Nutrition-Vitamins (Metabolic Biochemistry)

Nutrition

1. The dietary reference intake (DRI) is comprised of several reference values, including the recommended dietary allowance related to adequate intakes and upper levels of intakes.

2. The recommended dietary allowance (RDA) refers to the intakes needed for optimal health, it is not a minimum daily requirement.

Basal metabolic rate (BMR) and Respiratory exchange rate (RER)/Respiratory quotient (rate of oxygen consumption for different carbon sources)

Vitamins

-Vitamins can be divided into fat-soluble and water soluble.

(a) Fat soluble Vitamins

Vitamin A: Vision, epithelial tissue growth in children

Vitamin D: Bone mineralization, Blood Calcium regulation

Vitamin E: Antioxidant

Vitamin K: Clot factor synthesis

(b) Water-soluble vitamins

Function 1: Energy metabolism

-Thiamine (B1), Riboflavin (B2), Niacin (B3), Biotin (Vitamin H), Pantothenic Acid (B5)

Function 2: Amino acid metabolism

-Pyradoxine, Pyridoxal, Pyridoxamine (B6)

Function 3: RBC/Neural Development

-Folic acid, Cobalamin (B12)

Function 4: Collagen Synthesis

-Ascorbic Acid (Vitamin C)

Function 5: DNA and RNA formation

-Adenine (Vitamin B4)

 

 

  • Water Soluble Vitamins

———————————————————–Vitamin B———————————————————————————————

1. Vitamin B1 (Thiamine)

Sources of thiamine [Enriched/whole grain cereals, brewer’s yeast, meats, legumes and nuts, brown rice]

*Thiamine pyrophosphate is the active form of the vitamin.

Cofactor for dehydrogenases in oxidative decarboxylation of alpha keto acids (e.g. pyruvate dehydrogenase conversion of pyruvate into acetyl coA)

-Cofactor for transketolase (2-carbon transfer reactions) in the pentose phosphate pathway)

*Thiamine deficiency-Most commonly occurs in alcoholics or malnourished individuals

-Most clinical findings in thiamine deficiency reflect the loss of ATP from dysfunction of pyruvate and a-ketoglutarate dehydrogenase reactions, which normally gain 2NADH (6 ATP).

-IV infusion of glucose-containing fluid may precipitate acute thiamine deficiency in alcoholics (depleted by the pyruvate dehydrogenase pathway)–>Resulting in Wernicke-Korsakoff Syndrome (WKS)

 

WKS includes confusion, ataxia, nystagmus, eye muscle weakness and retrograde and antegrade memory deficits.

 

 

2. Vitamin B2 (Riboflavin)


-Sources of vitamin B2 [Milk, eggs, meat, poultry, fish and green leafy vegetables]

*Flavin adenine dinucleotide (FAD) and Flavin mononucleotide (FMN) are the active forms of riboflavin.

FAD is a cofactor associated with succinate dehydrogenase, which converts succinate to fumarate in the citric acid cycle (TCA).

FMN is the component of the electron transport chain and accepts two hydrogen atoms to become FMNH2 from NADH in a reaction catalyzed by NADH dehydrogenase.

 

-Riboflavin deficiency is usually seen in severely malnourished individuals or pure vegans who lack intake of diary products.

 

Riboflavin deficiency: Corneal neovascularisation, glossitis (soreness or swelling of the tongue), cheilosis (inflammation of the lips), angular stomatitis (inflammation of the structures in the mouth)

 

3. Vitamin B3 (Niacin/Nicotinic Acid)

-Sources of vitamin B3 [Enriched and whole grain cereals, Milk and eggs (contains tryptophan)]

-Excess tryptophan is metabolised into niacin and supplies about 10% of the niacin RDA.

 

Two active forms are NAD+ and NADP+

-NAD+ reactions are catabolic (e.g. glycolysis)

-NADP+ reactions are primarily anabolic (fatty acid synthesis)

 

Functions of Vitamin B3:

1. Lipid-lowering agent that decreases cholesterol and triacylglyerol.

2, Increases High density lipoproteins (‘good’ cholesterol)

 

Niacin deficiency: Known as pellagra, primarily occurs in individuals whose tryptophan is lost in urine and feces (Hartnup’s disease) or if excessively used (carcinoid syndrome)

-Individuals who consume corn-based diets are particularly prone to pellagra, because maize has a low tryptophan content and niacin is in a bound form that cannot be reabsorbed.

-Hartnup’s disease: An autosomal recessive disease with a defect in the intestinal and renal reabsorption of neutral amino acids (e.g. tryptophan)

-Carcinoid Syndrome: Tumour occurs in small intestine that metatasizes to the liver. Metastatic nodules secrete sertonin into hepatic vein tributaries producing this syndrome.   Tryptophan–>Serotonin (Results in flushing and diarrhea)

 

-Excessive niacin intake leads to flushing due to vasodilation.

 

4. Vitamin B5 (Pantothenic acid)

-Component of Coenzyme A and the fatty acid synthase complex, which is involved in fatty acid synthesis.

 

*Deficiency is uncommon, no clinical findings.

 

5. Vitamin B6 (Pyridoxine)

-Sources of pyridoxine [Whole grain cereals, eggs, meats, fish, soybreans and nuts]

*Active form: Pyridoxal phosphate

 

Function of pyridoxine:

1. Involved in transamination reactions

-These reactions are the reversible conversion of amino acids to alpha-ketoacids) which are catalysed by the transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

2. Cofactor for ALA synthase which catalayses the rate-limiting reaction that converts succinyl CoA + Glycine into ALA in heme synthesis.

3. Pyridoxine is involved in the synthesis of neurotransmitters such as GABA, serotonin and NAdr.

4. Cofactor in the following:

(a) Decarboxylation reactions (converts histidine to histamine)

(b) Glycogenolysis (Glycogen phosphorylase)

(c) Deamination reactions (e.g. conversion of serine to pyruvate and ammonia)

(d) Conversion of tryptophan to niacin

 

Pyridoxine deficiency: Heme defect and leads to sideroblastic anemia

*Deficiency is most commonly observed in alcoholics and in patients receiving Isoniazid therapy for tuberculosis.

 

-Deficiency may also be attributed to unfortified goat’s milk.

 

6. Cobalamin (Vitamin B12: Contains cobalt)

-Sources of cobalamin [Meats, shellfish, poultry, eggs and diary products only]

*Pure vegans lack Vitamin B12, whereas ovo-lacto-vegan (vegan but eats eggs and meat) obtain adequate sources from these sources.

-Pure vegans who are pregnant or breast feeding require vitamin B12 supplements to prevent anemia from developing in infant.

Functions of cobalamin (Vitamin B12):

 

1. Demethylation of N5-methyl FH4 for DNA synthesis

-Removes methyl group from N5-tetramethylhydrofolate to form tetrahydrofolate (FH4) used to synthesize deoxythymidine monophosphate (dTMP) from the deoxyuridine monophosphate (dUMP)–>DNA synthesis

2. Methyl group transfers

-Transfers methyl groups to homocysteine to form methionine (DNA synthesis)

3. Odd-chain fatty acid metabolism

-Propionyl-CoA is the product of odd-chain fatty acid metabolism. It is converted into methylmalonyl CoA

-Cofactor for methylmalonyl CoA mutase, which converts methylmalonyl CoA into succinyl CoA

-Increase in propionyl CoA proximal to the block leads to demyelination of the spinal cord, peripheral nerves and brain (dementia)

-Porpionyl CoA replaces acetyl CoA in myelin synthesis

 

Cobalamin Deficiency: Leads to an increase in plasma homocysteine levels which damages vessels and poses a risk for vessel thrombosis. Also results in an accumulation of methylmalonyl CoA.

 

  • How is Vitamin B12 metabolized in the body?

1. Vitamin B12 complexes with R factor in saliva which prevents degradation of Vitamin B 12 by stomach acid.

2. Intrinsic Factor (IF) is synthesized in parietal cells located in the body and fundus of the stomach.

*Autoantibodies in pernicious anemia destroy parietal cells, causing deficiency of intrinsic factor, leading to B12 deficiency

3. Pancreatic enzymes cleave off R factor and allows Vitamin B12 to complex with IF in the duodenum.

*Chronic pancreatitis causes malabsorption of Vitamin B12.

*Bacterial overgrowth destroys Vitamin B12-IF complex

*Fish tapeworm uses Vitamin B12 in its metabolism

4. The vitamin B12-IF complex binds to IF receptors in the terminal ileum and is absorbed.

*Crohn’s disease causes malabsorption of vitamin B12.

 

5. After absorption, Vitamin B12 is bound to transcobalamin II in the plasma and is delivered to metabolically active cells or stored in the liver.

 

*Vitamin B12 deficiency: Most commonly caused by autoimmune destruction of parietal cells (pernicious anemia)

 

 

*Indicates how diseases affect Vitamin B12 metabolism

 

 

7. Folic Acid

-Sources of folic acid [Green leafy vegetables, liver, legumes, whole-grain cereals and yeast]

1. Tetrahydrofolate (FH4) receives a methylene group (CH2) from serine to produce N5, N10-methylene tetahydrofolate

2. Methylene groups transferred by thmidylate synthase to dUMP to produce dTMP for DNA synthesis.

3. Folic acid aids in DNA replication due to production of purine nucleotidse and thymine.

 

How is Folic Acid metabolized?

1. Folic acid is ingested in a polyglutamate form.

2. Polyglutamates are converted into monoglutamates in the jejunum by intestinal conjugase.

*The drug phenytoin inhibits intestinal conjugase

3. Folate monoglutamate is absorbed in the jenum

*Absorption is blocked by alcohol and by oral contraceptives, leading to folic acid deficiency

4. Folic acid circulates and is measured in the blood as methyltetrahydrofolate

*Deficiency of Vitamin B12 traps N5-methyl FH4 in its circulating form, may falsely increase serum folate.

*Only 3-4 month supply of folic acid stored in the liver.

 

Folic acid deficiency – Caused by alcoholism and dietary insufficiency. Drugs such as 5-fluorouracil, methotrexate, trimetoprim, phenytoin, oral contraceptives may also result in deficiency. Pregnant or women undergoing lactation may also be susceptible. Rapidly growing cancers use up folic acid. Small bowel malabsorption (e.g. celiac disease) and fortified goats milk may also result in deficiency.

 

8. Biotin

-Sources of Biotin [Supplied by bacterial synthesis in the intestine]

Function:

1. Cofactor in carboxylase reactions (Pyruvate carboxylase, acetyl CoA Carboxylase, Propionyl CoA carboxylase)

Biotin deficiency: Caused by eating raw eggs (egg whites contain avidin, which binds biotin) and by taking broad spectrum antibiotics which prevents bacterial synthesis of the vitamin.

 

*Lack of Biotin: Dermatitis, alopecia (loss of hair from the body), glossitis, lactic acidosis

 

 

———————————————-Vitamin C (Ascorbic Acid)—————————–

 

Sources of Vitamin C: Citrus fruits, potatoes, green and red peppers, broccolli, tomatoes, spinach and strawberries

Functions:

1. Collagen synthesis

Hydroxylation of lysline and proline residues

2. Antioxidant activity (inactivates hydroxyl free radicals)

3. Reduces non-heme iron from plant (Fe3+ to Fe2+) for absorption in duodenum

4. Keeps FH4 in reduced form

5. Cofactor involved in neurotransmitter conversion (Dopamine to NAdr)

-Catecholamine synthesis

6. Reduces monocyte adhesion to endothelial cell wall (reduces artherosclerosis)

 

Vitamin C deficiency: Due to diet lacking fruits and vegetables (scurvy), smoking cigarettes (because vitamin used up in neutralizing free radicals in cigarette smoke).

-Scurvy, poor wound healing, glossitis, bleeding diathesis (ecchymoses, bleeding gums etc)

Excessive Vitamin C: May result in formation of renal calculi (salts form a crystal in kidneys–>Kidney stones)

 

 

 

  • Fat Soluble Vitamins

 

1. Vitamin A (Retinol)

-Sources include Cod liver oil, diary products and egg yolk

Active forms: Retinol (alcohol), retinal (aldehyde), retinoic acid

-B-Carotene (Provitamin A) is found in dark green leafy vegetables and yellow vegetables (spinach and carrots)

 

–>Retinol esters in diet are converted into retinol. An excess of B-carotene turns the skin yellow, but sclera remains white (unlike in jaundice)

-Retinol esters are packaged into chylomicrons and transported to liver for storage.

-Retinol is released from the liver, complexes with retinol binding protein (RBP) and is delivered to target tissues throughou the body (except heart and skeletal muscle)

-Retinoic Acid binds to nuclear receptors and forms a complex which activates gene transcription of protein products.

 

Functions of Retinol:

1. Visual component

-A component of visual pigments within rod and cone cells of epithelial

2. Important in cell differentiation

-Also prevents epithelial cells from undergoing squamous metaplasia (reversible replacement of one differentiated cell type with another mature differentiated cell type)

3. Bone and tooth development

4. Supports spermatogenesis and placental development

5. Drugs can be used to treat skin disorders and acute promyelocytic leukemia:

(a) Topical tretinoin used for psoriasis and mild acne

(b) Oral isotretinoin used to treat severe cystic acne, however it is teratogenic (women must be tested before drug is prescribed-Look below for more info)

(c) All-trans-retinoic acid is used to treat acute promyelocytic leukemia (Hypergranular M3) and is thought to induce maturation of the leukemic cells

 

Vitamin A deficiency: Dietary insufficiency of dark green leafy and yellow vegetables. Disease such as fat malabsorption (e.g. celiac disease) also play a role.

Vitamin A excess: Esating polar bear liver and isotretinoin therapy

 

 

 

2. Vitamin D

Sources of Vitamin D: Liver, Egg yolk, Saltwater fish and Vitamin D fortified foods

Humans can produce Vitamin D: Synthesis of Calcitriol (1,25-dihydroxycholecalciferol)

 

Intestinal absorption: Ergocalciferol (D2)–>Cholecalciferol (D3)–>Goes to liver–>25-Hydroxycholecalciferol–>Kidney (PCT)–>Calcitriol

Synthesis in skin: 7-Dehydrocholesterol + UV light–> Cholecalciferol (D3)–>Goes to Liver–>25-Hydroxycholecalciferol–>Goes to kidney (PCT)==>Calcitriol

*Active form: Calcitriol (Goes to various cells e.g. blood, intestinal cell)

-Parathyroid Hormone (PTH) increases the synthesis 1 alpha-hydroxylase in the PCT cells of kidneys

-Receptors for Vitamin D are located in intestine, kidneys and on osteoblasts in bone

 

Function of Vitamin D:

1. Increases intestinal absorption of calcium and phosphorus and renal absorption of calcium.

(a) Absorption of Ca and Phosphorus provides an adequate solubility product for Vit. D to mineralize bone.

(b) Vit D. interacts with its receptors on osteoblasts, alkaline phosphatase is released, leading to bone mineralization.

(c) Alkaline phosphatase hydrolyses pyrophosphate, an inhibitor of bone mineralisation

-This enzyme alkaline phosphatase is present 3 to 5 x higher in children than in adults

2. When combined with PTH, Vit D has these effects:

(a) Increases the mobilization of calcium from bone by stimulating the conversion of monocyte stem cells in the bone marrow to osteoclasts.

(b) Maintains the serum calcium concentration.

 

 

Vitamin D deficiency: Leads to rickets, osteomalacia, skeletal deformities, rachitic rosary (excess osteoid in epiphysis)

(a) Inadequate exposure to sunlight (decreased synthesis of Vitamin D3-Cholecalciferol)

(b) Fat malabsorption (unable to reabsorb fat-soluble vitamins, celiac disease)

(c) Chronic liver disease (cannot carry out hydroxylation of vit. D)

(d) Enhance liver cytochrome P450 system (e.g. by alcohol, phenytoin, barbiturates)–>increased conversion into inactive metabolite

(e) Renal failure (most common)-Due to deficiency of 1-a hydroxylase enzyme

(f) Primary hypoparathyroidism: PTH is required for enhancing the activity of 1a-hydroxylase

(g) Type 1 Vitamin D dependent rickets (Lacks 1a-hydroxylase)

(h) Type 2 Vitamin D dependent rickets (Lacks Vitamin D receptors in target tissue)

Vitamin D toxicity: Megadoses may lead to toxicity

 

3. Vitamin E (alpha-tocopherol)

-The highest biologic activity of naturally occuring tocopherols

-Sources: Fruits, vegetables, grains

Function of Vitamin E:

1. Antioxidant and scavenger of free radicals

-Removes free radicals and protects polyunsaturated fats and fatty acids in cell membranes from lipid peroxidation and protects low density lipoprotein (LDL) from oxidation.

2. Protects erthyrocytes (RBC) from oxidative damage that leads to hemolysis

 

Vitamin E deficiency: Uncommon and occurs in Children with malabsorption caused by cystic fibrosis and abetalipoproteinemia (autosomal recessive disorder that interferes with the ability to absorb fat-soluble vitamins)

Vitamin E toxicity: Due to megadoses or inability to make vitamin K-dependent coagulation factors in the liver

 

4. Vitamin K 

-Sources of Vitamin K: Green leafy vegetables (supplies Vitamin K1-phylloquinone) and bacterial synthesis in the colon (supplies vitamin K2-menaquinone)

-After absorption into the bowel, Vitamin K is oxidized to form an inactive epoxide.

-Most Vitamin K comes from bacterial synthesis by colonic bacteria.

*To be catalytically active, Vitamin K synthesized must be reduced by epoxide reductase in the liver.

  • Vitamin K γ-carboxylates glutamate residues in the Vitamin K-dependent coagulation factors (Factor II/Prothrombin, VII, IX, and X + Protein C and S)
  • Vitamin K-dependent coagulation factors are synthesized in the liver in a non-functional state.
  • *When carboxylated in the liver by Vitamin K, these coagulation factors are able to bind to calcium which is essential to the formation of a fibrin clot.

 

Prothrombin time (PT)- This is a coagulation test that evaluates all of the vitamin K-dependent factors except factor IX and proteins C and S

Coumarin derivatives act as anti-coagulants by inhibiting the activity of epoxide reductase, hence the vitamin K-dependent coagulation factors are useless (cannot bind to calcium)

 

Summary of Vitamin K functions:

1. Assist in carboxylating Vit-K dependent coagulation factors which allows them to bind to calcium for the formation of clot.

2. Bone calcification: γ-carboxylatse glutamate residues in osteocalcin.

 

Vitamin K deficiency: Bleeding diathesis (GIT bleeding, ecchymoses-Subcutaneous purpura), prolonged PTT

  1. Rare but can be caused by use of broad-spectrum antibiotics, which destroys colonic bacterial synthesis of vitamin.
  2. Also caused by therapy with Coumarin (Warfarin) derivatives: Inhibits hepatic epoxide reductase.
  3. Fat malabsorption: Cannot reabsorb fat-soluble vitamins (e.g. Celiac disease)
  4. Newborns: Lack bacterial colonisation of the bowel and must receive an intra-muscular vitamin K injection at birth to prevent hemorrhagic disease

Vitamin K toxicity: Uncommon even due to excessive intake

 

 

 

 

 

 

 

 

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