Metabolic Roles ofVITAMINS AND MINERALS

Gloanne C. Adolor, RPh, MD, FPCP, MSc, MBA

Objectives

• To determine the role of selected vitamins and minerals in metabolism

• To identify clinical abnormalities associated with vitamin/mineral excesses and deficiencies

Vitamins

Organic nutrients that are required in small quantities in the diet and serve specialized functions in the body

Water-soluble Fat-soluble

Background Information

• In 1912, Casimir Funk coined the term “vitamines” because these substances were required for life (“vita”) and contained nitrogen (“amine”).

• Future studies showed that not all vitamins contained nitrogen so the “e” was dropped.

Water-soluble Vitamins

Fat-soluble Vitamins

Function Precursors of coenzymes

Physiologic regulators or antioxidants

Absorption Readily absorbed in the intestine

Depends on mixed bile salt micelles

Transport Transported as such Constituents of lipoproteins or bound to plasma proteins

Excretion Excreted as such

(renal excretion)

Require prior metabolism to water-soluble products before excretion

Recommended Daily Allowances (RDAs)

• Defines a dietary intake that is considered optimal under ordinary conditions

• NOT a minimal requirement

• Depends on sex, age, body weight, diet, and physiologic status

• Increase during pregnancy and lactation

Classification of Vitamins

Fat-soluble Water-solubleA,D,E,K Vitamin C (ascorbic acid)

Vitamin B1 (Thiamin)

Vitamin B2 (Riboflavin)

Vitamin B3 (Niacin)

Vitamin B6 (Pyridoxine)

Vitamin B12 (Cobalamin)

Folic Acid or Folate

Pantothenic Acid

Thiamine or Vitamin B1

part of coenzyme thiamine pyrophosphate (TPP): needed for CHO metabolism

part of thiamine diphosphate (TDP): needed for glucose oxidation and transketolation reactions (conversion of glucose to fat)

helps maintain good appetite, good muscle tonus in GIT, normal nerve functioning

About 30mg are present in the body, 80% of this is in the form of TPP.

TPP-dependent reactions

• Aldehyde transfers– Oxidative

decarboxylation of alpha-ketoacids

• Transketolase reactions

Mitochondria

Cytoplasm

TPP-dependent catalytic mechanisms

• Pyruvate dehydrogenase

• Alpha-keto glutarate dehydrogenase

• Branched-chain alpha-ketoacid dehydrogenase

• Alpha-ketobutyrate dehydrogenase

TPP and PDH

In general, the major catabolic, energy-producingpathways are most dependent on TPP.

Thiamin or Vitamin B1

found in the intestinal lumen in its free form

its phophoesters being completely hydrolyzed by different phosphatases

mostly absorbed in the jejunum and ileum of the small intestine

Adult male RDA = 1.2 mg

Thiamin or Vitamin B1

1/2 within muscle tissue with much of the remainder in the heart, liver, kidneys and nervous tissue, including brain, which contains most of the triphosphate form

excreted from the body as thiamin-acetic acid and as various other metabolites produced by its degradation

Thiamin or Vitamin B1

Effects of Deficiency

Early stage: loss of appetite, weakness, easily fatigued, GIT disturbances, poor reflexes, irritability, retarded growth, numbness in extremities

Later stage: beriberi or nutritional polyneuritis: changes in GI, cardiovascular and nervous systems

infantile beriberi: in infants 2-5 months whose main nourishment is milk from a mother with beri-beri

Thiamin or Vitamin B1

Types of Beri-beri (full-blown deficiency)

Wet: aphonia (loss of voice), whining cry, cyanosis (bluish discoloration), difficulty of breathing, even death within a few hours

Dry: edema of lower extremities which progresses to body cavities as abdomen and chest, enlarged heart, arryhthmias, breathing difficulty

involves peripheral nerves: paresthesias

Thiamin or Vitamin B1

Effects of Deficiency

Wernicke-Korsokoff or Wernicke’s Syndrome: seen in alcoholics and pregnant women with excessive vomiting: memory loss, mental deterioration, abnormal perception, loss of eye control, sudden heart failure if untreated

Korsakoff psychosis, a severely debilatating anterogradeamnesia,is the most common form of amnesia in most countries.

Dimethylisoaloxazine ring

Sugar alcohol ribitol

Riboflavin or Vitamin B2

precursor of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)

(prosthetic groups of the flavoproteins)

Riboflavin FMN FAD(oxidized form)

ATP ADP ATP PPi

In the Respiratory Chain, FMN or FAD can transfer oneor two electrons at a time; they accept hydrogen/electronsfrom NADH and donate it to the cytochromes.

Riboflavin or Vitamin B2

Adult male RDA = 1.3mg/day

Deficiency:– Itchy eyes with burning sensation– Glossitis (magenta tongue)– Angular stomatitis– Sore throat– Seborrheic dermatitis of the

scrotum and nose– Normocytic normochromic

anemia

In Infants…

• Riboflavin deficiency can occur when receiving phototherapy for hyperbilirubinemia.

• Riboflavin supplements are given routinely in this situation.

Niacin or Vitamin B3

• Generic term for the vitamin-active pyrimidine derivatives:– Nicotinic acid (Niacin)– Nicotinamide (niacinamide)

• Present as a constituent of NAD and NADP

Niacin or Vitamin B3

• Acceptor of H+ and electrons: needed in energy metabolism (aerobic and anaeribic oxidation of glucose); fatty acid synthesis and oxidation; protein synthesis and catabolism

• Active coenzyme forms: nicotinamide adenine dinucleotide (NAD or Coenzyme I ), nicotinamide adenince dinucleotide phosphate (NADP or Coenzyme II)

This pathway is inefficient:60mg tryptophan is required for the synthesisof 1 mg niacin

Niacin or Vitamin B3 Adult male RDA = 16 niacin equivalents (NE)

1 NE = 1 mg niacin

DeficiencyEarly stages: anorexia, lassitude, indigestion, skin

changes, glossitis

Later stages: pellagra: characterized by 4 D’s: dermatitis, dementia, diarrhea, death

dermatitis: bilateral dermatitis: blackish or dark

scaly patches appearing symmetrically in area exposed to sunlight

Often associated with corn-based diet.

Niacin or Vitamin B3

Toxicity

Occurs following or after administration of massive doses: hypermotility and acidity of stomach, paralysis of respiratory center, niacin rash (painful flush and rash)

Niacin lowers LDL Cholesteroland increases HDL Cholesterol

V

Niacin-Induced Flushing Pathway: 2 Separate Sites of Action

• 1. Epidermal Langerhans’ Cells

• Niacin binds

• PGD2 is produced and released

• 2. Dermal Blood Vessels

• PGD2 binds to DP1

• Vasodilation results

PGD2 = prostaglandin D2; DP1 = prostaglandin D2 receptor 1.Benyó Z et al. Mol Pharmacol. 2006;70:1844–1849; Morrow JD et al. J Invest Dermatol. 1992;98:812–815; Cheng K et al. Proc Natl Acad Sci USA. 2006;103:6682–6687; Pike NB et al. J Clin Invest. 2005;115:3400–3403.

• Artistic rendering.

Pyridoxine or Vitamin B6

Forms:

Pyridoxal (aldehyde)Pyridoxamine (amine)Pyridoxal (alcohol)

Total body content = 25 mgin adults

Pyridoxine or Vitamin B6

part of pyridoxal phosphate: amino acid metabolism: decarboxylation, transamination, dehydration, other amino acid transformations

catalyzes urea production, synthesis of essential fatty acids, conversion of tryptophan to niacin

Pyridoxine or Vitamin B6 Adult male RDA = 1.3mg/day

Deficiencyrare in adults; induced under experimental conditions; nausea, vomiting, seborrheic or oily dermatitis, glossitis, conjunctivitis, depressive moods

in infants: may occur if milk formula is deficient in this vitamin: irritability, poor growth, anemia, convulsions

Pyridoxine or Vitamin B6

• Neurologic derangements may result from impaired activity of the PLP-dependent enzyme glutamate decarboxylase (forms GABA)

• Sideroblastic anemia - microcytic, hypochromic anemia caused by reduced activity of the PLP-dependent aminolevulinic acid synthase in the bone marrow (heme biosynthesis)

Vitamin B6 deficiency is most common in alcoholics.

Isoniazid and penicillamine can precipitate Vitamin B6deficiency by reacting nonenzymatically with the aldehydegroup of pyridoxal or pyridoxal phosphate (PLP)

Daily consumption of>500mg for severalmonths leads toperipheral sensoryneuropathy.

Vitamin B6 is toxic in high doses

Note: Used for treatmentof Carpal Tunnel Syndrome

Cobalamin or Vitamin B12

Cobalamin or Vitamin B12

• Absorption of dietary B12 requires intrinsic factor - a 50-kD glycoprotein secreted by the parietal cells of the stomach

Only two reactions require cobalamin coenzymes in human tissues:

1. Cytoplasmic methylation of homocysteine to methionine

requires methylcobalamin

2. Mitochondrial methylmalonyl-CoA mutase reaction

requires deoxyadenosylcobalamin

RDA = 2.4ug

Cobalamin or Vitamin B12

Effects of Deficiencypernicious anemia: hyperchromic and macrocytic RBCs, diminished RBC count, RBC failure to mature, anorexia, vomiting, diarrhea, achlorydria, abdominal pain, weight loss, retarded growth

advanced symptoms: liver and spleen enlargement, yellowish skin, nerve degeneration (especially of spinal cord), paresthesias (tingling sensation of limbs), loss of vibratory sense, difficulty of walking

Pernicious anemia

• Autoimmune disease

• Megaloblastic anemia (methyl folate trap)

• Neurologic dysfunction (demyelination)

Methyl folate trap hypothesis

During the metabolism of one-carbon units, a small amount of methylene-THF is irreversibly reduced to methyl-THF.

Methyl-THF has to be converted back to one of the other coenzyme forms. This can be done only by the Vitamin B12-dependent methylation of homocysteineto methionine.

Methyl-THF accumulates in Vitamin B12 deficiency.

Vegans are at risk of Vitamin B12 deficiency because all dietary Vitamin B12 is derived from animal products.

Unless their food is habitually contaminated withbacteria or fecal matter

Pantothenic Acid

Building block of Coenzyme A

Pantothenic Acid

• Deficiency has never been observed under ordinary conditions

• An amount of 5mg/day is recommended as a “safe and adequate intake”.

Biotin

Biotin

• Prosthetic group of:– Pyruvate carboxylase– Acetyl-CoA carboxylase– Propionyl-CoA carboxylase– Other ATP-dependent carboxylases

Biotin

• Humans need only 20ug per day

• Eating at least 20 raw egg whites per day induces biotin deficiency.

• Egg white - contains avidin which binds biotin avidly preventing its intestinal absorption.

Protein-bound biotin Biocytin

Biotin + Lysine

Proteases

Biotinidase

Biotinidase deficiency causes nondietary biotin deficiency

Affected infants present with hypotonia, seizures, opticatrophy, dermatitis and conjunctivitis.

Biotinidase deficiency is often included in newborn screeningprograms.

Folic Acid

Folic Acid

• Coenzyme in reactions involving single carbon fragments: • synthesis of heme ( iron-containing protein of Hb),

thymine (DNA component), purines (nucleoprotein components in all cells), methyl transfer of methionine and choline

• Erythropoiesis (RBC synthesis)

Folic Acid

• Clinical signs of folate deficiency are caused by impairment of DNA replication in dividing cells

Production of mature red blood cells slow downand the cells that are formed are oversized.

Megaloblastic or macrocytic anemia

Low levels of serum folate are often encountered in latepregnancy

Folic Acid

• RDA = 400ug

• Total body stores are 5 to 10mg

• Folate supplements are recommended for the prevention of neural tube defects (spina bifida and anencephaly) - present in about 1 per 400 births

• Daily doses of at least 500ug have also been found beneficial for the prevention of coronary heart disease.

Partly due to the homocysteine-lowering effectof this vitamin.

Vitamin C

Vitamin C

• biologically active forms:

L-ascorbic acid: reduced form

L– dehydroascorbic acid: oxidized form

• most easily destroyed of all vitamins: heat, alkali, light, O2, Fe, Cu

Ascorbate-dependent processes

1. Hydroxylation of prolyl and lysyl residues in procollagen

2. Carnitine synthesis

3. Dopamine synthesis

4. Bile acid synthesis

Ascorbic acid is a reducing agent and scavenger of free radicals (antioxidant)

Vitamin C

• formation and maintenance of collagen and intercellular cementing substance that binds cells together, thus maintains cellular integrity: collagenous connective tissues (tendons and ligaments), bone marrow, capillary walls, teeth, gums, skin, scars

• essential to normal functioning of all cellular units

Vitamin C

• essential for the following reactions:

folic acid Vitamin C folinic acid

wound healing, healing of fractures

prevention of megaloblastic anemia

prevention of petechial or pinpoint

hemorrhages

building of bodily resistance against infections

Vitamin C

• essential for the following reactions: insulin synthesis and production of steroid

hormones under severe stress: adrenocortico-hormones

metabolism of tyr and phe reduce ferric to ferrous form which is more

available for RBC maturation

Effects of Deficiency 1. Early stage: irritability, general weakness, lack of

appetite, lowered resistance to infections, pallor

2. Severe deficiency:• scurvy: spongy, bleeding, swollen gums; loose teeth;

swollen tender joints; internal hemorrhages under the skin; capillary fragility; megaloblastic anemia

• infantile scurvy: legs in “frog’s position”: flexing as a response to tender, painful and swollen thighs; delayed dentition and skeletal growth

Vitamin C

• Absorbed by a sodium-dependent transporter in the intestine– Can absorb only a maximum of 1 to 2 g of

ascorbic acid per day

Lesson: Megadoses are incompletely absorbed.

A daily intake of 20mg is sufficient to prevent and evencure scurvy. US RDA = 60mg.

Vitamin A

Forms1. Retinal (aldehyde)2. Retinol ( alcohol)3. Retinoic acid (acid)

Carotenoids: pigments commonly found in plants and animals, some of which have vitamin A activity. The carotenoid with the greatest vitamin A activity is -carotene.

• Retinal - prosthetic group of the rhodopsins

• Retinoic acid - gene regulator that acts through nuclear receptors; required for the maintenance of epithelial tissues

• Deficiency– Squamous metaplasia (folicular

hyperkeratosis with night blindness)– Xerophthalmia (“dry eyes”)

Adult RDA = 1 mg retinol (1000 retinol equivalents)

• Avitaminosis A: 0-500 ug RE/day; in adult, depletion of liver stores would take 1-2 years

1. In infants and children: impaired growth and skeletal development

2. Keratinization (hardening and sloughing) of mucous membranes or epithelial linings disturbances in respiratory, gastrointestinal and genitourinary tracts

Eyes

a. symptoms of mild deficiency: poor dark adaptation or night blindness; xerosis (drying of the cornea), Bitos’s spots (eye lesion), corneal keratinization, eye hemorrhages, conjunctival xerosis

b. symptoms of severe deficiency: xeropthalmia (progressive blindness caused by vit. A deficiency) keratomalacia ( softening of the cornea) leads to irreversible blindness: total blindness

Skin: skin lesions (“toad’s skin) or phrynoderma or follicular hyperkeratosis: dry, rough skin with papular eruptions around hair follicles; seen in thighs, abdomen, upper arms and back

5. Resistance to infection

6. Faulty skeletal and dental development

7. Progression of deficiency: nightblindness, xeropthalmia

keratinization of soft tissues in the eye, exhaustion

death

Vitamin A Toxicity

Hypervitaminosis A: rare occurrence; may occur with megadosing of preformed Vit. A: > 15,000 ug RE

1. Overstimulated cell division

2. Complete disintegration of bone matrix: bone abnormalities and fractures

3. Membranes prone to rupturing: thickening of the skin with peeling off; skin rashes

Vitamin A deficiency and Vitamin A

excess are teratogenic.

Vitamin D

Vitamin D

• Two forms:1. Secosteroid cholecalciferol (D3)- from cholesterol2. Ergocalciferol (D2) – from plant sterol

Vitamin D requirements can be met by dietary sources and skin photosynthesis

White skin produces about five times more Vitamin Dthan black skin.

• The main function of Vitamin D is to maintain serum calcium and phosphorus at concentrations that support cellular processes, neuromuscular functions and bone ossification

Units of Measurement of Vitamin D 1 I.U. of vitamin D = 0.025 ug

cholecalciferol 1 mg vitamin D = 40,000 I.U. vitamin D

Factors Effect on Vitamin D Utilization and Availability

Dietary fat • Enhances absorption of the vitamin

U.V. exposure • Conversion of inactive form to its active form in the skin:

In skin: 7-dehydrocholesterol (a precursor)

U.V.

previtamin D3

+ vitamin D from foods

In liver: vitamin D3 (inactive form)

hydroxylation

In kidneys: 25-hydroxy vitamin D3

hydroxylation

1,25-dihydroxy vitamin D3 (active form- calcitriol)

25-hydroxycholecalciferol is the major circulatingform of the vitamin

Factors Effect on Vitamin D Utilization and Availability

U.V. exposure

• Prolonged exposure degrades the precursor in the skin preventing conversion to the active form• Sunscreen with SPF 8 and above prevent Vitamin D synthesis

• Calcitriol is a hormone-like substance– acts on the intestines and kidneys to

increase the total amount of calcium and phosphate in the body

– Can be used for the treatment of osteoporosis

Vitamin D

• Deficiency– Rickets in children– Osteomalacia in adults

• Toxicity– Hypercalcemia– Hypercalciuria– Metastatic calcification

Hypervitaminosis D is caused by the overuse of VitaminD supplements.

Vitamin E

Vitamin E

A collective term for compounds that exhibit the biologic actions of alpha-tocopherol

Consists of 8 naturally occuring derivatives:

4 tocopherols

4 tocotrienols Very suceptible to destruction by oxygen,

metals, light and heat

Vitamin E

• The main function of Vitamin E is as an antioxidant

1. Oxidation of PUFA

2. Lipid peroxidation

Vitamin E

• Other Roles of Vitamin E 1. Inhibition of the protein kinase C

activity 2. Sparing of selenium 3. Protection of vitamin A from oxidative

damage 4. Prevents hemolysis of RBCs

• The most serious form of Vitamin E deficiency occurs in patients with abetalipoproteinemia, who develop neuropathic and myopathic changes in addition to hemolysis.

Abetalipoproteinemia is an inherited inability to form chylomicrons and VLDL.

Intervention studieshave shown a reducedrisk of coronary heartdisease in individualsconsuming Vitamin Esupplements in dosagesof approximately200mg/day.

Daily intake of 10mg ofalpha-tocopherol is considered adequate.

Vitamin K

1 unit Vitamin K = 1 ug menadione

Vitamin K

The generic term for several fat soluble substances belonging to a group of chemicals known as quinones.

Phylloquinone (k1) plant foods Menaquinones (k2) animal tissues and

intestinal bacteria Menadione (k3) synthetic

Stable in heat and during oxidation but destroyed by light, acid. Alkali and alcohol

Vitamin K

• Needed in synthesis of prothrombin in blood plasma, which helps in blood coagulation

• Participates in phosphorylation of glucose to facilitate its entry into cell membranes

• Helps in synthesis of osteocalcin, a protein found in bones which binds Ca

Vitamin K

• Not stored to any great extent

• Total body stores = 50-100ug

• Vitamin K is the first fat-soluble vitamin to be deficient in acute fat malabsorption.

Vitamin K

• Participates in the enzymatic carboxylation of glutamyl residues during the synthesis of prothrombin and other clotting factors in the liver

• Clotting disorder - only important deficiency sign

RDA is set at 60 to 80ug

Vitamin K

• Deficiency is most common in the newborn - hemorrhagic disease of the newborn (most common nutritional deficiency in newborns)

Question

Thiamine deficiency can cause both acute encephalopathy and irreversible memory impairment. These problems are most often seen in thiamine-deficient

A. Newborns

B. Alcoholics

C. Diabetics

D. Vegetarians

E. Medical students

Minerals

Inorganic nutrients

Macrominerals Microminerals(trace minerals)

- sodium, potassium, calcium,magnesium, phosphate-required in quantities of morethan 100mg/day

- required in small quantities- serve specialized biochemical functions

Assignment

• Iron

• Zinc

• Copper

References

• Meisenberg, G. and W. Simmons. 2006. Principles of Medical Biochemistry, 2nd edition. pp.523-546

• Pubmed

• Google and Google Scholar