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Domingo J Piñero, PhD Nutrition, Food Studies, and Public Health
• • • • Essential nutrients Vitamins and minerals Clinical signs of deficiencies B vitamins in alcoholism
Essential Nutrients for Humans
• • • • Water Amino acids: His, Ile, Leu, Lys, Met, Phe, Thr, Trp, Val Fatty acids: linoleic, α-linolenic Vitamins: A, D, E, K, ascorbic acid, thiamin, riboflavin, niacin, pyridoxine, pantothenic acid, folate, biotin, vitamin B12 Minerals: Ca, P, Mg, Fe Trace minerals: Zn, Cu, Mn, I, Se, Mo, Cr Electrolytes: Na, K, Cl Ultratrace elements: As, B, F, Ni, Si, V Energy sources
• • • • •
Criteria for Essential Nutrient • The substance is not synthesized de novo in the body • The substance is required for growth and/or maintenance of health • Lack of exogenous intake results in characteristic signs of a deficiency disease • The signs of deficiency are prevented only by the nutrient or a specific precursor of it .
elongated derivatives of w-6 and w-3 fatty acids. Tyr and taurine.. but which are essential for specific populations or under certain circumstances • Pathologic states (e. liver cirrhosis.Conditional Essentiality • Substances not ordinarily required in the diet for healthy humans.g. requires Cys. and carnitine) • Genetic defects (carnitine synthesis) . severe trauma requires Gln) • Immature infants (appear to require Cys and Tyr.
or functional abnormalities • Correction of both of 1 and 2 by a dietary supplement of the nutrient .Conditional Essentiality • Three tests proposed to establish a condition of “conditional essentiality”: • Decline in the plasma level of the nutrient into the subnormal range • Appearance of chemical. structural.
since is made on the surface of the skin when exposed to sunlight .. since it can be made from tryptophan • Vitamin D – when exposure to sunlight is low. the following vitamins could be considered “conditionally essential”: • Niacin – when there is a relative tryptophan deficiency.g.Conditional Essentiality • Grey area – e.
proteins and carbohydrates • Fat-soluble vitamins have a variety of function in some cases similar to hormones .Vitamins • A large group of potent organic compounds necessary in minute amounts in the diet • Divided based on their solubility characteristics • Water-soluble vitamins usually function as coenzymes in the metabolism of fats.
and the formation and maintenance of the body’s structure .Minerals • First subdivided based on the magnitude of need: macrominerals and microminerals • Function as cofactors in intermediary metabolism.
glycogenolysis B12 C D 1C metabolism hydroxylation bone remodeling gene expression E K Biotin Choline Folate tocopherols phytylmenaquinone multiprenylmenaquinone antioxidant coagulation bone remodeling gluconeogenesis. fa. respiration redox aa metabolism. aa pl 1C metabolism tca. tca.General functions of some vitamins A B2 B3 B6 retinoic acid retinal riboflavin niacin pyridoxine pyridoxamine pyridoxal cobalamin ascorbic acid cholecalciferol gene expression phototransduction redox. fa and cholesterol Panthotenic acid .
B12. calcium. Folate. riboflavin • Antioxidant capacity: Selenium. Zn. Cu. vitamin E. Cu . phosphorus. vitamin K. vitamin A. B6. vitamin C. Fe.Functional classification • Bone health: Vitamin A. magnesium • Nutritional anemias: Fe.
Pharmacological Uses of Micronutrients • In high doses.V. infusions of Mg are used to treat preeclampsia and myocardial infarction . some micronutrients have pharmacologic effects. different from their nutritional function. For example: • Large doses of nicotinic acid lower serum cholesterol • I.
so RDA = EAR + 20% .S. usually assume coefficient of variation (SD/mean) = 10%.Dietary Reference Intakes (DRIs) • Set of nutrient recommendations by Institute of Medicine (IOM) of the U. National Academy of Sciences • EAR (Estimated Average Requirement): daily intake level estimated to meet the requirement of half the healthy individuals in a particular life stage and gender group • RDA (Recommended Dietary Allowance): average daily intake level sufficient to meet the requirements for nearly all (97-98%) healthy individuals in a particular life stage and gender group • RDA = EAR + 2SD if SD available • If SD not known.
Dietary Reference Intakes (DRIs) • AI (Adequate Intake): used when an EAR and RDA cannot be determined. based on observed or experimentally determined approximations or estimates of intakes by a group of healthy people assumed to be adequate • UL (Tolerable Upper Intake Level): highest average longterm intake likely to pose no risk of adverse effects to almost all individuals in the general population .
5 0 Observed Level of Intake .0 RDA AI? UL Risk of Adverse Events Risk of Inadequacy 0.DRIs in Perspective EAR 1.
Nutrient Requirements Affected by: • • • • • Age. tryptophan intake affects niacin requirement.. sex (EARs.g. RDAs/AIs based on these) Genetics Drug-nutrient interactions Nutrient-nutrient interactions Amount of nutrient “precursor” (e. 60 mg tryp = 1 mg niacin) .
though it does store fat-soluble vitamins and many minerals • Urinary levels indicate recent intake and use • RBCs good for mid.however. or red or white blood cells nutrient levels • Serum/plasma levels indicate amount transported. the body doesn’t store water-soluble vitamins.Assessing Individual Nutritional Status • Dietary and medical history • Serum/plasma. WBC more complicated . not necessarily stored -.to long-term status. urine.
certain other minerals or certain B vitamins .Assessing Individual Nutritional Status • Assess status of specific tissues or organs to determine if specific micronutrient requirements are not met. poor growth and development of bones due to deficiency of vitamin D and/or calcium • Anemia. due to deficiency of iron. • Examples: • Rickets.
General Issues • Signs and symptoms non-specific • Function of nutrient not understood at molecular level • Lack of adequate assessment tools • Clinical nutrition physical assessment .
and modulation of apoptosis • Immune system integrity • Food sources: • • • • Liver Fish oil Eggs Fortified milk or other foods • Red.Vitamin A (and carotenoids) • Functions: • Normal vision • Growth and reproduction • Cell proliferation. and dark green veggies (carotenoids) . yellow. differentiation. orange.
proapoptotic agent as well as inhibitor of cell migration • Plays role in immunity • Calciotropic versus noncalciotropic functions • Sources: • Sunlight (10 – 15 min 2x a week) • Fish (with bones) • Fortified milk and other foods .Vitamin D (the sunshine vitamin) • Functions: • Calcium homeostasis • Antiproliferative. prodifferentiation.
leafy veggies .Vitamin E • Functions: • Antioxidant* • Sources: • Vegetable oils • Foods made from oil (salad dressing. margarine) • Nuts • Seeds • Wheat germ • Green.
CH3 HO CH3 O CH3 CH3 CH3 CH3 CH3 CH3 α-tocopherol •O2H2O2 Lipid-OO• Lipid-OOH O2 Vitamin E redox cycle •O2Dehydroascorbate Ascorbate CH3 GSSG GSH •O O CH3 CH3 CH3 CH3 CH3 CH3 CH3 α-tocopheroxyl .
Vitamin K Function COO- -OOC COOCH CH2 CH2 Vitamin K CO2 CH2 γ-glutamyl carboxylase γ-carboxy glutamic acid (Gla) in peptide Glu in peptide Carboxylation of glutamyl residues .
IX. leafy veggies • Some fruits. other veggies. cell survival. cell signaling • Sources: • Body can produce on its own (from bacteria in intestines) • Green. and X) and 3 anti-coagulant factors (proteins C. factors VII. and nuts .Vitamin K • Functions: • Blood coagulation: 4 procoagulant (prothrombin. S. and Z) • Bone health • Cell replication and transformation.
• Energy production • Metabolism of branchedchain amino acids • Pentose phosphate shunt
• Whole-grain and enriched grain products • Pork • Lentils • Fortified cereals
• Energy production • Niacin synthesis from tryptophan • Oxidant/antioxidant balance
• • • • • Milk Enriched cereals Eggs Almonds Green, leafy veggies
• Metabolism of sugars/fatty acids • Non-redox functions: • Deacetylases, ribosyl cyclases, ribosyl tranferases and oolyADP-ribose polymerases (PARPs)
• Foods high in protein typically (poultry, fish, beef, peanut butter, legumes) • Enriched and fortified grains
Pyridoxine (B6) • Functions: • Amino acid metabolism • Neurotransmitter synthesis • Glycogen metabolism • Heme synthesis • Sources: • Animal protein • Whole grains and fortified cereals • Bananas • Nuts • Legumes .
Folate (folic acid) • Functions: • 1-carbon metabolism • DNA. RNA expression • Homocysteine/methionine metabolism • Serine/glycine metabolism • Phospholipids • Catecholamines • Other methylation reactions • Sources: • Fortified and enriched grains and breakfast cereals • Orange juice • Legumes • Green. leafy veggies • Peanuts • Avocados .
other dairy .Vitamin B12 (cobalamin) • Functions: • Metabolism of amino acids and fatty acids • Synthesis of hemoglobin • Cofactor for methionine synthase • Sources: • • • • • Shellfish Liver Animal products Eggs Milk.
Biotin • Functions: • Energy production • Proteins. carbs. and fats metabolism • Fixation of CO2 • Sources: • • • • • • • Wide variety of foods Eggs Liver Wheat germ Peanuts Cottage cheese Whole grain bread .
and carbs • Whole grain cereals from food • Legumes • Milk • Fruits. fat. veggies .Pantothenic Acid • Component of CoA • Sources: • Found in almost all foods • Helps the body use • Meat. fish proteins. poultry.
Vitamin C • Functions: • Antioxidant • Posttranslational hydroxylation of proline and lysine in the formation of collagen • Collagen gene expression • CNS: neurotransmitter synthesis NE and serotonin) myelin synthesis • Iron absorption • Aldosterone and corticosteroids synthesis • Vasodilatory and anticlotting effects through PGA synthesis .
Vitamin C • Sources: • • • • • Black currants Broccoli. cauliflower Citrus fruits Green leafy vegetables Potatoes . Brussels sprouts.
What are minerals? • • • • Regulate body processes Give structure to things in the body No calories (energy) Cannot be destroyed by heat .
potassium) • Trace minerals • • • • • • • • Chromium Copper Flouride Iodine Iron Manganese Selenium Zinc . chloride.Categories of minerals • Major minerals • • • • Calcium Phosphorus Magnesium Electrolytes (sodium.
Calcium • • • • • Bone building Muscle contraction Heart rate Nerve function Helps blood clot .
repair) Almost all foods. RNA (cell growth. especially protein-rich foods. teeth Part of DNA.Phosphorus • • • • • Generates energy Regulate energy metabolism Component of bones. contain phosphorus .
nuts.Magnesium • • • • Part of 300 enzymes (regulates body functions) Maintains cells in nerves. muscles Component of bones Best sources are legumes. and whole grains .
beans. eggs. carries oxygen Brain development Healthy immune system Sources: • • • • Animals (heme) vs.Iron • • • • Part of hemoglobin. plants (non-heme) Better absorbed from heme Consume vitamin C with non-heme Fortified cereals. . etc.
membrane pink and moist Pale conjunctiva Night blindness Bitot’s spots Xerosis Redness and fissures in corners of eyelids Fe Vitamin A Vitamin A Vitamin A Riboflavin. smooth cornea. phosphorus Nonnutritional anemias Hereditary eye diseases Aging. pyridoxine Thiamin. allergies Normal eye movement Ophthalmoplegia to follow objects Brain lesion* . shiny. clear.Eyes Normal Clinical Findings Suspect Deficiency Other Causes Bright.
endocrine disorders. chemotherapy. firm. not easily plucked Normal appearing or thick Clinical Findings Suspect Deficiency Flag sign. Normal-appearing hair shaft and emergence from skin Corkscrew hairs and unemerged coiled hairs Vitamin C . easily plucked. biotin. medication. etc. zinc Other Causes Overprocessing of hair Alopecia from aging.Hair Normal Shiny. no pain. Sparse Protein (kwashiorkor/ marasmus) Protein.
concave. soft Mg? . Zinc? Normal if only in toenails Other Causes Koilonychia Fe (thinning. spoon-shaped) Brittle. flattening. rounded. smooth Clinical Findings Transverse ridging Suspect Deficiency Protein.Nails Normal Uniform.
hypervitaminosis E Vitamin C. riboflavin. smooth. esp. injury. flea bites Anticoagulant therapy. thrombocytopenia. EFAs. zinc. severe fever. healthy appearance Clinical Findings Scaling or nasolabial seborrhea Suspect Deficiency Vitamin A. pyridoxine Other Causes Hypervitaminosis A Petechiae. perifollicular Ecchymosis Vitamin C Abnormal blood clotting.Skin (1) Normal Uniform color. vitamin K .
vitamin C Niacin Other Causes Protein Aging process Excess carotene intake . palms of hands while sclera remains white Suspect Deficiency Vitamin A. esp.Skin (2) Normal Uniform color. smooth. healthy appearance Clinical Findings Follicular hyperkeratosis Pigmentation. desquamation of sunexposed areas Cellophane appearance Yellow pigmentation.
moon Protein. vitamin C. DM Body edema. smooth. steroids Poor skin care. esp. face thiamin Poor wound healing. decubitus ulcers Pallor. fatigue Protein. zinc.Skin (3) Normal Uniform color. kwashiorkor Fe Blood loss . healthy appearance Clinical Findings Suspect Deficiency Other Causes Medication.
niacin. tongue) pyridoxine . pyridoxine. folate. Fe Other Causes Excessive salivation due to ill-fitting dentures Tongue red Atrophic lingual without swelling. Riboflavin. niacin Riboflavin. papillae normal surface Glossitis (magenta. no sores Clinical Findings Cheilosis Angular stomatitis Suspect Deficiency Riboflavin.Oral (1) Normal Lips smooth. niacin. vitamin B12. vitamin B12. protein. raw folate. scarlet.
bleeding. periodontal disease Vitamin C Normal taste and smell Hypogeusia Hyposmia Normal gums and teeth Mottled enamel on teeth Eroded enamel Cavities.Oral (2) Normal Clinical Findings Suspect Deficiency Zinc Other Causes Medications (antineoplastic. retracted gums Swollen. sulfonylureas) Fluorosis Bulimia? Poor oral hygine. retracted gums . missing teeth.
paresthesias Ataxia. confabulation. disorientation Normal reflexes Foot and wrist drop and sensations Peripheral neuropathy – weakness. increase serum calcium…) Excess pyridoxine Thiamin Thiamin.Neurologic Normal Psychological stability Clinical Findings Dementia Memory loss. and decreased tendon reflexes Suspect Deficiency Niacin. vitamin B12 Thiamin Other Causes Disease or agerelated. vitamin B12 . pyridoxine. multiple causes (aluminum toxicity.
Alcoholism and B vitamins .
Effects • Alcoholism places individuals at increased risk for vitamin B deficiency because of: • decreased intake • decreased absorption/reabsorption • impaired utilization .
Thiamin The active form of thiamin .thiamin diphosphate (TDP) works as a coenzyme in the following important reactions: Transketolase reaction • The transfer of a 2C fragment from alpha-keto sugars to aldose acceptors in the pentose-phosphate shunt catalyzed by transketolase .
To provide the cell with ribose-5-phosphate (R5P) for the synthesis of the nucleotides and nucleic acids 3. It can operate to metabolize dietary pentose sugars derived from the digestion of nucleic acids as well as to rearrange the carbon skeletons of dietary carbohydrates into glycolytic/gluconeogenic intermediates (Enzymes that function primarily in the reductive direction utilize the NADP+/NADPH cofactor pair as opposed to oxidative enzymes that utilize the NAD+/NADH cofactor pair) .Transketolase catalyzes two critical reactions in the pentose phosphate pathway Functions of the pentose phosphate pathway: 1. for reductive biosynthesis reactions within cells 2. To generate reducing equivalents in the form of NADPH.
TDP in the pentose phosphate pathway Transketolase decreases early in thiamin deficiency. measuring its activity in RBCs has been used to assess thiamin nutritional status TK Thiamin (TDP) TK .
• The conversion of branched-chain alpha-keto acids to acyl-CoA's catalyzed by branched-chain alpha-ketoacid dehydrogenase. . Rate limiting. • The conversion of α-ketoglutarate to succinyl-CoA in the TCA cycle catalyzed by alpha-ketoglutarate dehydrogenase.Thiamin Oxidative decarboxylation of α-keto acids • The conversion of pyruvate to acetyl-CoA catalyzed by pyruvate dehydrogenase complex.
Leu and Ile undergo reversible transamination to their corresponding α-keto acids (by BCAA aminotransferase) Val Leu Ile ● + α-KG Glu + α-ketovalerate α-ketoisocaproate α-keto-β-methylvalerate The keto acids.Metabolism of BCAAs Val. then go through an irreversible decarboxylation of the carboxyl group by the branched chain ketoacid (BCKA) dehydrogenase to liberate CO2 ● The BCAAs are the only essential amino acids to undergo transamination. branched-chain amino acids and their ketoacids are toxic in excess (maple syrup urine disease) but have to be conserved for protein synthesis .
FAD. and lipoic acid . respectively. and branched chain ketoacid (BCKA) dehydrogenase are mitochondrial enzyme complexes • Catalyze the decarboxylation of pyruvate.Oxidative decarboxylation of α-keto acids • Pyruvate dehydrogenase. all of which play critical roles in the production of energy from food In addition to the thiamin coenzyme (TDP). α-ketoglutarate dehydrogenase. succinyl-coenzyme A. and branched-chain keto acids to form acetyl-coenzyme A. each dehydrogenase complex requires CoA. α-ketoglutarate. NAD. and derivatives of branched chain keto acids (acyl-CoAs).
Glucose TDP-dependent enzymes Ribose-5-P Xylulose-5P G6P Pentose shunt Glyceraldehyde-3-P Pyruvate Lactate TK Sedoheptulose-7P Leu PDHC Pyruvate mitochondria Ile BCKADH Acetyl-CoA OXA Citrate Propionyl CoA Bt Methylmalonyl CoA B12 α-KG Succinyl CoA α-KGDH Glu Val MMA GABA .
Non-coenzyme function of thiamin • Less understood than TDP coenzyme role • TTP concentrated in nerve and muscle cells • Activates membrane ion channels. possibly by phosphorylating them • Impaired formation of TTP may play role in neurological symptoms of severe thiamin deficiency .
● and TDP effect on ETKA: ● ● ● Normal: 0-15% increase with TDP Marginal deficiency: 15-25% increase with TDP Deficiency: > 25% increase with TDP . lactate. medical history.Evaluation of Thiamin Status ● Subject’s history: dietary assessment. demographic data. and psychological history should be recorded. ● Laboratory tests: ● urinary thiamin excretion ● blood TDP levels ● CSF thiamin concentration ● blood pyruvate. family history. and α-KG levels ● erythrocyte transketolase activity (ETKA).
the inhibition of which leads to a failure in ATP synthesis ● Synthesis mechanisms: reflected by the importance of the transketolase reaction in the formation of NADPH and pentose ● Neurotransmitters and nerve conduction: changes in GABA and glutamate . muscular. but thiamin may as well play three major roles at the cellular level: ● Energy metabolism: related to the oxidative decarboxylation of α-keto acids. ● Cardiac failure. nervous and gastrointestinal systems. and gastrointestinal malfunction. peripheral and central neuropathy. ● The precise biochemical defects have not been established. muscle weakness.Deficiency ● Affects the cardiovascular.
Beriberi: Clinical Signs ● Clinical signs vary with age and the organ systems involved ● Infantile ● Adult ● Dry ● Wet ● Wernicke encephalopathy and Wernicke- Korsakoff Syndrome (sometimes referred to as “cerebral beriberi”) .
with death occurring within a few hour of the onset unless thiamin is administered ● Aphonic beriberi: the tone of the child’s cry varies from hoarseness to complete aphonia ● Pseudomeningitic beriberi: infants exhibit vomiting. vomiting. and cardiomegaly. dyspnea.Infantile beriberi ● Most common between 2-6 mo ● Cardiac (acute fulminating) beriberi: acute attack that includes a loud piercing cry. tachycardia. purposeless movements of the extremities. nystagmus. and convulsion accompanied by a normal cerebrospinal fluid . cyanosis.
diminished sensation and weakness in the legs and arms ● Muscle pain/tenderness and difficulty rising from a squatting position also observed ● Seizures may be seen in severe deficiency Wet beriberi (cardiac) ● In addition to neurologic symptoms. wet beriberi is characterized by cardiovascular manifestations. and ultimately congestive heart failure . edema. difficulty breathing.Adult Beriberi Dry beriberi (paralytic or nervous) ● Main feature: peripheral neuropathy ● Early on: "burning feet syndrome" may occur ● Other symptoms: exaggerated reflexes. cardiomegaly. which include rapid heart rate.
Beri beri .
● Wernicke-Korsakoff Syndrome = spectrum with 2
separate sets of symptoms, one of which tends to start when the other subsides
● Wernicke's encephalopathy common in alcoholics, but
can also appear in people with HIV/AIDS, GI disease, or glucose IV without adequate B1 supplementation ● Involves damage to multiple nerves in both the central and peripheral nervous system ● Abnormal eye movements (e.g., nystagmus, ophtalmoplegia) ● Stance and gait abnormalities ● Abnormalities in mental function (apathy, memory problems) ● Peripheral neuropathy in 80% of patients
● Korsakoff syndrome, or Korsakoff psychosis ● Involves impairment of memory (retrograde
as well as inability to learn) - patients often attempt to hide their poor memory by confabulating (making up stories about experiences or situations) ● Impairment of conceptual functions and decreased spontaneity and initiative. ● IV thiamin to WKS patients generally improves eye symptoms, but effects on motor coordination and memory may be less, depending on how long symptoms were present (nerve damage)
● Wernicke encephalopathy is underdiagnosed
doctors look for the classical triad: ophthalmoplegia, ataxia, confusion
● Thiamin deficiency should be suspected in
grossly impaired nutritional status (especial attention to alcoholism, GI diseases, HIVAIDS, persistent vomiting)
● Thiamin should be administered parenterally
as soon as possible
● Essential before glucose solutions or
followed by 10 mg/d orally until recovery ● Change dietary habits / stop drinking alcohol ● Rationale for high dosage: ● Replenish thiamin stores ● Stimulate TDP-dependent reactions maximally ● Improve cardiovascular disease .Treatment ● Beriberi patients should receive thiamin administration as soon as possible ● Usual dose = 50 .100 mg/d IV or IM for 1-2 weeks.
Riboflavin Antioxidant function ● Glutathione reductase is an FAD-dependent enzyme that participates in redox cycle of glutathione. such as hydroperoxides 72 . which protects organisms from reactive oxygen species.
Glutathione Redox Cycle 73 .
catalyzes oxidation of hypoxanthine to xanthine and further to uric acid.Functions: Antioxidant ● Xanthine oxidase. one of the most effective water-soluble antioxidants in the blood ● Riboflavin deficiency can result in decreased xanthine oxidase activity. an FAD-dependent enzyme. reducing blood uric acid levels 74 .
75 Schematic diagram of the purine degradation pathway Pacher et al. 2006 . Pharmacol Rev 58(1):87-114.
niacin ● Conversion of vitamin B6 to its coenzyme form. increasing risk of niacin deficiency ● Methylene tetrahydrofolate reductase (MTHFR). an FAD-dependent enzyme. folate. requires the FMNdependent enzyme pyridoxine 5'-phosphate oxidase ● Synthesis of NAD and NADP from tryptophan requires the FAD-dependent enzyme kynurenine monooxygenase ● Severe riboflavin deficiency can decrease conversion of tryptophan to NAD and NADP. pyridoxal 5'-phosphate (PLP). which is required to form methionine from homocysteine 76 . plays important role in maintaining this specific form of folate (Me-THF).Functions: Nutrient Interactions B-complex vitamins B6. B12.
Nutrient Interactions: Riboflavin. Folate. and Vitamin B12 77 .
impaired Fe mobilization from ferritin and/or impaired iron utilization for the synthesis of hemoglobin ● In humans. but may involve impaired iron absorption. increased intestinal loss of iron.Functions: Interaction with Iron ● Riboflavin deficiency alters iron metabolism ● Mechanism not clear. improving riboflavin nutritional status has been found to increase circulating hemoglobin levels ● Correction of riboflavin deficiency in individuals who are both riboflavin deficient and iron deficient improves the response of irondeficiency anemia to iron therapy 78 .
4 deficient 79 . or 24-hour specimens or by load return tests ● Erythrocyte riboflavin concentration: <27 nmol (10 μg)/dL = deficiency ● Erythrocyte glutathione reductase activity coefficient. EGRac (before and after FAD addition) <1.Assessment ● Urinary excretion of the vitamin in fasting. random.2 acceptable. >1.
usually occurs in combination with deficiencies of other water-soluble vitamins ● Symptoms include ● sore throat ● redness (hyperemia) and swelling (edema) of the lining ● ● ● ● ● ● of the mouth and throat cracks or sores on the outsides of the lips (cheilosis) and at the corners of the mouth (angular stomatitis) inflammation and redness of the tongue (magenta tongue) a moist.Deficiency (Ariboflavinosis) ● Rarely found in isolation. and thombocytopenia peripheral neuropathy (hyperesthesia. and decreased sensitivity) 80 . scaly skin inflammation (seborrheic dermatitis) corneal vascularization normochromic normocytic anemia with reticulopenia. leukopenia.
Biotin: fixing CO2 ● Biotin serves as a covalently bound coenzyme for four important enzymes known as carboxylases ● These carboxylases catalyze an essential metabolic reaction: the incorporation of bicarbonate as a carboxyl group into a substrate ● In all 4 carboxylases. biotin functions as a coenzyme or prosthetic group that serves as a carrier for CO2 in a multistep reaction 86 .
The four carboxylases are: ● Acetyl-CoA carboxylase (ACC) catalyzes the binding of bicarbonate to acetyl-CoA to form malonyl-CoA. ● Pyruvate carboxylase (PC) is a mitochondrial enzyme critical in gluconeogenesis. ● Propionyl-CoA carboxylase (PCC). and odd-chain fatty acids. Located in mitochondria. Cytosolic and mitochondrial. participates in essential steps in the metabolism of amino acids. cholesterol. Malonyl-CoA is required for the synthesis of fatty acids. Also mitochondrial. Catalyzes the incorporation of bicarbonate into pyruvate to form oxaloacetate. 87 . ● Methylcrotonyl-CoA carboxylase (MCC) catalyzes an essential step in the metabolism of leucine.
FUNCTIONS OF BIOTIN isoleucine 3-hydroxypropionate methionine methylcitrate. propionylglycine threonine odd-chain fatty acid valine Leucine propionyl-CoA 3-hydroxyisovalerate* 3-methylcrotonylglycine Propionyl-CoA Carboxylase d-methylmalonyl-CoA succinyl-CoA 3-methylcrotonyl-CoA Methylcrotonyl-CoA Carboxylase 3-methylglutaconyl-CoA fatty acid synthesis. elongation Ø FA oxidation malonyl-CoA glucose TCA cycle oxaloacetate pyruvate acetyl-CoA Pyruvate Carboxylase lactate Acetyl-CoA Carboxylase 88 .
89 .Deficiency Very rare. alcoholism. dialysis. the human requirement for dietary biotin has been demonstrated in two different situations: ● prolonged intravenous feeding without biotin supplementation. ● Long-term anticonvulsant therapy can lead to biotin depletion to a level severe enough to interfere with amino acid metabolism ● Other causes of depletion: pregnancy?. and ● consumption of raw egg white for a prolonged period (many weeks to years).
enzyme required for the synthesis Met from homocysteine ● Met is required for the synthesis of Sadenosylmethionine (SAM). a methyl group donor used in many methylation reactions (DNA and RNA) ● Inadequate function of methionine synthase can lead to an accumulation of homocysteine.Vitamin B12 Cofactor for methionine synthase: ● Methylcobalamin is a cofactor and folate is a substrate for the function of methionine synthase. which has been associated with increased risk of cardiovascular diseases .
SHMT: serine hydroxymethyl transferase.10methylene THF. 5-CH3THF: 5-methyl THF.One-carbon metabolism and transsulfuration pathway Ser Gly B6 SHMT Gly B6 GLDC 5.10-CH2THF: 5. AK: adenosine kinase. GLDC: glycine decarboxylase . 5. ADA: adenosine deaminase. CTH: cystathione gamma lyase. SAM: S-adenosylmethionine.10-CH2THF Ser Thymidine and purines CTH THF: tetrahydrofolate. CBS: cystathionine beta synthase. MS: methionine synthase. SAH: Sadenosylhomocysteine. SAHH: SAH hydrolase. MAT: methionine adenosyltransferase. BHMT: betaine-homocysteine methyltransferase.
FUNCTION 2 Cofactor for L-methylmalonyl-CoA mutase: ● 5-Deoxyadenosylcobalamin is required by the enzyme L-methylmalonyl-CoA mutase that catalyzes the conversion of Lmethylmalonyl-CoA to succinyl-CoA ● Important in the production of energy from fats and proteins ● Succinyl CoA is also required for the synthesis of Hb .
isoleucine methionine threonine valine propionyl-CoA Leucine 3-methylcrotonyl-CoA Propionyl-CoA Carboxylase MMCoA mutase Methylmalonic acid d-methylmalonyl-CoA Methylcrotonyl-CoA Carboxylase 3-methylglutaconyl-CoA fatty acid synthesis. elongation Ø FA oxidation succinyl-CoA glucose TCA cycle oxaloacetate pyruvate acetyl-CoA malonyl-CoA Pyruvate Carboxylase Acetyl-CoA Carboxylase .
Diet Salivary glands Protein-B12 R IF HCl R TC I-B12 IF R-B12 IF R B12 IF-B12 TC II i r t o R-B12 Pancreatic proteases Parietal cells Chief cells Pepsin B12 Ileal IF-B12-Receptor (cubilin) Portal circulation TC II-B12 .
B12 Pyrimidines synthesis Purines synthesis .
H+ Pentose phosphate pathway Glucose-6-P Ribulose-5-P . superoxide radical anion (O2-) Glutathione peroxidase (Se) Glutathionered (GSH) +H2O2 Glutathioneox (GSSG) Glutathione reductase (FAD) Antioxidants working together NADP+ NADPH.Lipid peroxyl radical LOO LOOH Vit Ered VIT Eox reduced products Vit Cox Vit Cred Fe3+ (ferric) Cu2+ (cupric) hydroxyl radical (OH).
B6: From diet to cell .
neurotransmitters .Functions • The coenzyme PLP plays a vital role in the function of >100 enzymes that catalyze essential chemical reactions in the human body: • Decarboxylation of amino acids to produce amines – important in neurotransmitter synthesis • Transamination of amino acids to keto acids – fuel • Phosphorolytic cleavage of glycogen to G1P • One-carbon metabolism and transsulfuration • Synthesis of: • Carbohydrates. amino acids. heme. sphingolipids.
in B6 deficiency.Amino acid metabolism • Transamination: ALT and AST among others • Transsulfuration (met to cys): cytathione synthase and cystathionase • Selenoamino acid metabolism: release of Se from selenohomocysteine by the enzymes selenocysteine αand γ-lyase • Tryptophan-niacin conversion • Kynureninase catalyzes an important step. the pathway is impaired and kynurenic and xanthurenic acids accumulate in urine • Histamine synthesis (histidine decarboxylase) .
Glucose metabolism • Transaminations (in gluconeogenesis) • Glycogen utilization • coenzyme for glycogen phosphorylase in the phosphorylation of glucose to G-1P. This function accounts for more than half the activity of B6 in the body .
and norepinephrine) • DOPA decarboxylase (aromatic L-amino acid decarboxylase) • GABA • L-glutamic acid decarboxylase • Energy production • Neuronal function .CNS function • Neurotransmitter synthesis • Serotonin • Tryptophan decarboxylase • Dopamine (and epi.
hypochromic anemia • B6 binds to the α and β chains enhancing O2 binding and inhibiting sickling in sickle-cell Hb . precursor of the porphyrin ring microcytic.Hemoglobin synthesis and function • Synthesis of heme • δ-aminolevulinate synthase condensates succinyl CoA and glycine to form δ-aminolevulinate.
Lipid metabolism • Synthesis of sphingolipids (serine palmitoyl transferase) • Biosynthesis of carnitine (3-hydroxymethyl-lysine hydrolase). . This reaction also needs iron.
glyceraldehyde-3-phosphate dehydrogenase) and to decrease mRNA levels for others (RNA polymerase I and II) .Gene expression • Elevated intracellular B6 alters steroid hormone receptor-induced enzymes • Decreased response to glucocorticoids • Elevated expression of albumin mRNA in B6 deficiency • Known to suppress mRNA levels for a a number of other proteins (apolipoprotein A-1.
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