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Metabolic Roles of VITAMINS 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. - PowerPoint PPT Presentation
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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