Vitamin B12 and Folic Acid

Objectives

1. Chemistry of vitamin B12

2. Metabolism of Vit. B12

3. Functions

4. Sources and daily requirement

5. Deficiency

VITAMIN B 12

SYNONYMS:SYNONYMS:

• Anti – pernicious anemia factorAnti – pernicious anemia factor

• Extrinsic factor of CastleExtrinsic factor of Castle

• Animal protein factor Animal protein factor

CHEMISTRY

• Vitamin B12 is water soluble, heat stable and red in color.

• It contains 4.35 % cobalt by weight.

• It contains 63 carbon, 14 nitrogen and one cobalt atoms.

• Four pyrrole rings co-ordinated with cobalt atom is called a corrin ring.

CHEMISTRY

• The 5th valency of the cobalt is covalently linked to a substituted benzamidazole ring.

• This is then called cobalamin.

• The sixth valency of the cobalt is satisfied by any of the following groups: cyanide, hydroxyl, adenosyl or methyl.

http://en.wikipedia.org/wiki/File:Cobalamin.png

CYNO COBLAMIN

• When cyanide is added at the R

position, the molecule is called

cynocobalamine

HYDROXY COBLAMIN

• When hydroxyl group is attached at the R position, it is called hydroxy coblamin.

• When taken up by the cells, these groups are removed and deoxyadenosyl coblamin is formed.

METHYL COBLAMIN

• When the methyl group replaces adenosyl group, it is known as methyl coblamin.

• This is the major form seen in blood circulation as well as cytoplasm.

RDA

• Normal daily requirement is 1 – 2 μg /

day.

• During pregnancy and lactation, this is

increased to 2 μg / day.

DIETARY SOURCESDIETARY SOURCES

• Vitamin B12 is not present in

vegetables.

• Liver is the richest source.

• Meat, fish and egg are good sources.

• Curd is also good source, because

lactobacillus can synthesize B12.

ABSORPTION OF VITAMIN B12

• Vitamin B12 combines with the intrinsic factor (IF) of castle.

• Hence the B12 is otherwise is known as extrinsic factor (EF), that is the factor derived from external sources.

• Intrinsic factor is secreted by the gastric parietal cells.

• It is a glycoprotein with a molecular It is a glycoprotein with a molecular weight of 50,000.weight of 50,000.

• One molecule of IF can combine with One molecule of IF can combine with two molecule of vitamin Btwo molecule of vitamin B1212..

• This IF-BThis IF-B1212 complex is attached with complex is attached with

specific receptor on mucosal cells.specific receptor on mucosal cells.

• The IF-BThe IF-B1212 complex is internalized. complex is internalized.

• It may be noted that, vitamin BIt may be noted that, vitamin B1212 is is

absorbed from ileum, while folic acid is absorbed from ileum, while folic acid is from jejunum.from jejunum.

TRANSPORT & STORAGETRANSPORT & STORAGE

• The IF is digested inside the mucosal The IF is digested inside the mucosal and Band B1212 is transported to the circulation. is transported to the circulation.

• In the blood methyl BIn the blood methyl B1212 form is form is

predominant.predominant.• Transcobalamin II, a glycoprotein, is Transcobalamin II, a glycoprotein, is

the specific carrier.the specific carrier.

• It is stored in the liver cells, as ado-BIt is stored in the liver cells, as ado-B1212

form, in combination with form, in combination with Transcobalamin I.Transcobalamin I.

• Generally, B complex vitamins are not

stored in the body, B12 is an exception.

• Whole liver contain about 2 mg of B12

• Which is the sufficient for the

requirement for 2 – 3 years.

• So, B12 deficiency is seen only years

after gastrectomy.

BIOCHEMICAL FUNCTIONSBIOCHEMICAL FUNCTIONS

• Synthesis of Methionine from homocystineSynthesis of Methionine from homocystine:

Homocysteine

N5 METHYL THF THF

METHIONINE

Methyl Coblamin B12

FOLATE TRAP

BIOCHEMICAL FUNCTIONS

• Vitamin B12 deficiency leads to impairment

of Methionine synthase, resulting in

accumulation of Homocysteine and

trapping folate as methyl tetra hydrofolate.

• This known as folate trap.

BIOCHEMICAL FUNCTIONSBIOCHEMICAL FUNCTIONS

• ISOMERISATION OF METHYL ISOMERISATION OF METHYL MALONYL COA TO SUCCINYL COAMALONYL COA TO SUCCINYL COA

DEFICIENCY DEFICIENCY MANIFESTATIONSMANIFESTATIONS

• Adult pernicious anemiaAdult pernicious anemia

• Mucosal atrophy of stomachMucosal atrophy of stomach

• Glossitis, hypersegmented neutrophilsGlossitis, hypersegmented neutrophils

• StomatitisStomatitis

• PharyngitisPharyngitis

• AchlorhydriaAchlorhydria

• Folate TrapFolate Trap

DEFICIENCY DEFICIENCY MANIFESTATIONSMANIFESTATIONS

• Damage to nervous system, the sub Damage to nervous system, the sub

acute combined degeneration.acute combined degeneration.

• Demyelination and neural death.Demyelination and neural death.

• Mild deficiency may cause depression, Mild deficiency may cause depression,

confusion and less alertnessconfusion and less alertness..

Peripheral blood smear showing Peripheral blood smear showing hypersegmented neutrophils, characteristic hypersegmented neutrophils, characteristic of megaloblastic anemia.of megaloblastic anemia.

Megaloblastic anemia

CAUSES OF B12 DEFICIENCY

NUTRITIONAL:

• Vitamin B12 deficiency is very common in India, especially among vegetarians of low socioeconomic group.

• The only source for B12 in vegetarian diet is curd/ milk and lower income group may not able to afford it.

CAUSES OF B12 DEFICIENCYCAUSES OF B12 DEFICIENCY

• Decrease in absorption

• Elderly people

• Addisonian pernecious anemia

• Gastric atrophy

• Fish tapeworm

• Pregnancy

• Inherited defects

FISH TAPEWORM

FISH TAPEWORM

FISH TAPEWORM

TREATMENT

• If megaloblastic anemia is treated with folic acid alone, the anemia may improve, but associated nervous lesions are aggravated.

• Hence all macrocytic anemia's are generally treated with Folate and vitamin B12.

• Therapeutic dose of B12 is 100 – 1000 microgram by intramuscular injection.

Folic Acid

Objectives

1. Chemistry

2. Metabolism

3. Functions

4. Sources and daily requirement

5. Deficiency

6. Folic acid antagonist

FOLIC ACID

SYNONYMS:

• Liver lactobacillus

• Caseifactor

• Vitamin M

• Streptococcus Lactis R (SLR) factor

• pteroyl glutamic acid (PGA).

FOLIC ACID CHEMISTRYFOLIC ACID CHEMISTRY

The designation folic acid is applied to a The designation folic acid is applied to a number of compounds which contain number of compounds which contain the following group.the following group.

• Pteridine nucleusPteridine nucleus

• Para Amino Benzoic AcidPara Amino Benzoic Acid

• Glutamic AcidGlutamic Acid

RDARDA

• AdultsAdults : 400 – 500 : 400 – 500 μμg/ dayg/ day

• InfantsInfants : 50 : 50 μμg/ dayg/ day

• ChildrenChildren : 100 – 300 : 100 – 300 μμg/ dayg/ day

Requirement increases in pregnancy & Requirement increases in pregnancy & lactationlactation

• Pregnant womenPregnant women : 800 : 800 μμg/ dayg/ day

• Lactating womenLactating women : 600 : 600 μμg/ dayg/ day

DIETARY SOURCESDIETARY SOURCES

• Folic acid is widely distributed in Folic acid is widely distributed in

nature.nature.

• Rich sources are green leafy Rich sources are green leafy

vegetables, whole grains, cereals, liver, vegetables, whole grains, cereals, liver,

kidney, yeast and eggs. Milk is rather kidney, yeast and eggs. Milk is rather

poor source of folic acid.poor source of folic acid.

ABSORPTION, TRANSPORT ABSORPTION, TRANSPORT AND STORAGEAND STORAGE

• Most of the dietary folic acid found as Most of the dietary folic acid found as polyglutamate with 3 – 7 glutamate polyglutamate with 3 – 7 glutamate residues is not absorbed in the residues is not absorbed in the intestine.intestine.

• The enzyme folate conjugase present in The enzyme folate conjugase present in duodenum and jejunum split the duodenum and jejunum split the glutamate residues.glutamate residues.

• Only the monoglutamate of folic acid is Only the monoglutamate of folic acid is absorbed from the intestineabsorbed from the intestine.

BIOCHEMICAL FUNCTIONS• Tetrahydrofolate, the coenzyme of folic acid is

actively involved in the one carbon metabolism.• THF is serves as an acceptor or donor of one

carbon units (formyl, methyl etc.).COMPOUND SYNTHESIZE IN 1 CARBON METABOLISM:

1.Purines ( carbon 2 & 8), deoxy thymydylic acid.

2. Glycine, serine, ethanolamine and choline.

3.N – formylmethionine.

DEFICIENCY SYMPTOMS

• In folic acid deficiency, decreased production of purines and dTMP is observed which impairs DNA synthesis.

• Due to block in DNA synthesis, the maturation of erythrocytes is slowed down leading to macrocytic RBC.

NORMAL RBC SMEAR

MACROCYTIC ANEMIA

SPINA BIFIDA

• Folic acid deficiency during pregnancy may lead to neural tube defects in the fetus.

• Folic acid prevents birth defects, fetal malformations such as spina bifida.

• So, high doses of folic acid are recommended in pregnancy.

SPINA BIFIDA

RISK OF EXCESS OF FOLIC ACID

• Irreversible nerve damage.

• Solubility of folic acid is low, hence

large doses of folic acid if given

parenterally there is risk of

crystallization in kidney tubules leading

to renal damage.

HOMOCYS.– A RISK FACTOR FOR CHD

Folic Acid Deficiency and Homocysteinimia

Folic Acid antagonist

•Aminopterin and Amethopterin (Methotrexate)

Clinical Use:inhibit DNA synthesis especially in cancer cell.

•Trimethoprim

Clinical Use: used to treat for bacterial infections along with sulfomethaxozole

VITAMIN LIKE COMPOUNDS

CHOLINECHOLINE

• Choline is trimethyl hydroxy ethanolamine.Choline is trimethyl hydroxy ethanolamine.

• Best and Huntsman (1934) found that, Best and Huntsman (1934) found that,

Choline deficiency in rats produced fatty Choline deficiency in rats produced fatty

liver and established its nutritional liver and established its nutritional

importance.importance.

STRUCTURE OF CHOLINE

H3C N+

CH3

CH2 CH2 OH

CH3

BIOCHEMICAL FUNCTIONSBIOCHEMICAL FUNCTIONS

• Choline, as a component of Choline, as a component of phospholipids is involved in membrane phospholipids is involved in membrane structure and lipid transport. structure and lipid transport.

• Due to the presence three methyl Due to the presence three methyl groups, choline is actively involved in groups, choline is actively involved in one carbon metabolism.one carbon metabolism.

• Choline is a precursor for the synthesis Choline is a precursor for the synthesis of acetylcholine which is required for of acetylcholine which is required for transmission of nerve impulse.transmission of nerve impulse.

INOSITOLINOSITOL

• Inositol is hexahydroxy – cyclohexane.Inositol is hexahydroxy – cyclohexane.

• It is also known as myo – Inositol or It is also known as myo – Inositol or

meso – inositol.meso – inositol.

STRUCTURE OF INOSITOL

BIOCHEMICAL FUNCTIONSBIOCHEMICAL FUNCTIONS

• Inositol is required for the synthesis of Inositol is required for the synthesis of phosphatidyl Inositol which is a phosphatidyl Inositol which is a constituent of cell membrane.constituent of cell membrane.

• It act as a lipotropic factor ( along with It act as a lipotropic factor ( along with choline) and prevents the accumulation choline) and prevents the accumulation of fat in liver.of fat in liver.

BIOCHEMICAL FUNCTIONSBIOCHEMICAL FUNCTIONS

• For some hormones, inositol act as a For some hormones, inositol act as a

second messenger at the membrane second messenger at the membrane

level for the release of Calevel for the release of Ca2+ 2+ ions. ions.

LIPOIC ACIDLIPOIC ACID

• Lipoic acid is a sulphur containing fatty Lipoic acid is a sulphur containing fatty

acids.acids.

• It exists in an oxidized and reduced It exists in an oxidized and reduced

form. form.

• Lipoic acid is fat as well as water Lipoic acid is fat as well as water

soluble.soluble.

STRUCTURE OF LIPOIC ACID

BIOCHEMICAL FUNCTIONSBIOCHEMICAL FUNCTIONS

• Lipoic acid is involved in the Lipoic acid is involved in the

decarboxylation reactions along with decarboxylation reactions along with

other vitamins.other vitamins.

• The conversion of pyruvate to acetyl The conversion of pyruvate to acetyl

CoA and CoA and αα – ketogluterate to succinyl – ketogluterate to succinyl

CoA require CoA require LIPOIC ACID.LIPOIC ACID.

PARA AMINO BENZOIC ACIDPARA AMINO BENZOIC ACID

• Para amino benzoic acid (PABA) is a Para amino benzoic acid (PABA) is a

structural constituent of folic acid.structural constituent of folic acid.

• The deficiency of PABA was first found The deficiency of PABA was first found

to be associated with failure of to be associated with failure of

lactation graying of black hair in rats.lactation graying of black hair in rats.

PARA AMINO BENZOIC ACID

PARA AMINO BENZOIC ACIDPARA AMINO BENZOIC ACID

• PABA is synthesized by the bacteria and is PABA is synthesized by the bacteria and is

essential for their growth.essential for their growth.

• The sulfa drug sulfonilamide is a structural The sulfa drug sulfonilamide is a structural

analogue of PABA.analogue of PABA.

BIOFLAVONOIDS

• Szent – Gyorgi and his associates (1936) observed that, flavonoids, isolated from lemon peel were responsible for maintenance of normal capillary permeability.

• The term vitamin P was used to this group of substance.

• However, they are commonly known as BIOFLAVONOIDS.

BIOFLAVONOIDS

BIOFLAVONOIDS

BIOCHEMICAL FUNCTIONSBIOCHEMICAL FUNCTIONS

• Bioflavonoids act as antioxidant and Bioflavonoids act as antioxidant and

protect ascorbic acid from being protect ascorbic acid from being

destroyed.destroyed.

• It is suggested that, this antioxidant It is suggested that, this antioxidant

property may be responsible for property may be responsible for

maintenance of capillary permeabilitymaintenance of capillary permeability.