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Izumi Lab. 15

As you can see in the figure, there was a greater rise in the plasma alpha-tocopherol levels after receiving RRR-alpha-tocopherol vs. all-rac-alpha-tocopherol. This is not a surprise because approximately 50% of all-rac-alpha-tocopherol is 2R alpha-tocopherol that binds well with alpha-TTP. You can also see that the plasma gamma-tocopherol concentration is much lower than either natural or synthetic alpha-tocopherol. From VLDL and subsequent lipoproteins, vitamin E reaches tissues, with most vitamin E in the body being found in the adipose tissue. There are 2 main routes of vitamin E excretion. The major route of excretion is through bile that is then excreted in feces. The second route is in the urine after vitamin E is chain-shortened in a process similar to beta-oxidation to make them more water-soluble. Reference 1. Traber MG, Elsner A, Brigelius-Floh R. (1998) Synthetic as compared with natural vitamin E is preferentially excreted as alpha-CEHC in human urine: Studies using deuterated alpha-tocopheryl acetates. FEBS Lett 437(1-2): 145-148.

The best food sources of vitamin E are primarily oils and nuts. As you can see below, the forms of vitamin E that nuts and oils contain varies, with the two major forms being alpha and gamma-tocopherol. Soybean, corn, and flaxseed oils are good sources of gamma-tocopherol. Palm and canola oils contain almost equal amounts of alpha-tocopherol and gamma-tocopherol. Safflower oil, almonds, sunflower oil, and wheat germ oil are good sources of alpha-tocopherol. Beta-tocopherol and delta-tocopherol are found in lower levels in foods. Tocotrienols, for the most part, are not found in high levels in the diet. The amount of tocopherols in different nuts and oils are shown in the figure below.

Three-fourths of the oil Americans consume is soybean oil. As a result, it is estimated that we consume 2-4 times more gamma-tocopherol than alpha-tocopherol. Europeans consume more olive, sunflower, and canola oil and thus are believed to consume at least 2 times more alpha-tocopherol than gamma-tocopherol1. Despite Americans’ higher intake of gamma tocopherol compared to other countries, our serum (liquid portion of blood without coagulation proteins) concentrations do not differ much as illustrated in the table below.

Vitamin E deficiency is extremely rare. Depletion studies require years on a vitamin E-deficient diet to cause deficiency1. Deficiency primarily occurs in people with lipid malabsorption problems or Ataxia with Isolated Vitamin E Deficiency (AVED). Individuals with AVED have a mutation in their alpha-TTP that prevents it from functioning correctly. The primary symptoms of vitamin E deficiency are neurological problems. High levels of vitamin E intake do not result in a noted toxicity. However, higher levels of intake of alpha-tocopherol (like achieved by taking supplements) are associated with decreased blood coagulation. In particular, hemorrhagic stroke has been linked to high alpha-tocopherol intake levels. The link below shows that in this condition a blood vessel ruptures or leaks in the brain.

Before 2001, all forms of vitamin E contributed to the RDA, using a measure called alpha-tocopherol equivalents. This indicator essentially provided a value for all forms relative to alpha-tocopherol. In 2001, the Dietary Reference Intake (DRI) committee decided only 2R forms of alpha-tocopherol should be used to estimate the requirement, because these forms bind to alpha-TTP. Thus, other forms of vitamin E (gamma-tocopherol, tocotrienols etc.) do not count toward the requirement and the unit is now mg of alpha-tocopherol. As a result, soybean, corn, and flaxseed oils, which are good sources of gamma-tocopherol, are no longer considered to be good sources of vitamin E. The figure below is a reminder of the tocopherol content of different nuts and oils.

Another level of complexity is added by international units (IU). IUs are a unit that are used to describe the bioactivity of different compounds, including 4 vitamins: A, D, E, and C. You might be wondering why these 4 vitamins, it is because these are the ones that were chosen by those who set IUs. Most likely because these vitamins are commonly included in supplements. It would be less confusing if these units were not used. However, most supplements use IUs, IUs are not as common on food items.

Example 2. For a supplement containing 100 IU of all-rac-alpha tocopherol: 100 IU X 0.45 = 45 mg alpha-tocopherol2,3 References & Links Wagner KH, Kamal-Eldin A, Elmadfa I. (2004) Gamma-tocopherol--an underestimated vitamin? Ann Nutr Metab 48(3): 169-188. DRI (2000) Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/

Vitamin C is well-known for being a water-soluble antioxidant. Humans are one of the few mammals that do not synthesize vitamin C, making it an essential micronutrient. Other mammals that do not synthesize vitamin C include primates, guinea pigs, and other less prevalent species1. This means that some species like rats, mice, dogs and cats are not great options for human vitamin C research since it is not an essential nutrient for them.

The figure below shows the reaction through which ascorbic acid can stabilize or quench 2 free radicals. The 2 circled hydrogens are lost and replaced by double bonds when ascorbic acid is oxidized to dehydroascorbic acid. Reducing dehydroascorbic acid back to ascorbic acid is the

Ascorbic acid is believed to be a part of an antioxidant network (shown below) where it is oxidized to reduce alpha-tocopherol radicals. Dehydroascorbic acid can be reduced by thioredoxin reductase, a selenoenzyme, to regenerate ascorbic acid. Figure 9.34 The theorized antioxidant network4 Subsections: Absorption & Tissue Accumulation of Vitamin C Enzymatic Functions Vitamin C Deficiency (Scurvy) Vitamin C Toxicity, Linus Pauling & the Common Cold

Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. http://en.wikipedia.org/wiki/File:Ascorbic_acid_structure.png http://en.wikipedia.org/wiki/File:Dehydroascorbic_acid.png Packer L, Weber SU, Rimbach G. (2001) Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr 131(2): 369S-373S.

Vitamin C is found in foods primarily as ascorbic acid (80-90%), but dehydroascorbic acid (10-20%) is also present. The bioavailability of vitamin C is high at lower doses as shown below, but drops to less than 50% at higher doses.

Ascorbic acid is actively absorbed by the sodium vitamin C cotransporter (SVCT) 1. This active transport is driven by the sodium electrochemical gradient created by sodium-potassium ATPase. Ascorbic acid then diffuses into the capillary and ultimately enters general circulation. Vitamin C generally circulates as ascorbic acid.

Most water-soluble vitamins are not stored in the body. Vitamin C is not stored, but is accumulated in certain tissues in the body where it can be 5-100 times higher than found in the plasma2. The table below shows the concentrations of vitamin C in different tissues and fluids.

As shown below, SVCT 1 and SVCT 2 transport ascorbic acid or ascorbate into the cell against the concentration gradient (represented by the orange wedge in the figure below). Like absorption, this uptake is driven by the action of sodium-potassium ATPase. This mechanism is saturable, meaning that at high concentrations it reaches a threshold where it cannot take up ascorbic acid any faster. Thus, there is a limit to how much can be taken up through this mechanism3.

In ascorbic acid recycling, ascorbic acid is oxidized to dehydroascorbic acid (DHA). DHA is then transported into the cell moving with its concentration gradient using GLUT1 or 3. Once inside the cell, DHA is reduced back to ascorbic acid, thus maintaining the DHA gradient. As a result, the cell is able to accumulate high levels of ascorbic acid3. The figure below depicts ascorbic acid recycling.

References & Links Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins. Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. Li Y, Schellhorn H. (2007) New developments and novel therapeutic perspectives for vitamin C. J Nutr 137(10): 2171-2184.

In addition to its antioxidant function, vitamin C is also a cofactor for a number of enzymes or contributes to reducing a cofactor in others. Proline hydroxylase and lysyl hydroxylase are two enzymes that vitamin C is needed for them to carry out their catalytic function. These enzymes are important in the formation of the protein collagen. Hydroxylase means that the enzymes add alcohol (hydroxyl, -OH) to the amino acids proline and lysine, as shown below.

As shown below, prolyl and lysyl hydroxylases require ferrous iron (Fe2+) to function. But in the course of the hydroxylating proline or lysine, ferrous iron (Fe2+) is oxidized to ferric iron (Fe3+). Ascorbic acid is required to reduce Fe3+ to Fe2+, forming semidehydroascorbic acid in the process. With Fe2+, the enzyme is then able to continue to hydroxylate proline and lysine.

Why should you care about collagen formation? Because collagen is estimated to account for 30% or more of total body proteins5. Collagen contains a number of hydroxylated prolines and lysines that are needed for collagen strands to properly cross-link. This cross-linking is important for collagen to wind together like a rope, forming the strong triple helix known as tropocollagen. This process is shown in the following animation, as well as in the figure below.

References & Links https://en.wikipedia.org/wiki/Proline#/media/File:Prolin_-_Proline.svg http://en.wikipedia.org/wiki/File:Hydroxyproline_structure.svg https://en.wikipedia.org/wiki/Lysine#/media/File:L-lysine-monocation-2D-skeletal.png http://en.wikipedia.org/wiki/File:Hydroxylysine.png Di Lullo G, Sweeney S, Korkko J, Ala-Kokko L, San Antonio J. (2002) Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen. The Journal of Biological Chemistry 277(6): 4223-4231. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:Catecholamines_biosynthesis.svg

Why should you care about the details of prolyl and lysyl hydroxylases and their actions on collagen hydroxylation and tropocollagen formation? Because they explain the symptoms of vitamin C deficiency. While it is rare in the United States, vitamin C deficiency, known as scurvy, displays symptoms that are a result of weak tropocollagen, that in turn, weakens connective tissue throughout the body. Symptoms of scurvy include bleeding gums, pinpoint hemorrhages, and corkscrew hairs as shown in the figure and link below.

Additional symptoms include impaired wound and fracture healing, easy bruising, and loose or decaying teeth. Scurvy can be fatal if not treated. Scurvy was the first discovered nutrition deficiency in 1746 by James Lind, who is shown below.

Keep in mind as you read the description below that suggesting scurvy was due to a diet deficiency, at that time, sounded like flu was caused by not consuming green beans. Sounds pretty crazy, right? Because the concept of vitamines and compounds that would become vitamins were not proposed until around 150 years later. Lind was a surgeon on a British navy ship. Frequently during voyages the sailors would develop scurvy for reasons that were not understood at the time. It was known that citrus fruits could cure or prevent scurvy, but it was believed this was due to their acidity. Lind performed clinical trials comparing citrus juice to dilute sulfuric acid and vinegar and found that only citrus juice caused the sailors to recover, as depicted in the link below. As a result of the discovery, the British sailors became known as "Limeys" because they would drink lime juice to prevent the development of the disease4. References & Links http://en.wikipedia.org/wiki/File:Scorbutic_gums.jpg Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:James_lind.jpg Carpenter K. (2003) A short history of nutritional science: Part 3 (1912-1944). J Nutr 133(10): 638-645.

Vitamin C does not have a toxicity per se, but in some people over 2 grams/day can lead to diarrhea and gastrointestinal distress. In addition, high intake of vitamin C increases excretion of uric acid (urate) and oxalic acid (oxalate). The structure of these 2 compounds are shown below.

Calcium oxalate is one of the primary forms of kidney stones with uric acid stones being more rare3. However, a link between excretion of these compounds and actual stone formation has not been established. Nevertheless, high-dose vitamin C supplementation should be approached with some caution, since it is not clear whether it increases the risk of forming kidney stones5.

The person who popularized taking megadoses of vitamin C was Dr. Linus Pauling. Dr. Pauling was a chemist, and is the only person to receive 2 unshared Nobel Prizes. The Nobel Prize is a prestigious award, and Dr. Pauling was close to solving the structure of DNA. This would have likely netted him another Nobel prize, but Watson and Crick beat him to it.

Later in his life Pauling became convinced that megadoses of vitamin C could prevent the common cold. In 1970 his book Vitamin C and the Common Cold was released and became a bestseller. Later he came to believe that vitamin C could prevent cardiovascular disease, cancer, and combat aging7. However, critics of his beliefs countered that all megadose supplementation was doing was creating "expensive urine". This refers to the fact that the RDA is only 75-90 mg/day for adults and Pauling recommended taking 1-2 grams of vitamin C daily8. Thus, with vitamin C being water-soluble, most of the vitamin C that people on the regimen were paying to consume was being excreted in the urine, thus making it “expensive”. A review of vitamin C and colds found that that routine megadoses of vitamin C do not reduce the risk of the common cold in most individuals. However, there is some evidence that it might benefit people exposed to brief periods of severe physical exercise (marathon runners) or cold environments (skiers and soldiers in subarctic conditions). There has been little research conducted in children, so it is not known whether vitamin C supplementation is beneficial in this age group9. References & Links http://en.wikipedia.org/wiki/File:Harns%C3%A4ure_Ketoform.svg http://en.wikipedia.org/wiki/File:Calcium_oxalate.png https:// https://commons.wikimedia.org/wiki/File:Pos-renal.png Massey L, Liebman M, Kynast-Gales S. (2005) Ascorbate increases human oxaluria and kidney stone risk. J Nutr 135(7): 1673-1677. https:// 8. _pauling

Selenium can be divided into 2 categories: organic and inorganic. The organic forms contain carbon, while the inorganic forms do not. The primary inorganic forms of selenium are selenite (SeO3) and selenate (SeO4). Selenite and selenate are not commonly found alone in nature; they are usually complexed with sodium to form sodium selenite (Na2SeO3) and sodium selenate (Na SeO )1. Selenomethionine is the most common organic form of selenium. The structure of selenomethionine is shown above the structure of the amino acid methionine in the figure below. Figure 9.41 Structures of organic forms of selenium and similar sulfur-containing amino acids In comparing the structures of selenomethionine or methionine, you can see that the only difference is that selenium has been substituted for sulfur (S) in methionine. Selenocysteine is considered the 21st amino acid by some, because there is a codon that directs its insertion into selenoproteins. Like selenomethionine versus methionine, the only difference between selenocysteine and cysteine is the substitution of selenium for sulfur. The last organic form is methylselenocysteine (aka Se-methylselenocysteine). Notice that its structure is like selenocysteine, but with a methyl group added (like the name suggests). The selenium content of plants is dependent on the soil where they are grown. As shown below, soil selenium levels vary greatly throughout the United States, meaning that the selenium content of plant foods also vary greatly. Figure 9.42 United States soil selenium levels2

Inorganic forms of selenium are commonly used in supplements. Selenomethionine is the most common organic form of selenium in supplements and food. It is found in cereal grains such as wheat, corn, and rice as well as soy. Yeast are typically used to produce selenomethionine for supplements. It should be noted that selenomethionine accumulates at much higher concentrations in the body than other forms of selenium. This is because it can be nonspecifically incorporated into body proteins in place of methionine. However, despite accumulating at higher levels, selenomethionine is less effective than the methylselenocysteine in decreasing cancer incidence or growth in animal models3. However, methylselenocysteine is not commonly consumed, because it is a form that plants accumulate to prevent selenium from becoming

As mentioned earlier, selenium's antioxidant function is not due to the mineral itself, but a result of the action of selenoenzymes. Selenoenzymes is a term used to describe the subset of selenoproteins that are enzymes. This is illustrated in the figure below, where the different colored circles represent amino acids in the crescent shaped enzyme. In most enzymes, the mineral is a cofactor that is external to the enzyme, as shown on the left. Selenoenzymes contain selenocysteine as an amino acid in the active site of the enzyme. Thus, in selenoenzymes, selenium does not serve as a cofactor, which is different than most minerals required for enzyme function.

Hopefully from looking at the table, you see that the glutathione peroxidase enzymes and thioredoxin reductases are antioxidant enzymes. The iodothyronine 5'-deiodinases are involved in the metabolism of thyroid hormones, which will be discussed further in the iodine section. For the vast majority of the other selenoproteins, their function is not known, so they were named selenoprotein and given a letter. As described earlier and shown below, glutathione peroxidase converts hydrogen peroxide into water.

References & Links Gladyshev V, Kryukov G, Fomenko D, Hatfield D. (2004) Identification of trace element-containing proteins in genomic databases. Annu Rev Nutr 24: 579-596. Beckett G, Arthur J. (2005) Selenium and endocrine systems. J Endocrinol 184(3): 455-465. Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. Packer L, Weber SU, Rimbach G. (2001) Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr 131(2): 369S-373S.

Selenium is highly absorbed. Thus, selenium levels in the body are not regulated by absorption, but rather by urinary excretion. Organic selenium forms may be absorbed slightly better than inorganic forms, as one study found that 98% of a dose of selenomethionine was absorbed, compared to 84% of selenite1.

Selenium toxicity can be a problem, especially for animals living in or around a body of water in an area with high soil selenium levels. This is because runoff from the soil causes selenium to collect in the water in high levels and then starts working its way up the food chain and causing problems, as shown in the following link.

The questionable selenium deficiency is Keshan disease. This disease occurred primarily in the mountainous regions of China, causing heart lesions. Below is a topographical map of China to give you an idea of what areas are mountainous.

However, sodium selenate supplementation failed to totally eradicate Keshan disease like you would expect if it was caused by selenium deficiency. The incidence of Keshan disease also fluctuated seasonally and annually, which is unusual for a deficiency and more consistent of an infectious disease. Research found coxsackievirus in the heart of Keshan disease victims. They isolated this virus and used it to perform the experiment illustrated below.

One group of mice was fed an adequate selenium diet and another group a deficient selenium diet. They were then infected with coxsackievirus that was mostly avirulent, but also contained some virulent viruses. A virulent virus is one that causes a disease, and an avirulent virus is one that does not cause a disease (some vaccines use avirulent viruses). After a period of time, they found that the selenium deficient animals developed severe heart pathology, while the selenium adequate animals did not develop heart pathology. They then isolated the virus from the hearts of the mice from both groups and found that the coxsackievirus from the deficient animals’ hearts had become mostly virulent3. They then took it one step further as shown in the figure below. Figure 9.423 Keshan disease experiment continued3 They took the isolated virus from the selenium-deficient mouse hearts and infected selenium adequate animals with it. The selenium adequate animals developed severe heart pathology like the selenium-deficient animals had previously. What's going on? They found mutations in the virus from the selenium-deficient animals that they believe caused it to become virulent. They believe that high oxidative stress, as a result of inadequate antioxidant selenoenzymes, in these animals leads to mutations in the virus causing it to become virulent. Who cares? Research has found similar results with vitamin E. Researchers are also examining the effects on other viruses such as influenza (flu) and HIV. If they find a similar phenomenon occurring in other viruses, it means that you and your friend who eats a horrible diet (eats no fruit and vegetables) could be exposed to a virus. You don't know you were exposed because your immune system fights off the virus. However, your friend gets sick. He/she can serve as a host in which the virus mutates making it more virulent, which when you're exposed a second time, may make you sick. References & Links Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. http://en.wikipedia.org/wiki/File:China_100.78713E_35.63718N.jpg Beck M, Handy J, Levander O. (2004) Host nutritional status: The neglected virulence factor. Trends Microbiol 12(9): 417-423.

All but three of these will be covered in this section. You will learn about vitamin B12 in the one-carbon metabolism chapter and magnesium in the electrolyte chapter. You have learned about vitamin C in the antioxidant chapter. We are left with iodine, manganese, and many of the B vitamins. You will learn about the 2 minerals followed by the B vitamins with the order for the sections as follows:

Why is iodine first in this chapter? Partly because it is a mineral (but so is manganese), but there is also a connection between iodine and selenium (last antioxidant in the previous chapter). Iodine's only, yet critical, function is that it is required for thyroid hormone synthesis. The figure below shows that the thyroid gland is a butterfly-shaped organ found in the neck. The parathyroid glands are also found within the thyroid gland.

Iodine is found in foods primarily as iodide (I-), some bread dough has iodate (IO -) added to help with gluten cross-linking2. This used to be more commonly used in the past than it is now. Like selenium, iodide concentrations of the soil vary greatly, causing food concentrations to greatly fluctuate. Sea water is high in iodine, thus foods of marine origin, such as seaweed and seafood, are good dietary sources of iodine. Dairy products also tend to be good sources of iodide because it is added to cattle feed. Cattle receive iodine-containing medications, and iodide-containing sanitizing solutions are used in dairy facilities3,4. For most Americans, we consume ample iodine through the consumption of iodized salt. Consumption of 1/2 teaspoon of iodized salt meets the RDA for iodine. There is a global logo for iodized salt. However, I must admit that I do not recall ever seeing it myself. The other link below is to a page that contains a scorecard map that depicts access to iodized salt worldwide. It also contains a Youtube video that displays the reduction in iodine deficiency over the last 2 decades.

The U.S. uses potassium iodide, but the form, and amount, used varies from country-to-country. Most Americans’ salt intake comes from processed foods, many of which are made with non-iodized salt. Iodine is well absorbed (~90%). Some dietary compounds interfere with thyroid hormone production or utilization. These compounds are known as goitrogens5. However, it is not believed that goitrogens are of clinical importance unless there is a coexisting iodine deficiency5.

References & Links http://en.wikipedia.org/wiki/File:Illu_thyroid_parathyroid.jpg Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. Whitney E, Rolfes SR. (2008) Understanding nutrition. Belmont, CA: Thomson Wadsworth. Anonymous. (2001) Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, D.C.: National Academies Press. http://en.wikipedia.org/wiki/File:Casava.jpg http://en.wikipedia.org/wiki/File:Manihot_esculenta_dsc07325.jpg http://en.wikipedia.org/wiki/File:PeeledCassava.jpg https://en.wikipedia.org/wiki/Millet#/media/File:Grain_millet,_early_grain_fill,_Tifton,_7-3-02.jpg https://en.wikipedia.org/wiki/Staple_food#/media/File:Pearl_millet_after_combine_harvesting.jpg

The enzymes that metabolize thyroid hormones are known as deiodinases. There are three deiodinases (Type I , Type II, Type III) that are selenoenzymes whose location and function are summarized in the table below.

Thyroid hormone regulates the basal metabolic rate and is important for growth and development. Thyroid hormone is particularly important for brain development, but hypothyroidism (low thyroid hormone) also leads to decreased muscle mass and skeletal development3. References & Links http://en.wikipedia.org/wiki/File:Triiodothyronine.svg http://en.wikipedia.org/wiki/File:Thyroxine.svg Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier.

There are two iodine deficiency disorders (IDD): goiter and cretinism. Goiter is a painless deficiency condition that results from the enlargement of the thyroid to help increase its ability to take up iodine. A couple of pictures of goiter are shown below.

A more serious consequence of iodine deficiency occurs during pregnancy to the fetus. Iodine deficiency during this time can lead to cognitive impairment and stunted growth and known as cretinism. This condition is characterized by severe hypothyroidism, speech loss, and paralysis3,4. The following links show some examples of individuals with cretinism. The World Health Organization calls iodine deficiency "the world's most prevalent, yet easily preventable, cause of brain damage5." By saying it is easily preventable, they are referring to the ability of salt iodization to prevent brain development problems. The following New York Times article talks about how salt iodization may be the cheapest way to raise the world's IQ. Iodine toxicity is rare, but like iodine deficiency, it can result in thyroid enlargement, and hypothyroidism or hyperthyroidism. Acute toxicity results in gastrointestinal irritation, abdominal pain, nausea, vomiting, and diarrhea6. References & Links http://en.wikipedia.org/wiki/File:Kone_med_stor_struma.jpg http://en.wikipedia.org/wiki/File:Goitre.jpg Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins.

Absorption of manganese is not well understood but is believed to be pretty low (<5%). It is mainly excreted (90%) through bile/feces5. Deficiency and toxicity of manganese is extremely rare. The deficiency is so rare in humans that there isn't much information available on the symptoms of the condition. Symptoms in those who were deliberately made deficient include vomiting, dermatitis, changes in hair color, & skeletal defects5. Toxicity symptoms include neurological disorders similar to schizophrenia and Parkinson's disease. In Chilean miners exposed to Mn-containing dust the toxicity was named Manganese Madness7,8.

http://en.wikipedia.org/wiki/File:Urea.png Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:Illu_synovial_joint.jpg Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins.

Since it was one of the original vitamins, (remember it was the primary part of Factor B), it was originally named thiamine (consistent with vitamine). The -e has since been dropped in its spelling. Thiamin is sensitive to heat, so prolonged heating causes the cleavage of thiamin between the 2 rings destroying its activity2. Like most of the B vitamins, thiamin's primary function is as a cofactor for enzymes. It is not thiamin alone that serves as a cofactor but instead thiamin diphosphate (thiamin + 2 phosphates), which is more commonly referred to as thiamin pyrophosphate (TPP). The structure of thiamin pyrophosphate is shown below.

Thiamin uptake and absorption is believed to be an efficient process that is passive when thiamin intake is high and active when thiamin intakes are low4. There are two thiamin transporters (THTR), THTR1 and THTR2, that are involved in thiamin uptake and absorption. THTR1 is found on the brush border and basolateral membrane, while THTR2 is only found on

References & Links http://en.wikipedia.org/wiki/File:Thiamin.svg Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. http://en.wikipedia.org/wiki/File:Thiamine_diphosphate.png Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Said H, Mohammed Z. (2006) Intestinal absorption of water-soluble vitamins: An update. Curr Opin Gastroenterol 22(2): 140-146.

As shown below the conversion of pyruvate to acetyl CoA in the transition reaction is a decarboxylation reaction that requires TPP as a cofactor. CO2 (circled) is produced as a result of this reaction. Figure 10.313 The transition reaction requires TPP as a cofactor3

TPP is a cofactor for the enzyme transketolase. Transketolase is a key enzyme in the pentose phosphate (aka hexose monophosphate shunt) pathway. This pathway is important for converting 6-carbon sugars into 5-carbon sugars (pentose) that are needed for synthesis of DNA, RNA, and NADPH. In addition, pentoses such as fructose are converted to forms that can be used for glycolysis and gluconeogenesis4. Transketolase catalyzes multiple reactions in the

Thiamin deficiency is rare in developed countries, but still occurs in poorer countries where white (aka polished) rice is a staple food. During the polishing process, thiamin, and many other nutrients, are removed. Some people also have a mutation in THTR1 that causes them to become thiamin deficient1. Thiamin deficiency is known as beriberi, which, when translated, means "I can't, I can't." The symptoms of beriberi are illustrated in the link below. There are two major forms of beriberi: dry and wet. Dry beriberi affects the nervous system, with symptoms such as loss of muscle function, numbness, and/or tingling. Wet beriberi affects the cardiovascular system resulting in pitting edema, along with enlargement of the heart1. A picture of a person with beriberi is shown below.

The thiamin deficiency found in alcoholics is known as Wernicke-Korsakoff Syndrome. Symptoms of this condition include paralysis or involuntary eye movement, impaired muscle coordination, memory loss and confusion3. The following video shows some of the symptoms of this condition.

http://en.wikipedia.org/wiki/File:Beriberi_USNLM.jpg Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier.

Since this question is leading off the riboflavin section, you have probably surmised that riboflavin is somehow involved. Indeed, flavin means yellow in Latin, and riboflavin is bright yellow as shown below. Figure 10.41 Riboflavin in solution1 Riboflavin is a water-soluble B vitamin, so the student was excreting large amounts of riboflavin in his urine, leading it to become "bright, practically neon yellow." The structure of riboflavin is shown below. Figure 10.42. Structure of riboflavin2

The structure of FMN as shown below, is similar to FAD, except that it only contains one phosphate group (versus 2) and doesn't have the ring structures off the phosphate groups that are found in FAD.

Riboflavin is photosensitive, meaning that it can be destroyed by light. This was a problem in the old days when the milkman delivered milk in clear glass bottles. These have now been replaced by cartons or opaque plastic containers to help protect the riboflavin content of the milk.

Riboflavin in foods is free, protein-bound, or in FAD or FMN. Only free riboflavin is taken up so it must be cleaved, or converted before absorption6. Riboflavin is highly absorbed through an unresolved process, though it is believed that a carrier is involved7. As you would guess from the description above, riboflavin is primarily excreted in the urine.

References & Links http://en.wikipedia.org/wiki/File:Riboflavin_solution.jpg http://en.wikipedia.org/wiki/File:Riboflavin.svg http://en.wikipedia.org/wiki/File:Flavin_adenine_dinucleotide.png http://en.wikipedia.org/wiki/File:FAD_FADH2_equlibrium.png http://en.wikipedia.org/wiki/File:Flavin_mononucleotide.png Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Said H, Mohammed Z. (2006) Intestinal absorption of water-soluble vitamins: An update. Curr Opin Gastroenterol 22(2): 140-146.

Citric Acid Cycle - FAD is reduced to FADH2 in the citric acid cycle when succinate is converted to fumarate by succinic dehydrogenase as circled below. Figure 10.411 The citric acid cycle requires FAD2 Electron Transport Chain - Under aerobic conditions, the electron transport chain is where the FADH2 is used to produce ATP. Complex I of the electron transport chain includes an FMN molecule. The electron transport chain is shown below.

Antioxidant Enzymes - The antioxidant enzymes glutathione reductase and thioredoxin reductase both require FAD as a cofactor. Thioredoxin reductase is a selenoenzyme. The function of glutathione reductase is shown in the following link. Glutathione reductase can reduce glutathione that can then be used by the selenoenzyme glutathione peroxidase to convert hydrogen peroxide to water.

References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:Citric_acid_cycle_with_aconitate_2.svg http://en.wikipedia.org/wiki/File:Mitochondrial_electron_transport_chain%E2%80%94Etc4.svg https://commons.wikimedia.org/wiki/File:Nicotinic_acid_biosynthesis2.png http://en.wikipedia.org/wiki/File:Pyridoxine_structure.svg https://en.wikipedia.org/wiki/Pyridoxal_phosphate#/media/File:Pyridoxal-phosphate.svg http://en.wikipedia.org/wiki/File:Dopamine_degradation.svg http://en.wikipedia.org/wiki/File:Serotonin_biosynthesis.svg

http://en.wikipedia.org/wiki/File:Angular_Cheilitis.JPG Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill.

There are two forms of niacin: nicotinic acid and nicotinamide (aka niacinamide), that have a carboxylic acid group or amide group, respectively. The structure of nicotinic acid and nicotinamide are shown below.

Niacin is important for the production of two cofactors: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP+). The structure of NAD is shown below; you can clearly see the nicotinamide at the top right of the molecule. Figure 10.53 Structure of NAD3

Niacin is unique in that it can be synthesized from the amino acid tryptophan as shown below. An intermediate in this synthesis is kynurenine. Many reactions occur between this compound and niacin, and riboflavin and vitamin B6 are required for two of these reactions.

To account for niacin synthesis from tryptophan, niacin equivalents (NE) were created by the DRI committee to account for the amount of niacin in foods as well as their tryptophan content. It takes approximately 60 mg of tryptophan to make 1 mg of niacin. Thus, the conversions to niacin equivalents are:

products, niacin bioavailability is low. In these foods, some niacin (~70% in corn) is tightly bound, making it unavailable for absorption. Treating the grains with a base frees the niacin and allows it to be absorbed. After absorption nicotinamide is the primary circulating form7,9.

References & Links http://en.wikipedia.org/wiki/File:Niacinstr.png http://en.wikipedia.org/wiki/File:Nicotinamide_structure.svg http://en.wikipedia.org/wiki/File:NAD%2B_phys.svg http://en.wikipedia.org/wiki/File:NAD_oxidation_reduction.svg http://en.wikipedia.org/wiki/File:NADP%2B_phys.svg https://commons.wikimedia.org/wiki/File:Nicotinic_acid_biosynthesis2.png Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Said H, Mohammed Z. (2006) Intestinal absorption of water-soluble vitamins: An update. Curr Opin Gastroenterol 22(2): 140-146.

References & Links http://en.wikipedia.org/wiki/File:CellRespiration.svg http://en.wikipedia.org/wiki/File:Citric_acid_cycle_with_aconitate_2.svg http://en.wikipedia.org/wiki/File:Ethanol_flat_structure.png https://en.wikipedia.org/wiki/Acetaldehyde#/media/File:Acetaldehyde-2D-flat.svg

Pellagra is a niacin deficiency. This is no longer a common deficiency in developed countries, but was in the U.S. in the early 1900s. This was because corn was a staple crop, meaning it was what people primarily consumed. The bioavailability of niacin from corn is poor unless treated with a base to release the bound niacin. The symptoms of pellagra are the 3 D's:

Dietary niacin toxicity is rare. However, nicotinic acid (not nicotinamide) can improve people's lipid profiles when consumed at levels far above the RDA. For instance the RDA and upper limit (UL) is 14 or 16 (women & men) and 35 mg (both), respectively. Many people are taking 1-2 grams (up to 6 g/day) to get the benefits in their plasma lipid profiles as shown in the table below4,5.

It should be pointed out that there are special supplements for this purpose that include a slower release nicotinic acid that helps prevent the toxicity symptoms (nicotinamide is not toxic). A slow (aka long or extended) release form of niacin for people with atherosclerosis is Niaspan®. The link below is to Niaspan’s site. A study found that Niaspan plus a statin was no better than a statin alone in preventing heart attacks, despite improvements in HDL and triglyceride concentrations. This result challenged the understanding of the importance of HDL and triglyceride concentrations to heart attack risk. The link below explains this study’s results. The most well known of the toxicity symptoms is "niacin flush", which is a dilation of capillaries accompanied by tingling that can become painful. This symptom is noted to occur at lower levels than the other toxicity symptoms6. Other symptoms include:

A nicotinic acid receptor GPR109A, which is present in adipocytes and immune cells, is believed to mediate niacin flush, but the beneficial effects on lipid profiles do not appear to be mediated by it7,8. It is not clear at this time the mechanism of action for the improvements in lipid profiles7. Thus, nicotinic acid supplementation can improve lipid profile and lead to niacin flush, while nicotinamide supplementation does not result in either outcome.

http://en.wikipedia.org/wiki/File:Pellagra_NIH.jpg Gille A, Bodor E, Ahmed K, Offermanns S. (2008) Nicotinic acid: Pharmacological effects and mechanisms of action. Annu Rev Pharmacol Toxicol 48: 79-106. Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Whitney E, Rolfes SR. (2008) Understanding nutrition. Belmont, CA: Thomson Wadsworth. Ginsberg HN, Reyes-Soffer G.. (2013) Niacin: A long history, but a questionable future. Curr Opin Lipidol. 24: 475-479. Liu D, Wang X, Kong L, Chen Z. (2015) Nicotinic acid regulates glucose and lipid metabolism through

Most pantothenic acid in food is found as CoA, which is cleaved prior to absorption. It is then taken up into the enterocyte through the sodium-dependent multivitamin transporter (SMVT) as shown below. Approximately 50% of pantothenic acid is absorbed; it is excreted primarily in urine3. Figure 10.66 The absorption of pantothenic acid Deficiency of pantothenic acid is very rare. Pantothenic acid supplementation did relieve the symptoms (burning feet and numbness of toes) of "burning feet syndrome" in prisoners in World War II6. It is believed that pantothenic acid deficiency was the cause of this syndrome. Other symptoms noted are vomiting, fatigue, weakness, restlessness, and irritability3. No toxicity has been reported. References & Links http://en.wikipedia.org/wiki/File:Pantothenic_acid_structure.svg http://en.wikipedia.org/wiki/File:Coenzym_A.svg Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:CellRespiration.svg https://en.wikipedia.org/wiki/File:Animal_mitochondrion_diagram_en_%28edit%29.svg Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins.

Vitamin B6 is composed of three compounds: pyridoxine, pyridoxal, and pyridoxamine. Pyridoxine contains a methylhydroxyl group (-CH3OH), pyridoxal an aldehyde (-CHO), and pyridoxamine an aminomethyl group (-CH3NH2), as shown below.

All three forms can be activated by being phosphorylated. The phosphorylated forms can be interconverted to the active, or the cofactor form of vitamin B6, pyridoxal phosphate (PLP). This active form has a phosphate group added in place of a hydroxyl group. The enzyme that catalyzes this reaction requires FMN (riboflavin cofactor), as shown below.

In animal products, vitamin B6 is found in its cofactor forms, PLP and pyridoxamine phosphate (PMP). The latter cofactor is less common than PLP. In plants, vitamin B6 is primarily found as pyridoxine, with up to 75% being pyridoxine glucoside, which is believed to be the plant storage form6. Pyridoxine glucoside has a glucose added to pyridoxine as shown below.

Vitamin B6 is well absorbed from foods (~75%) through passive diffusion. PLP and PMP are dephosphorylated before uptake into the enterocyte. Some of the pyridoxamine glucoside is cleaved to form free pyridoxine, but some pyridoxine glucoside is absorbed intact. Pyridoxine glucoside absorption is lower (~50%) than pyridoxine alone. The primary circulating forms of vitamin B6 are pyridoxal and PLP. Vitamin B6 is primarily excreted in the urine, and like many other B vitamins, vitamin B6 is destroyed during cooking or heating6.

References & Links http://en.wikipedia.org/wiki/File:Pyridoxine_structure.svg http://en.wikipedia.org/wiki/File:Pyridoxal.png http://en.wikipedia.org/wiki/File:Pyridoxamine.png https://en.wikipedia.org/wiki/Pyridoxal_phosphate#/media/File:Pyridoxal-phosphate.svg

PLP is a cofactor for over 100 different enzymes, most are involved in amino acid metabolism. In fact, without PLP, all amino acids would be essential because we would not be able to synthesize nonessential amino acids. Below are some of the functions of PLP and PMP1:

PLP is required for decarboxylase enzymes that are involved in the synthesis of the neurotransmitters GABA, serotonin, histamine, and dopamine. As an example, DOPA decarboxylase uses PLP to convert L-DOPA to dopamine as shown below1. Figure 10.714 DOPA decarboxylase uses PLP to synthesize dopamine4

References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:Transaminierung.svg http://en.wikipedia.org/wiki/File:DesaminierungCtoU.png http://en.wikipedia.org/wiki/File:Catecholamines_biosynthesis.svg http://en.wikipedia.org/wiki/File:Heme_synthesis.png https://commons.wikimedia.org/wiki/File:Nicotinic_acid_biosynthesis2.png

Vitamin B6, unlike many of the B vitamins, can produce toxicity. High doses of vitamin B6, taken for an extended period of time, can lead to neurological damage2. There are some potential uses of vitamin B6 supplementation that are important to be done with consultation with a physician. The levels at which vitamin B6 is supplemented for these uses is usually nearing its UL, which is why care should be taken in how this is done.

While the evidence is not conclusive, it appears that vitamin B6 supplementation may be beneficial to those suffering from carpal tunnel syndrome and may be tried alone, or in combination with other complementary treatments, before surgery is undertaken3,4. Morning sickness (hyperemesis gravidarum) that occurs early in pregnancy is another condition where vitamin B6 supplementation is utilized. The evidence again is not clear on whether it is beneficial5,6, but The American College of Obstetricians and Gynecologists suggests that vitamin B6 may be tried first to treat nausea and vomiting during pregnancy7. In 2013, the FDA approved doxylamine-pyridoxine (Diclegis) for use in pregnancy8. It is not known exactly what causes morning sickness, but it is believed that lower circulating vitamin B6 levels are associated with increased morning sickness severity9. The last condition that vitamin B6 is commonly supplemented for is premenstrual syndrome (PMS). A systematic literature review found that it is inconclusive whether vitamin B6 supplementation is beneficial in managing PMS10. References & Links Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. Ryan-Harshman M, Aldoori W. (2007) Carpal tunnel syndrome and vitamin B6. Canadian Family Physician 53(7): 1161-1162. Aufiero E, Stitik T, Foye P, Chen B. (2004) Pyridoxine hydrochloride treatment of carpal tunnel syndrome: A review. Nutr Rev 62(3): 96-104. Koren G, Maltepe C. (2006) Preventing recurrence of severe morning sickness. Canadian Family Physician 52(12): 1545-1546. Tan P, Yow C, Omar S. (2009) A placebo-controlled trial of oral pyridoxine in hyperemesis gravidarum. Gynecol Obstet Invest 67(3): 151-157. Slaughter SR, Hearns-Stokes R, van der Vlugt T, Joffe HV. (2014) FDA approval of doxylamine-pyridoxine therapy for use in pregnancy. N Engl J Med. 370: 1081-1083. Wibowo N, Purwosunu Y, Sekizawa A, Farina A, Tambunan V, Bardosono S. (2012) Vitamin B6 supplementation in pregnant women with nausea and vomiting. 116: 206-210. Whelan A, Jurgens T, Naylor H. (2009) Herbs, vitamins and minerals in the treatment of premenstrual syndrome: A systematic review. The Canadian Journal of Clinical Pharmacology 16(3): e407-e429.

Free biotin is believed to be highly absorbed. Before uptake, biocytin is acted on by the enzyme biotinidase, forming free biotin and lysine. Free biotin is then taken up into the enterocyte through the sodium-dependent multivitamin transporter (SMVT), as shown below1,4,5.

References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:Biotin_structure.svg http://commons.wikimedia.org/wiki/File:Biocytin.svg Said H, Mohammed Z. (2006) Intestinal absorption of water-soluble vitamins: An update. Curr Opin Gastroenterol 22(2): 140-146. Zempleni J, Wijeratne SSK, Hassan Y. (2009) Biotin. Biofactors 35(1): 36-46.

Biotin is an important cofactor for carboxylase enzymes. As the name sounds, these enzymes add carboxylic acid groups (-COOH) to whatever compound they act on. In fatty acid synthesis, biotin is required by the enzyme that forms malonyl-CoA from acetyl-CoA, as shown below1.

References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:Animal_mitochondrion_diagram_en_%28edit%29.svg http://en.wikipedia.org/wiki/File:CellRespiration.svg Scheinfeld N, Dahdah MJ, Scher R. (2007) Vitamins and minerals: their role in nail health and disease. 6(8): 782-787. Famenini S, Goh C. (2014) Evidence for supplemental treatments in androgenetic alopecia. 13(7): 809-812.

What is epigenetics? Epigenetics means "above the genome." To use a computer analogy, if the DNA sequence is the hardware, epigenetics can be viewed as the software. The nucleotide sequence of the human genome is known, and there is surprisingly little difference between individuals. However, the 2 main epigenetic modifications play a major role in determining what genes are expressed:

DNA does not exist simply as long strands of double helix, instead it is packaged and shaped so that it can fit in the nucleus of our cells. The first part of this packaging is that DNA is wrapped around proteins called histones as shown below. Figure 10.821 DNA is wrapped around histones1 Histone modification occurs when there are additions or subtractions to the histones themselves. The most common is acetylation (addition of an acetyl group) or deacetylation of histones. The structure of acetyl is shown below. Figure 10.822 Structure of acetyl2

Together, these modifications to DNA and histones are known as the epigenetic code. The following two videos do a good job explaining epigenetics and tying together its two different methods of modification. The Tale of 2 Mice describes how great impact that the methylation status (whether it is methylated or unmethylated) of the agouti gene has on physical characteristics genetically identical mice. The second video illustrates how histone modifications impact gene transcription. How does this relate to biotin? Histones can be biotinylated, or have biotin added to the histone. However, it should be noted that histone biotinylation is rare (<0.001% of human histones H3 and H4), so it is questionable how much impact this action has3. References & Links http://en.wikipedia.org/wiki/File:Nucleosome_structure.png http://en.wikipedia.org/wiki/File:Acetyl.svg Kuroshi T, Rios-Avila L, Pestinger V, Wijeratne SSK, Zempleni J. (2011) Biotinylation is a natural, albeit rare, modification of human histones. Mol Genet Metab, 104, 537-545.

There are a couple of ways that a person could develop a deficiency in biotin. First, a very small number of people are born with a mutation in biotinidase that results in them not being able to cleave biocytin for absorption1. Another way is through the consumption of raw eggs. Drinking raw eggs is not something that most people do. However, some people do it to imitate Sylvester Stallone's movie character Rocky, who consumed them as part of his boxing training regimen. If you are not familiar with this movie the link below shows you how Rocky consumed his raw eggs. The potential problem with consuming raw eggs routinely is that raw egg whites contain a protein called avidin which binds biotin and prevents its absorption. However, it would take more than two dozen egg whites consumed daily over many months to cause a deficiency, making this an unlikely occurrence2. Cooking denatures avidin and prevents it from binding biotin, meaning that cooked eggs are not a concern.

References & Links Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. Whitney E, Rolfes SR. (2008) Understanding nutrition. Belmont, CA: Thomson Wadsworth.

Three B vitamins are involved in what is known as 1-carbon metabolism. This is the movement of 1 carbon units, generally methyl groups (CH3). It is similar to the movement of the amino group that occurs in transamination. As shown in the figure below, folate, vitamin B12, and vitamin B6 are the B vitamins involved in 1-carbon metabolism. Figure 11.1 One-carbon metabolism depiction. 5-methyltetrahydrofolate (THF) donates a methyl group to cobalamin forming methylcobalamin. Methylcobalamin donates a methyl group to homocysteine, forming methionine (an amino acid). Alternatively, vitamin B6 can be utilized to convert homocysteine into cysteine. Vitamin B6 has been described in the previous chapter, so this chapter is going to focus on folate and vitamin B12. We will examine this figure in pieces, so that hopefully by the time this chapter is completed, you will understand the role of all these vitamins in 1-carbon metabolism.