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M1 ‐ Biochemistry

Water‐Soluble Vitamins9/22/08

Dr. Matthew Beckman

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Objectives

• Know the physiological differences between fat‐soluble and water‐soluble vitamins

• *Be able to identify the major function of each water‐soluble vitamin

• *Understand the major deficiency symptoms of each water‐soluble vitamin

• Know the particular clinical indications involved in excess of water‐soluble vitamins

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“Vitamin B12 and health.” Ryan‐Harshman M, Aldoori W

• A MEDLINE search from 1999 to 2007 was performed using the key word vitamin B12.The most relevant articles (129) dealt with cardiovascular disease, cancer, mental health, and birth outcomes;most studies presented level II evidence. MAIN MESSAGE: Vitamin B12 might confer health benefits; however, such benefits are difficult to ascertain because of the complementary functions of vitamin B12 and folic acid. Vitamin B12 might lower high homocysteine levels below a threshold level achieved by folic acid alone. Furthermore, the interactions between the nutritional environment and genotype might have an important influence on vitamin B12, chronic disease risk, and risk of neural tube defects. CONCLUSION: Vitamin B12 might help protect against chronic disease and neural tube defects, but more research, particularly in the area of nutritional genomics, is needed to determine how vitamin B12 might augment the benefits of folic acid. Some consideration should be given to the potential value of fortifying foods with vitamin B12 in addition to the current mandatory folic acid fortification of grains.

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Vitamins: Fat Versus Water Soluble

• ‐Vitamins are classified as fat soluble:• Vitamin A• Vitamin D• Vitamin E• Vitamin K•• ‐or water soluble:• B vitamins• Vitamin C

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This difference affects nutrition in several ways

• Fat‐soluble vitamins: These vitamins dissolve in fats (lipids). They are stored in the liver and in fatty tissues. If too much of the fat‐soluble vitamins A or D are consumed, they can accumulate and may have harmful effects.

• ‐Because fats in foods help the body absorb fat‐soluble vitamins, a low‐fat diet may result in a deficiency. Some disorders interfere with absorption of fats and thus of fat‐soluble vitamins. Examples are chronic diarrhea, Crohn's disease, cystic fibrosis, pancreatitis, and blockage of the bile ducts. Some drugs, such as mineral oil, have the same effect. Fat‐soluble vitamins dissolve in mineral oil, which the body does not absorb. So when people take mineral oil,it carries these vitamins unabsorbed out of the body.

• ‐Cooking does not destroy fat‐soluble vitamins.

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This difference affects nutrition in several ways

• Water‐soluble vitamins: These vitamins dissolve in water. They are eliminated in urine and tend to be eliminated from the body more quickly than fat‐soluble vitamins. 

• ‐Water‐soluble vitamins are more likely to be destroyed when food is stored and prepared. 

• ‐Refrigerating fresh produce, storing milk and grains out of strong light, and using the cooking water from vegetables to prepare soups can help prevent the loss of the vitamins.

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Introduction to Vitamins

• Vitamins are a vital part of a healthy diet.

• The recommended dietary allowance (RDA)—the amount most healthy people need each day to remain healthy—has been determined for most vitamins. 

• A safe upper limit (tolerable upper intake level) has been determined for some vitamins. Intake above this limit increases the risk of a harmful effect (toxicity).

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Introduction to Vitamins

• ‐Consuming too little of a vitamin can cause a nutritional disorder. However, people who eat a variety of foods are unlikely to develop most vitamin deficiencies. 

• Deficiency of vitamin D is an exception. It is common among certain groups of people (such as older people) even if they eat a variety of foods. 

• For other vitamins, deficiency can develop if people follow a restrictive diet that does not contain enough of a particular vitamin. For example, vegans, who consume no animal products, may become deficient in vitamin B12, which is available in animal products. 

• Consuming large amounts (megadoses) of certain vitamins (usually as supplements) without medical supervision may also have harmful effects.

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Recommendations

• Vitamins are called essential micronutrients because the body requires them but only in small amounts.

• ‐Some vitamins—A, D, E, and K—are fat soluble. Other vitamins—B vitamins and vitamin C—are water soluble. 

• B vitamins include biotin, folate (folic acid), niacin, pantothenic acid, riboflavin (vitamin B2), thiamin (vitamin B1), and vitamins B6 (pyridoxine) and B12 (cobalamins). 

• Deficiency of biotin or pantothenic acid almost never occurs.

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• ‐The body does not store most vitamins. Therefore, people must consume them regularly. 

• Vitamins A, B12, and D are stored in significant amounts, mainly in the liver. 

• ‐Disorders that impair the intestine's absorption of food (calledmalabsorption disorders) can cause vitamin deficiencies. Some disorders impair the absorption of fats. 

• These disorders can reduce the absorption of fat‐soluble vitamins—A, D, E, and K—and increase the risk of a deficiency. Such disorders include chronic diarrhea, Crohn's disease, cystic fibrosis, pancreatitis, and blockage of the bile ducts.

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Vitamins Important to Human Health

Vitamin Good Sources

Main Functions

Recommended Dietary Allowance

Safe Upper Limit

 

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Biotin

Biotin Liver,

kidneys, egg

yolks, milk,

fish, dried

yeast,

cauliflower,

nuts, and

legumes

Required for the

metabolism of

carbohydrates

and fatty acids

30 micrograms (but no

RDA has been

established)

—

 

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Folic AcidFolate (folic

acid)

Fresh green

leafy

vegetables,

asparagus,

broccoli,

fruits

(especially

citrus), liver,

other organ

meats, dried

yeast, and

enriched

breads,

pastas, and

cereals

(Note:

Extensive

cooking

destroys 50–

95% of the

folate in

food.)

Required for the

formation of red

blood cells, for

DNA and RNA

synthesis, and

for normal

development of

the nervous

system in a

fetus

400 micrograms

600 micrograms for

pregnant women

500 micrograms for

breastfeeding women

1,000

micrograms

 

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Niacin

Niacin

(nicotinic

acid or

nicotinamide

)

Dried yeast,

liver, meat,

fish,

legumes,

and whole-

grain or

enriched

cereal

products

Required for the

metabolism of

carbohydrates,

fats, and many

other

substances

14 milligrams for

women

16 milligrams for men

35

milligrams

 

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Pantothenic Acid

Pantothenic

acid

Liver, beef,

egg yolks,

yeast,

potatoes,

broccoli, and

whole grains

Required for the

metabolism of

carbohydrates

and fats

5 milligrams (but no

RDA has been

established)

—

 

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Riboflavin

Riboflavin

(vitamin B2)

Milk, cheese,

liver, meat,

fish, eggs,

and enriched

cereals

Required for the

metabolism of

carbohydrates

and amino acids

and for healthy

mucous

membranes,

such as those

lining the mouth

1.1 milligrams for

women

1.3 milligrams for men

1.4 milligrams for

pregnant women

1.6 milligrams for

breastfeeding women

—

 

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Thiamin

Thiamin

(vitamin B1)

Dried yeast,

whole

grains, meat

(especially

pork and

liver),

enriched

cereals,

nuts,

legumes,

and potatoes

Required for the

metabolism of

carbohydrates

and for normal

nerve and heart

function

1.1 milligrams for

women

1.2 milligrams for men

1.4 milligrams for

pregnant or

breastfeeding women

—

 

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Vitamin AVitamin A

(retinol)

As vitamin

A: Fish liver

oils, liver,

egg yolks,

butter,

cream, and

fortified milk

As

carotenoids

(converted

to vitamin A

in the body),

such as

beta-

carotene:

Dark green

and yellow-

orange

vegetables,

and yellow-

orange fruits

Required to

form light-

sensitive nerve

cells

(photoreceptors)

in the retina,

helping maintain

night vision

Helps maintain

the health of the

skin, cornea,

and lining of the

lungs, intestine,

and urinary tract

Helps protect

against

infections

700 micrograms for

women

900 micrograms for

men

770 micrograms for

pregnant women

1,200 micrograms for

breastfeeding women

3,000

micrograms

 

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Vitamin B6

Vitamin B6 Dried yeast,

liver, other

organ

meats,

whole-grain

cereals, fish,

and legumes

Required for the

metabolism of

amino acids and

fatty acids, for

normal nerve

function, for the

formation of red

blood cells, and

for healthy skin

1.3 milligrams

1.5 milligrams for

women older than 50

1.7 milligrams for men

older than 50

1.9 milligrams for

pregnant women

2.0 milligrams for

breastfeeding women

100

milligrams

 

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Vitamin B12

Vitamin B12

(cobalamins)

Meats

(especially

beef, pork,

liver, and

other organ

meats),

eggs,

fortified

cereals,

milk, clams,

oysters,

salmon, and

tuna

Required for the

formation and

maturation of

red blood cells,

for nerve

function, and for

DNA synthesis

2.4 micrograms

2.6 micrograms for

pregnant women

2.8 micrograms for

breastfeeding women

—

 

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Vitamin DVitamin D Formed in

the skin

when the

skin is

exposed to

direct

sunlight

Fortified

milk, fatty

fish, fish

liver oils,

and egg

yolks

Promotes the

absorption of

calcium and

phosphorus

from the

intestine

Required for

bone formation,

growth, and

repair.

Strengthens the

immune system

and reduces the

risk of

autoimmune

disorders

200 IU for people aged

50 and younger

400 IU for people aged

51 to 70

600 IU for people older

than 70

2,000 IU

 

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Vitamin E

Vitamin E Vegetable

oil,

margarine,

nuts, and

wheat germ

Acts as an

antioxidant,

protecting cells

against damage

by free radicals

15 milligrams (22 IU of

natural or 33 IU of

synthetic)

19 milligrams for

breastfeeding women

1,000

milligrams

 

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Vitamin K

Vitamin K Green leafy

vegetables

(such as

collards,

spinach, and

kale) and

soybean and

canola oils

Helps in the

formation of

blood clotting

factors and thus

is necessary for

normal blood

clotting

Required for

healthy bones

and other

tissues

90 micrograms for

women

120 micrograms for

men

—

 

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*Water‐Soluble Vitamins Up Close

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Folate (folic acid)

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Folic Acidpositions 7 & 8 carry hydrogens in dihydrofolate (DHF)positions 5-8 carry hydrogens in tetrahydrofolate (THF)

**Vitamin B9 (Folic acid) deficiency results in elevated levels of homocysteine. Deficiency in pregnant women can lead to birth defects.

Folate gets its name from the Latin word folium, leaf.

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Folate

• Also known as folic acid or folacin or pteroylglutamicacid (PGA)

• **Primary coenzyme form ‐‐ tetrahydrofolate (THF) – part of enzyme complex required for metabolism of single‐carbon compounds 

– Required for making of new cells

– Helps synthesize DNA 

• **Helps convert  vitamin B12 to its active form

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*Folate Deficiency

• Deficiency first affects cells which divide and multiply rapidly– Blood cells and GI tract cells

• Results in:– Macrocytic or megaloblastic anemia 

– Abnormal digestive function

– Neural tube defects

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*Folate Deficiency

• Symptoms include:– macrocytic anemia

– heartburn, diarrhea, constipation

– immune system suppression, frequent infections

– smooth red tongue

– depression, mental confusion, fainting

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Active center of tetrahydrofolate (THF). Note that the N5 position is the site of attachment of methyl groups, the N10 the site for attachment of formyl and formimino groups and that both N5 and N10 bridge the methylene and methenyl groups.

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Neural Tube Defects

• **Spina bifida (Latin: "split spine") describes birth defects caused by an incomplete closure (an opening) of one or more vertebral arches of the spine, resulting in malformations of the spinal cord. 

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Niacin (nicotinic acid)

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Nicotinamide Nicotinic Acid

**Vitamin B3 (Niacin) deficiency, along with a deficiency of tryptophan causes Pellagra. Symptoms include aggression, dermatitis, insomnia, weakness, mental confusion, and diarrhea. In advanced cases, pellagra may lead to dementia and death.

The designation vitamin B3 also includes the amide form, nicotinamide or niacinamide.

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Structure of NAD+NADH is shown in the box insert.The -OH phosphorylated in NADP+ is indicated by the red arrow

**Niacin, also known as nicotinic acid or vitamin B3, is a water-soluble vitaminwhose derivatives such as NADH, NAD, NAD+, and NADP play essential roles in energy metabolism in the living cell and DNA repair.

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*Pellagra

• Thought to be contagious until diet connection made

• Occurs in poorly nourished people and alcoholics

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Niacin Deficiency and Pellegra

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Riboflavin (vitamin B2)

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Riboflavin structure

**Vitamin B2 (Riboflavin) deficiency causes Ariboflavinosis. Symptoms may include cheilosis (cracks in the lips), high sensitivity to sunlight, angular cheilitis, glossitis (inflammation of the tongue), seborrheic dermatitis or pseudo-syphilis(particularly affecting the scrotum or labia majora and the mouth), pharyngitis, hyperemia, and edema of the pharyngeal and oral mucosa.

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Structure of FADnitrogens 1 & 5 carry hydrogens in FADH2

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Thiamin (vitamin B1)

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Thiamin

Structure helpful

Names, key absorption features, functions, & deficiency symptoms

**Vitamin B1 (Thiamin) deficiency causes Beriberi. Symptoms of this disease of the nervous system include weight loss, emotional disturbances, Wernicke'sencephalopathy (impaired sensory perception), weakness and pain in the limbs, periods of irregular heartbeat, and edema (swelling of bodily tissues). Heart failure and death may occur in advanced cases.

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Thiamin pyrophosphate

active form

Thiamine pyrophosphate (TPP) is a coenzyme for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and transketolase. The first two of these enzymes function in the metabolism of carbohydrates, while transketolasefunctions in the pentose phosphate pathway to synthesize NADPH and the pentose sugars deoxyribose and ribose. TPP is synthesized by the enzyme thiamine pyrophosphokinase (thiamin diphosphotransferase), which requires free thiamine, magnesium, and adenosine triphosphate.

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Vitamin B12 (cobalamines)

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Cyanocobalamin

The structure of B12 is based on a The structure of B12 is based on a corrincorrin ring, which, although similar to the ring, which, although similar to the porphyrinporphyrin ring found in ring found in hemeheme, , chlorophyllchlorophyll, and , and cytochromecytochrome, has two of the , has two of the pyrrolepyrrolerings directly bonded. The central metal ion is Co (rings directly bonded. The central metal ion is Co (cobaltcobalt).).

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Structure

• B12 cannot be made by plants or by animals, as the only type of organisms that have the enzymes required for the synthesis of B12 are bacteria and archaea. 

• The total synthesis of B12 was reported in 1973 by Robert Burns Woodward, and remains one of the classic feats of total synthesis. 

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*B12 FunctionsIn humans there are only two coenzyme B12‐dependent enzymes:• Methylmalonyl Coenzyme A mutase (MUT), which uses the AdoB12 (5’‐

deoxyadenosine) form to catalyze a carbon skeleton rearrangement.– MUT's reaction converts MMl‐CoA to Su‐CoA, an important step in the extraction of 

energy from proteins and fats.

• 5‐methyltetrahydrofolate‐homocysteine methyltransferase, a methyl transfer enzyme, which uses the MeB12 (N5‐methyltetrahydrofolate) and reaction type 2 to catalyzes the conversion of the amino acid Hcy into Met.

– The enzyme works in two steps in a ping‐pong reaction. First, methylcobalamin is formed by a methyl group transfer from N5‐mTHF with formation of MeB12 and tetrahydrofolate (THF). In the second step, MeB12 transfers this methyl group to (homocysteine), regenerating the cofactor cobalamin and releasing the product methionine

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Inter‐relationship of B12 & THF

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*B12 Deficiency 

• The usual daily intake in the Western diet is 5–7 µg; the daily requirement is 1–2 µg. B12 is mostly absorbed in the terminal ileum. The production of intrinsic factor in the stomach is vital to absorption of this vitamin. 

• Megaloblastic anemia can result from inadequate intake of B12, inadequate production of intrinsic factor (pernicious anemia), disorders of the terminal ileum resulting in malabsorption

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*Sources of B12

• Only in foods of animal origin

• Serious problem for strict vegetarians or vegans– need to eat B12 fortified foods OR take supplements

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Vitamin B6 (pyridoxine)

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Pyridoxine Pyridoxal Pyridoxamine

**Vitamin B6 (Pyridoxine) deficiency may lead to anemia, depression, dermatitis, high blood pressure (hypertension) and elevated levels of homocysteine.

Pyroluria is one potential cause of vitamin B6 deficiency. Another cause of vitamin B6 deficiency is the use of the tuberculostatic medication isoniazid, and for this reason, it is recommended to supplement with vitamin B6 when using this drug.

Pyroluria, or malvaria (from the term mauve factor), is the metaboliccondition when a person has too many pyrroles in the urine.

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Pyridoxal Phosphate

**The three major forms of vitamin B-6 are pyridoxine, pyridoxal, and pyridoxamine, which, in the liver, are converted to pyridoxal 5'-phosphate (PLP) — a cofactor in many reactions of amino acid metabolism. PLP also is necessary for the enzymatic reaction governing the release of glucose from glycogen.

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Vitamin C (ascorbic acid)

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Vitamin C (Ascorbic Acid)

**Vitamin C is a water-soluble nutrient and vitamin essential for life and for maintaining optimal health. It is also known by the chemical name of its principal form ascorbic acid. It is used by the body for many purposes.

**Deficiency in vitamin C leads to the disease scurvy due to the role of the vitamin in the post-translational modification of collagens.

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Functions• As a participant in hydroxylation, vitamin C is needed for the production 

of collagen in the connective tissue. These fibers are ubiquitous throughout the body, providing firm but flexible structure. Some tissueshave a greater percentage of collagen, especially: skin, mucous membranes, teeth and bones. 

• Vitamin C is required for synthesis of dopamine, noradrenaline and adrenaline in the nervous system or in the adrenal glands. 

• Vitamin C is also needed to synthesize carnitine, important in the transfer of energy to the cell mitochondria. 

• The tissues with greatest percentage of vitamin C — over 100 times the level in blood plasma — are the adrenal glands, pituitary, thymus, corpus luteum, and retina. 

• The brain, spleen, lung, testicle, lymph nodes, liver, thyroid, small intestinal mucosa, leukocytes, pancreas, kidney and salivary glands usually have 10 to 50 times the concentration present in blood plasma. 

• Vitamin C is an antioxidant and acts as a substrate for ascorbateperoxidase. 

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*Vitamin C (ascorbic acid) deficiency symptoms

• Inactive prolyl and lysylhydroxylase

• Impaired collagen synthesis

• Skin lesions, vascular fragility, poor wound healing and bone and joint disease