chromated arsenate (CCA), also known as pressure-treated wood, wasphased out for residential use in 2003, but wood treated prior could still be in existing structures. CCA-treated wood is still used in industrial applications. 

Organic arsenic found in seafood is relatively nontoxic, while the inorganic forms are toxic.

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. Asparagine is rapidly converted to aspartic acid by the enzyme asparaginase. Interestingly, L-asparaginase has been successfully used as a chemotherapeutic agent for decades.

It causes extracellular depletion of asparagine which seems to play a critical role in cellular adaptations to glutamine and apoptosis.

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. 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. In addition to diet and supplementation, β-alanine can also be endogenously produced. This occurs via degradation of uracil in the liver but it can also be made by intestinal bacteria such as E. coli.

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.

β-hydroxy-β-methylglutaric acid (HMG) is a precursor to cholesterol and coenzyme Q10 (CoQ10) synthesis. It is a product of hydroxymethylglutaryl-coenzyme A (HMGCoA). HMGCoA- reductase is a rate limiting enzyme in cholesterol production. Medications that interfere with this enzyme may result in elevated HMG and subsequent low levels of cholesterol and CoQ10. CoQ10 is important for cellular energy production in the mitochondrial respiratory chain.

β-hydroxybutyrate is a ketone body. During periods of fasting, exercise, and metabolic disease, ketone bodies are generated in the liver and become an energy source instead of glucose.

BARIUM SOURCES:

Radiologic testing contrast, paint, bricks, ceramics, glass and rubber. Air, water, and food. Fish and aquatic organisms can accumulate barium.

BARIUM NUTRIENT INTERACTIONS:

Barium toxicity can induce severe hypokalemia.

Behenic acid is a VLSFA which contains 22 carbons (22:0). Its name is derived from Ben oil (behen oil) from the Moringa oleifera tree. Commercially, products containing Moringa oil have high amounts of behenic acid in them such as hair conditioners, topical moisturizers, and other cosmetic oils. It can also be obtained through the diet in canola (rapeseed) oil and peanut oil. Using the elongase enzyme, it can be synthesized from arachidic acid.

Benzoic acid and hippuric acid are formed from the bacterial metabolism of polyphenols. Urinary benzoic acid may also come from ingestion of food preservatives such as sodium benzoate. Hippuric acid is made when sodium benzoate is conjugated with glycine.

Used in alloys, electronics, batteries, crystal ware, cosmetics, flame retardants,and in antimicrobial therapy (H. pylori), antiseptic dressings, paraffin paste. Bismuth medical therapies exhibit high therapeutic effects and little side effects, though over-dosage can cause toxicity.

Very limited absorption in the GI tract. When absorbed, it binds mainly to transferrin and lactoferrin, interacts with enzymes due to a high affinity to cysteine residues, blocking the active site. Can accumulate in the kidney, lung, spleen, liver, brain, and muscles, while being eliminated in urine and feces via bile and intestinal secretions.

SOURCES:

Found in food such as shellfish, leafy vegetables, rice, cereals, cocoa butter, dried seaweed, and legumes. Also present in nickel cadmium batteries, cigarette smoke (including second-hand smoke), insecticides, fertilizer, motor oil, emissions and exhaust. Drinking water, air, and occupational exposures are also seen.

NUTRIENT INTERACTIONS:

Iron deficiency is associated with higher cadmium burden and absorption of cadmium may increase during very early stages of iron deficiency. Zinc deficiency is associated with an increase in Cadmium, as a result of the antagonistic relationship between the elements.

Dietary cadmium inhibits GI absorption of calcium and interferes with calcium and vitamin D metabolism. Low dietary calcium stimulates synthesis of calcium- binding protein which enhances Cadmium absorption.

Carnosine (beta-alanyl-L-histidine) is a urinary biomarker which comes from the consumption of beef, pork, and to a lesser extent, poultry.

It is a dipeptide consisting of the amino acids histidine and beta-alanine and is concentrated in skeletal and heart muscle, brain, and kidneys. Carnosine has antioxidant properties, antiglycation effects, enhanced calcium sensitivity, and pH buffering activity during highintensity exercise.

It also has neuroprotective properties and may play an important role in Alzheimer’s disease and other neurodegenerative diseases.

Carnosine is also protective against secondary diabetic renal complications.

Naturally occurring Cs can be found in a stable form. Radioactive Cs is produced by the fission of uranium in fuel elements, usually near nuclear power plants. These are unstable but eventually become stable through radioactive decay. Some Cs can be found in air, water, and soil (and thereby food) based on location near nuclear plants.

Higher levels of vitamin D (25(OH)D3) have been linked to enhanced absorption of radioactive isotopes like cesium. Cs and potassium compete for uptake and cell membrane potential.

A two-carbon group from Acetyl-CoA is transferred to oxaloacetate to form citric acid. Citric acid is then converted to isocitric acid through a cis-aconitic intermediate using the enzyme aconitase. Aconitase is an iron-sulfate protein that controls iron homeostasis.

Citramalic acid and tartaric acid are yeast metabolites that are also influenced by dietary intake of fruits, wine, and sugars.

A two-carbon group from Acetyl-CoA is transferred to oxaloacetate to form citric acid. Citric acid is then converted to isocitric acid through a cis-aconitic intermediate using the enzyme aconitase. Aconitase is an iron-sulfate protein that controls iron homeostasis.

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. Because citrulline is produced in enterocytes, it has been proposed as a marker of enterocyte mass in conditions of villous atrophy.

Sources:

Legumes, mushrooms, chocolate, nuts and seeds, shellfish and liver are high in copper all greater than 2.4 µg per gram.

Food, water and air (via combustion and fossil fuels and agriculture) are sources of copper.

Copper pipes and fixtures in household plumbing may allow copper to leak into water.

Urinary creatinine is commonly used as a laboratory standardization when evaluating urinary analytes. Creatinine excretion is influenced by muscle mass and body habitus since creatinine formation occurs in muscle.

Dietary intake of proteins containing arginine and glycine (precursors of creatine) and creatine supplementation can elevate levels.

Hydration status may also play a role in urinary creatinine levels.

A urine creatinine concentration is part of every FMV analysis. All urinary biomarkers are ratioed to the creatinine concentration for standardization.

Urinary creatinine is commonly used as a laboratory standardization when evaluating urinary analytes. Creatinine excretion is influenced by muscle mass and body habitus since creatinine formation occurs in muscle. Dietary intake of proteins containing arginine and glycine (precursors of creatine) and creatine supplementation can elevate levels. Hydration status may also play a role in urinary creatinine levels.

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. Currently, there is no known source or physiologic function for cystathionine other than serving as a transsulfuration intermediate. Some literature suggests that cystathionine may exert protection against endoplasmic reticulum stress-induced tissue damage and cell death, but studies are sparse.

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 -cyst(e)ine.

Cystine is formed from the oxidation of cysteine, or from the degradation of glutathione oxidation products. It is two cysteines linked together with a disulfide bond.

The urine FMV amino acid test reports cysteine and cystine separately. The plasma amino acid test combines both cysteine and cystine as one biomarker.

D-arabinitol is a sugar alcohol produced specifically by Candida spp. The majority of the published literature shows a correlation between serum or urinary D-arabinitol levels and systemic invasive candidiasis in immunocompromised individuals. Several articles have suggested that D-arabinitol is a useful marker for diagnosis of candidiasis in this patient population as well as potentially be a prognostic indicator in a broad range of conditions.

Dihomo-gamma-linolenic acid (DGLA) is a 20-carbon omega-6 with 3 double bonds (20:3n6) derived from the essential linolenic acid. LA is metabolized to GLA, which is rapidly elongated to DGLA. There are only trace amounts of DGLA found in organ meats, otherwise it must be synthesized from GLA. The inability to convert precursor fatty acids to DGLA is associated with various pathologic and physiologic conditions such as aging, diabetes, alcoholism, atopic dermatitis, rheumatoid arthritis, cancer, and cardiovascular disease.

Dihydroxyphenylpropionic Acid (DHPPA), also known as 3,4 dihydroxyphenylpropionic acid, is a byproduct of the fermentation of dietary phenols by several bacteria, including some Clostridia spp. and others. Although once thought to identify the presence of specific dysbiotic bacteria, ongoing research suggests there are several bacterial species potentially involved.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid with 22 carbons and 6 double bonds (22:6n3). It can be obtained from the diet, supplemented, or created by conversion from DPA using elongase and desaturase enzymes. DHA is present in fatty fish such as salmon, tuna, and mackerel, and low levels of DHA can be found in meat and eggs. Both individually or in combination with EPA, DHA is widely supplemented due to the enormous amount of research available regarding its anti-inflammatory role in many clinical conditions such as cardiovascular disease, cognitive decline, autoimmune disease, fetal development, visual disturbances, cancer, and metabolic syndrome.

Docosapentaenoic acid (DPA) is an omega-3 fatty acid with 22 carbons and five double bonds (22:5n3). It is formed from its precursor, EPA, by way of the elongase enzyme which adds two carbons. It can be supplemented or obtained in the diet from foods such as marine oily fish.

Not only is DPA found in most fish and marine foods but it is also present in lean red meat from ruminant animals.

Docosatetraenoic acid (DTA) is a very long chain omega-6 fatty acid with 22 carbons and 4 double bonds (22:4n6).

It is synthesized by adding 2 carbons atoms to the backbone of arachidonic acid using the elongase enzyme. It is sometimes referred to by its common name adrenic acid and is one of the most abundant fatty acids in the early human brain and the adrenal gland. DTA has not been well studied, though it has recently been shown to have important physiologic functions. It is now believed to be a pro-resolving mediator in inflammation by blocking neutrophilic metabolites and dampening the inflammation response. For example, in osteoarthritis DTA enhances phagocytosis by macrophages which clears products of cartilage breakdown in the joint space. Supplementation of DTA is being studied as a promising intervention in osteoarthritis to dampen inflammation and prevent structural damage.

Eicosadienoic acid (EDA) is a rare, omega-6 fatty acid with a 20-carbon backbone and two double bonds (20:2n6). It is mainly formed through the downstream metabolism of omega-6s by elongating LA. EDA can be metabolized to form DGLA and AA. Literature is sparse regarding its role in the inflammatory cascade though it is known to modulate the metabolism of other PUFAs and to alter the responsiveness of macrophages to stimulate inflammation.

Eicosapentaenoic acid (EPA) is an omega-3 fatty acid with 20 carbons and 5 double bonds (20:5n3).

EPA can either be made from the downstream metabolism of ALA or it can be obtained in the diet. Food sources include oily fish such as salmon, mackerel, cod, and sardines. In addition to diet and ALA desaturation, EPA is also available as a fish oil supplement. The desaturation of ALA to EPA is not a very efficient process, therefore dietary intake or supplementation is important.

Elaidic acid (EA) is an 18-carbon chained fatty acid with one double bond in the trans formation at the 9th carbon (18:1n9t). It is the trans isomer of oleic acid. EA is the principal and most abundant trans fatty acid in the Western diet. It is found in partially hydrogenated vegetable oil and margarine. There are trace amounts of EA in the meat and dairy products from ruminant animals. EA has been shown to induce oxidative stress and alter mitochondrial signaling. It is quickly incorporated into triglycerides and cholesterol esters. Once incorporated into plasma membranes, it activates nuclear factorkB to induce adhesion molecules and become proinflammatory leading to endothelial dysfunction.

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.

Formiminoglutamic Acid (FIGlu) is an intermediary organic acid in the conversion of the amino acid histidine to glutamic acid. This enzymatic conversion requires tetrahydrofolic acid.

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.

γ-linolenic acid (GLA) is an omega-6 fatty acid containing 18 carbons and 3 double bonds (18:3n6).

It is synthesized from LA by adding a double bond using the delta-6-desaturase enzyme. This enzymatic reaction is very slow and further impaired in vitamin and mineral deficiencies such as zinc and cobalt.

Stress, smoking, alcohol, and systemic inflammatory conditions can also slow this conversion.

Used as a nuclear MRI contrast agent (usually in its chelated form). Also used in magnets, compact discs, superconductors, magnets, and fluorescent materials.Can also be found in ground and drinking water.

Gdions in chelates can be exchanged with cations like zinc, copper, calcium, or iron. Zinc is a major contributor, therefore adequatezinc levels improve Gd excretion.

Gdcan accumulatein tissue, bone, and brain. Usually removed via kidney. Chelated Gd can dissociate under certain metabolic conditions and inhibit intracellular calcium signalingand disrupt the action of thyroid hormone. Gd targets iron recycling macrophages, induces cellular iron import/export, and labile iron release, which participates in systemic fibrosis.

Used in integrated circuits, LED’s, solar cells, laser diodes. It is also used in medicine, where the radioisotopes are used as imaging agents,and stable compounds are used in chemotherapy. Ga can be a antimicrobial agent, and used to treat life-threatening, malignancyrelated hypercalcemia. Can be found in ground water near mining, manufacturingand coal combustion plants. Most commonly seen in occupationalexposures, while thereis less data on consumer electronic exposures.

Ga competes with iron for transferrin binding and inhibits receptor-mediated iron uptake by cells, renderingcells irondeficient. Iron replacement has been shown to restore hemoglobin production in Ga exposed cells. It was also found to interact with bone metabolism and to lower calcium levels in the blood.

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.

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.

Glutaric Acid is formed from the essential amino acids lysine and tryptophan through the intermediaries of alpha ketoadipic acid and glutaryl-CoA. Glutaryl-CoA is further metabolized to glutaconyl- and crotonyl-CoA by an enzyme called glutaryl-CoA dehydrogenase. This enzyme requires riboflavin (vitamin B2) as a cofactor.

Glyceric acid is an organic acid that stems from the catabolism of the amino acid serine. Severe elevations in glyceric acid are an indication of a rare inborn error of metabolism known as glyceric aciduria. One form of glyceric aciduria is the result of a defect in the enzyme glycerate kinase which removes glyceric acid from the system. While many case studies have linked this disorder with severe developmental abnormalities, there is some debate as to whether glycerate kinase deficiency is the cause or rather a confounding variable. Another glyceric aciduria is referred to as primary hyperoxaluria type 2 (PH2). This rare genetic condition results in excessive production of oxalates in the system in the form of oxalic acid. Over time, systemic deposition of oxalates in body tissues can occur which is a process known as oxalosis. This disease is characterized by urolithiasis, nephrocalcinosis, and deposition of oxalates in other body tissues.

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.

Glycolic acid is another byproduct of the oxalate pathway and comes from the conversion of glyoxylic acid. Urinary levels of glycolic acid have most commonly been studied in the rare inborn error of metabolism primary hyperoxaluria type 1 (PH1). PH1 is caused by a deficiency of alanine:glyoxylate aminotransferase (AGT) which converts glyoxylic acid into glycine.

Benzoic acid and hippuric acid are formed from the bacterial metabolism of polyphenols. Urinary benzoic acid may also come from ingestion of food preservatives such as sodium benzoate. Hippuric acid is made when sodium benzoate is conjugated with glycine.

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. 

Homovanillic acid (HVA), or 3-methoxy-4- hydroxyphenylacetic acid, is a metabolite of dopamine. Although dopamine is an important brain neurotransmitter, a substantial amount of dopamine is produced in the GI tract.

In neurotransmitter production, dopamine is formed from phenylalanine and tyrosine using several enzymes which require nutrient cofactors such as iron, tetrahydrobiopterin, and pyridoxal phosphate.

Indoleacetic acid (IAA), or indole-3-acetate, is produced by the bacterial fermentation of the amino acid tryptophan.

IAA can be formed from several common gut microbes such as Clostridia species, Escherichia coli, and Saccharomyces species.

A two-carbon group from Acetyl-CoA is transferred to oxaloacetate to form citric acid. Citric acid is then converted to isocitric acid through a cis-aconitic intermediate using the enzyme aconitase. Aconitase is an iron-sulfate protein that controls iron homeostasis.

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).

Isovalerylglycine is produced from leucine catabolism. It is further metabolized via isovaleryl-CoA dehydrogenase. This enzyme requires vitamin B2 as a cofactor.

Because of the specific inflammatory component of quinolinic acid, as well as the potentially protective role of kynurenic acid peripherally, laboratories measure the ratio of kynurenic acid to quinolinic acid. This ratio can act as a measure of disturbed kynurenine pathway metabolism. It suggests that tryptophan is catabolized via the kynurenine pathway, rather than the serotonin pathway.

Kynurenic acid and Quinolinic acid are tryptophan metabolites formed through the kynurenine pathway. Tryptophan is the amino acid precursor to serotonin; its major route for catabolism is the kynurenine pathway. Important products of the kynurenine pathway include xanthurenic acid and kynurenic acid, which can further metabolize into quinolinic acid. The historical importance of this pathway has mainly been as a source of the coenzyme NAD+, which is important for all redox reactions in the mitochondria.

However, it is now understood that kynurenic and quinolinic acid have physiologic implications. This alternate pathway is upregulated in response to inflammation and stress, which can lead to deficient serotonin production. Kynurenic acid has shown some neuroprotective properties in the brain, since it can stimulate NMDA receptors. However, its importance on the periphery is still not fully elucidated. Some studies outline antiinflammatory, analgesic, antiatherogenic, antioxidative, and hepatoprotective properties to peripheral kynurenic acid.

The correlation to levels of urinary excretion needs further study. Quinolinic acid, in and of itself, can be inflammatory and neurotoxic.

Lactic Acid and Pyruvic Acid are byproducts of glycolysis. Carbohydrates, which contain glucose, are broken down through glycolysis to form pyruvate and two ATP molecules. Pyruvate can also be generated through the catabolism of various amino acids, including alanine, serine, cysteine, glycine, tryptophan and threonine. Magnesium is an important cofactor for a number of glycolytic enzymes necessary to produce pyruvate. Optimally, pyruvic acid is oxidized to form Acetyl-CoA to be used aerobically via the Citric Acid Cycle to produce energy. In an anaerobic state, lactic acid is formed instead.

Found naturally in soil. More often found in fossil fuels, gasoline/exhaust, manufacturing, lead-acid batteries, ammunitions, metal solder and pipes, X-ray shields, paint, glass, pigments, and sheet lead.

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).

Lignoceric acid has 24 carbons and no double bonds (24:0). It can be formed from behenic acid using the elongase enzyme. It is found in peanuts, nut and seed oils. It can also be found in wood tar. Lignoceric acid is one of many fatty acids which compose brain tissue and myelin.

Linoleic acid (LA) is the only essential omega-6 fatty acid and must be obtained from the diet.

From LA, other omega-6s can be created using elongase and desaturase enzymes. LA contains 18 carbons, with 2 double bonds, the first of which is at the 6th carbon position (18:2n6).

LA is found in nuts and vegetable oils (corn, soybean, canola, sunflower, etc.) as well as most meats. When the double bonds of LA are arranged differently, the term conjugated LA (CLA) is used. Although technically CLA can be termed a trans-fat, a natural type of CLA can be obtained in the dietary intake of meat and milk from ruminant animals. There are many isomers of CLA – some beneficial and others are not as well defined. There is some controversy regarding how much LA is needed from the diet for adequacy. Although LA is needed to synthesize downstream fatty acids, it may lead to increased inflammatory fatty acid production.

LA/DGLA is a fatty acid ratio.

LA/DGLA stands for linolenic acid (=LA) and dihomogammalinolenic acid (=DGLA).

The LA/DGLA ratio is a biomarker that can indicate functional zinc deficiency.

Lipid peroxides are a class of reactive oxygen species (ROS) that preferentially oxidize polyunsaturated fatty acids (PUFAs) linoleic, arachidonic, and docosahexaenoic acids (omega-6 PUFAs).

Lipid peroxides exert their toxic effects via two mechanisms. One is by altering the assembly, composition, structure and dynamics of cell membrane lipid bilayers. The second is by producing more reactive oxygen species or by degrading into reactive compounds capable of damaging DNA and proteins.

The central nervous system is particularly prone to lipid peroxidation due to the high quantity of ROS as a byproduct of ATP synthesis in a lipid-enriched environment.16 Circulating LDLs can be affected by lipid peroxidation and are implicated in diseases including atherosclerosis, metabolic syndrome, and diabetes.

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.

Fumaric acid uses the fumarase enzyme to become malic acid. Malate dehydrogenase catalyzes the conversion of malic acid into oxaloacetate. Two forms of this enzyme exist in eukaryotes. One operates within the mitochondria to contribute to the Citric Acid Cycle; the other is in the cytosol where it participates in the malate/ aspartate shuttle. Riboflavin is an important cofactor for this enzyme and overall mitochondrial energy production and cellular function. At the end of each Citric Acid Cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Margaric acid is also known as heptadecanoic acid. It is a 17-carbon saturated fatty acid (17:0). Food sources mainly include milk and dairy products, though it can be endogenously made as well.

Most research in fatty acid metabolism has focused on even-chain fatty acids since they represent >99% of total human lipid concentration. For years, it had been concluded that odd chain saturated fatty acids (OCSFAs) were of little significance and used only as internal standards in laboratory methodology. However, there is now a realization that they are, in fact, relevant and important physiologically.

SOURCES:

Mercury (Hg) has three forms:

Elemental (metallic)- older glass thermometers, fluorescent light bulbs, dental amalgams, folk remedies, combustion, electrical industry (switches, batteries, thermostats), solvents, wood processing

Organic (methyl mercury)- seafood, thimerosal (preservative), fungicides

Inorganic- skin lightening compounds, industrial exposure, folk medicine, lamps, photography, disinfectants

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).

Methylmalonic Acid (MMA) is formed from propionylCoA via methylmalonyl-CoA. Major dietary sources of propionyl-CoA include valine, isoleucine, methionine, threonine, and odd chain fatty acids. MethylmalonylCoA is converted to succinyl-CoA to feed the Citric Acid Cycle via the enzyme methylmalonyl-CoA mutase. This enzyme is very vitamin B2 dependent. In B12 deficiency, methylmalonyl-CoA is hydrolyzed to methylmalonic acid.

Sources of Molybdenum:

- Beans (lima, white, red, green, pinto, peas),

- grains (wheat, oat, rice),

- nuts,

- vegetables (asparagus, dark leafy, Brassicas),

- milk, cheese.

Absorption factors:

- Molybdenum absorption is passive in the intestines.

- Urinary excretion is a direct reflection of dietary Molybdenum intake, not necessarily Molybdenum status.

- Increased Mo intake may elevate urinary copper excretion.

Nervonic acid (NA) is an omega-9 MUFA with a 24-carbon backbone and one double bond (24:1n9). It is a very important fatty acid in the white matter of the brain and is responsible for nerve cell myelin biosynthesis. There are small amounts of NA in cooking fats, vegetable oils and borage oil. It can also be synthesized in the body by elongating oleic acid (which is essentially desaturated stearic acid). NA is essential for the growth and maintenance of the brain and peripheral nervous tissue enriched with sphingomyelin.

Oleic acid (OA) has an 18-carbon backbone with one double bond at the 9th position (18:1n9). Oleic acid’s main dietary source is olive oil, and it is also available as a supplement. OA can also be synthesized in the body by adding a double bond to stearic acid using the enzyme delta-9-desaturase. Oleic acid is important in cell membrane fluidity and has attracted a lot of positive attention due the amount of olive oil found in the ‘Mediterranean diet.’

The omega-3 index is defined as the RBC percentage sum of EPA+DHA, both of which are important antiinflammatory omega-3 fatty acids. This index was first proposed in 2004 as a cardiovascular risk factor by Dr. Willian S. Harris and Dr. Clemons von Schacky as a way of assessing risk for coronary artery disease and related death. Since then, it has been repeatedly verified as an important cardiovascular biomarker, and studied in other diseases including obesity, mood disorder, and insulin resistance.

A reasonable target for the omega-3 index is >8% to decrease disease risk. Drs. Harris and von Schacky stratified risk zones as high risk (8%). These percentages have been continually verified in outcome studies and risk assessment.

Dietary intervention to increase the omega-3 index should include oily fish, flax, walnut, and chia. Fish oil supplementation can also be considered.

There has been a significant change in the balance of Omega-6s to Omega-3s with the evolution of the Western diet. Close to a 1:1 balance existed throughout history. However, rapid dietary changes and food industry advances have altered this to now be vastly in favor of Omega-6s by upwards of 20:1. This change correlates with many chronic diseases such as cardiovascular disease, cancer, metabolic syndrome, obesity, mood disorders, autoimmunity, and neurogenerative disease.

Dietary interventions which favor omega-3, in lieu of omega-6s, is recommended with elevations in this ratio to achieve a closer balance between the two.

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.

Orotic Acid is an organic acid which serves as an intermediate in nucleotide synthesis and is linked to arginine metabolism as a urea cycle marker for nitrogen balance.

It is formed from aspartic acid and carbamoyl phosphate. Carbamoyl phosphate plays an important role in the body because it brings nitrogen into the urea cycle for detoxification and disposal. Carbamoyl phosphate enters the urea cycle to react with ornithine to form citrulline. When ammonia levels significantly increase or the liver’s capacity for detoxifying ammonia into urea decreases, carbamoyl phosphate leaves the mitochondria and instead enters the pyrimidine pathway. This stimulates orotic acid biosynthesis and subsequent urinary excretion. Orotic acid can also be found in the diet. The richest dietary sources include cow’s milk and dairy products.

Oxalic acid is the metabolic end-product of the glyoxylase pathway and is derived from the oxidation of glyoxylate.

In the cell, the majority of glyoxylate is converted into glycine or glycolic acid. However, in some instances there may be greater oxidation of glyoxylate to oxalic acid. This leads to increased urinary excretion of oxalic acid.

As 80% of kidney stones are calcium-oxalate stones, an increase in oxalic acid is strongly correlated to frequency of urolithiasis.

Palmitic acid (PA) is a 16-carbon saturated fatty acid (16:0) and the most common fatty acid in the human body. It can be obtained via diet or synthesized from carbohydrates, other fatty acids, and amino acids. As the name suggests, it is a major component of palm oil, but can also be found in meat, dairy, cocoa butter, coconut oil, and olive oil.

Palm oil and palmitic acid are also found in many products ranging from skincare products, margarine, cereals, and baked goods.

Palmitoleic acid (POA) is a monounsaturated omega-7 fatty acid (16:1n7).

The main dietary sources of palmitoleic acid include dairy products, avocado oils, oily fish, and macadamia nuts. Macadamia nuts contain the cis- isomer of POA, while dairy products mainly contain the trans- isomer. Like many fatty acids, POA can also be endogenously made from the breakdown of triglycerides, the desaturation of palmitic acid, or de novo synthesis from carbohydrates. POA is an important signaling lipokine, produced mainly by white adipose tissue, that regulates important metabolic processes such as skeletal muscle glucose disposal, insulin sensitivity, and hepatic lipid deposition. It is also a modulator of adipocyte lipolysis, however, studies are mixed as to POA’s specific role in obesity. Epidemiologic studies show that circulating POA levels are involved in cholesterol metabolism and hemostasis, though the results are mixed as to their specific cardiovascular outcomes.

Pentadecanoic acid is a 15-carbon saturated fatty acid (15:0) and hence an Odd-Chain Saturated Fatty Acids (OCS-FAs).

Its major dietary source is the butterfat in cow’s milk. It can also be synthesized from propionate.

Most research in fatty acid metabolism has focused on even-chain fatty acids since they represent >99% of total human lipid concentration. For years, it had been concluded that odd chain saturated fatty acids (OCSFAs) were of little significance and used only as internal standards in laboratory methodology. However, there is now a realization that they are, in fact, relevant and important physiologically.

Phenylacetic acid (PAA) is produced by the bacterial metabolism of phenylalanine. Several bacterial strains are known to produce PAA, including Bacteroidetes and Clostridium species. Dietary polyphenols may also contribute to PAA elevation.

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 serine-to-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. Elevated phosphoethanolamine reflects brain phospholipid turnover, an indicator of neural membrane synthesis and signal transduction. Research into neurologic conditions like Alzheimer’s disease and Huntington’s disease suggests that depletions of both phosphoethanolamine and ethanolamine accompany neuronal death. Phosphoethanolamine is also important in cartilage structure and function, especially in bone and teeth.

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. In addition to dietary sources, proline can be synthesized from glutamate/glutamine, arginine, and ornithine. It can also be synthesized within enterocytes from degradation of small peptides.

Pyroglutamic acid (5-oxoproline) is produced and utilized in the gamma-glutamyl cycle. This cycle is needed to assist in the production and recycling of glutathione (GSH), a powerful antioxidant.

Glutathione is a tripeptide, consisting of glutamate, cysteine, and glycine. Using the gamma-glutamyl cycle, GSH is divided into cysteinyl glycine and a gammaglutamyl molecule which attaches to another amino acid for transport across a membrane or into a cell. Gammaglutamyl transferase then splits off that attached amino acid, and the glutamate becomes pyroglutamic acid (5-oxoproline).

Cysteinyl glycine is also broken down and transported into the cell as cysteine and glycine. The entire GSH molecule needs to be reformed intracellularly from pyroglutamic acid by recombining cysteine, glycine, and glutamic acid using GSH synthetase.

This enzymatic reformation requires cofactors such as ATP and magnesium.

Lactic Acid and Pyruvic Acid are byproducts of glycolysis. Carbohydrates, which contain glucose, are broken down through glycolysis to form pyruvate and two ATP molecules. Pyruvate can also be generated through the catabolism of various amino acids, including alanine, serine, cysteine, glycine, tryptophan and threonine. Magnesium is an important cofactor for a number of glycolytic enzymes necessary to produce pyruvate. Optimally, pyruvic acid is oxidized to form Acetyl-CoA to be used aerobically via the Citric Acid Cycle to produce energy. In an anaerobic state, lactic acid is formed instead.

Kynurenic acid and Quinolinic acid are tryptophan metabolites formed through the kynurenine pathway. Tryptophan is the amino acid precursor to serotonin; its major route for catabolism is the kynurenine pathway. Important products of the kynurenine pathway include xanthurenic acid and kynurenic acid, which can further metabolize into quinolinic acid. The historical importance of this pathway has mainly been as a source of the coenzyme NAD+, which is important for all redox reactions in the mitochondria.

However, it is now understood that kynurenic and quinolinic acid have physiologic implications. This alternate pathway is upregulated in response to inflammation and stress, which can lead to deficient serotonin production. Kynurenic acid has shown some neuroprotective properties in the brain, since it can stimulate NMDA receptors. However, its importance on the periphery is still not fully elucidated. Some studies outline antiinflammatory, analgesic, antiatherogenic, antioxidative, and hepatoprotective properties to peripheral kynurenic acid.

The correlation to levels of urinary excretion needs further study. Quinolinic acid, in and of itself, can be inflammatory and neurotoxic.

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. Some clinicians use sarcosine elevation as a marker of ‘excess methyl supplementation’ or ‘over-methylation.’ Currently, there is no literature to support this hypothesis, but rather it is based on physiology.

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

Stearic acid (SA) is a saturated fatty acid with an 18-carbon backbone (18:0). Although it is mainly abundant in animal fat, cocoa butter and shea butter are also very high in SA. It is also commonly used in detergents, soaps, cosmetics, shampoos, and shaving cream. Additionally, it can be synthesized in the body from palmitic acid. SA is not a strong substrate to make triglycerides compared to other saturated fatty acids and it generates a lower lipemic response.

Dietary fatty acids are metabolized into fuel sources using beta-oxidation. Fatty acid conversion into Acetyl-CoA requires transport across the mitochondrial membrane via the carnitine shuttle. When beta-oxidation is impaired, fats are metabolized using an alternate pathway called omega-oxidation. Omega-oxidation results in elevated levels of dicarboxylic acids such as adipic acid and suberic acid. Impaired beta-oxidation occurs in carnitine deficiency or enzymatic dysfunction due to lack of nutrient cofactors. Vitamin B2 and magnesium play a role in optimizing beta-oxidation.

Succinyl CoA becomes succinic acid using succinyl CoA synthetase. This reaction produces NADH which directly provides electrons for the electron transport chain or respiratory chain. Succinic acid requires the enzyme succinate dehydrogenase to become fumarate. This enzyme is ironbased and requires vitamin B2 to support flavin adenine dinucleotide (FAD) as a redox coenzyme. Succinate dehydrogenase plays a critical role in mitochondrial metabolism. Impairment of this enzyme’s activity has been linked to a variety of diseases such as cancer and neurodegenerative diseases.

- Tartaric acid is a compound found in plant foods. It has been identified as a biomarker of grape intake, though it has also been identified in other foods. Tartaric acid levels peak at 4–8 hours after intake. Levels in foods vary significantly between types of foods and within individual foods.

- Tartaric acid cannot be processed by humans and is either excreted or utilized by gut bacteria as a carbon source. Some bacteria have genes for tartaric metabolizing enzymes, so levels can be impacted by gut microbiome. The process starts once tartaric acid is released (i.e., grapes are crushed or are invaded by pathogens), making it susceptible to catabolic enzymes from microorganisms, which may reduce it to oxaloacetate, glyceric acid, and pyruvic acid.

Common Dietary Sources:

Wine/grapes, chocolate, food additive/preservative

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).

It has been proposed that taurine acts as an antioxidant, intracellular osmolyte, membrane stabilizer, and a neurotransmitter.

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.

Tricosanoic acid is an 23-carbon, odd-chain saturated fat (23:0) synthesized initially from propionic acid and can be derived in the diet from sesame, sunflower, and hempseed oils. It can furthermore be found in milk and dairy products, as well as some wild mushroom species. It can also be endogenously made.

Most research in fatty acid metabolism has focused on even-chain fatty acids since they represent >99% of total human lipid concentration. For years, it had been concluded that odd chain saturated fatty acids (OCSFAs) were of little significance and used only as internal standards in laboratory methodology. However, there is now a realization that they are, in fact, relevant and important physiologically.

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. Within the metabolism of tyrosine to form neurotransmitters and other hormones, there are several important nutrient cofactors involved including vitamin B1, vitamin B6, tetrahydrobiopterin, copper, vitamin C, among others.

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.

Vaccenic acid (VA) is a monounsaturated omega-7 fatty acid (18:1n7).

VA is a naturally occurring trans-fat unlike those produced industrially. The trans-configuration occurs around carbon 11, therefore VA is sometimes denoted as trans11-18:1n7. Ruminant animals produce vaccenic acid in a fermentation process in their microbiome. The dairy products (cheese, milk, butter) or meat obtained from these animals contain VA. There is also a cis-configuration of vaccenic acid created by de novo lipogenesis.

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).

Sources:

Mushrooms, shellfish, black pepper, parsley, dill seed, beer, wine, grains, sweeteners, infant cereals.

Fossil fuels, welding, catalysts, steel alloys, batteries, photographic developer, drying agent in paints/varnishes, reducing agent, pesticides, black dyes/inks/pigments in ceramics, printing and textile industries.

Vanilmandelic acid (VMA) is formed in the liver by the oxidation of 3-methoxy-4-hydroxyphenylglycol.

As a downstream metabolite of tyrosine-derived catecholamines, levels of VMA can reflect the overall synthesis and metabolism of catecholamines.

Whether norepinephrine or epinephrine are metabolized into VMA or 3-methoxy-4-OH-phenylglycol (MHPG) depends on the presence and specificity of various available aldehyde reductase and dehydrogenase enzymes.

Xanthurenic acid is produced as part of the kynurenine pathway of tryptophan catabolism, along with kynurenic and quinolinic acid.