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:

•

Anti – pernicious anemia factor

•

Extrinsic factor of Castle

•

Animal protein factor

CHEMISTRY

• • • •

Vitamin B 12 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 5 th valency covalently linked benzamidazole ring.

of to satisfied by any of the a This is then called cobalamin.

the cobalt is substituted The sixth valency of the cobalt is following groups: cyanide, hydroxyl, adenosyl or methyl.

CYNO COBLAMIN

•

When cyanide is added position, the cynocobalamine molecule at is the R called

HYDROXY COBLAMIN

•

When hydroxyl group is attached at the R position, coblamin

.

it is called hydroxy

•

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 SOURCES

•

Vitamin B 12 vegetables.

is not present in

•

Liver is the richest source.

•

Meat, fish and egg are good sources.

•

Curd is also good source, because lactobacillus can synthesize B 12 .

ABSORPTION OF VITAMIN B12

• • •

Vitamin B 12 combines with the intrinsic factor (IF) of castle.

Hence the B 12 is otherwise is known as extrinsic factor (EF), that is the factor derived from external sources.

Intrinsic factor is gastric parietal cells.

secreted by the

• • • • •

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

One molecule of IF can combine with two molecule of vitamin B 12 .

This IF-B 12 complex is attached with specific receptor on mucosal cells.

The IF-B 12 complex is internalized.

It may be noted that, vitamin B 12 absorbed from ileum, while folic acid is from jejunum.

is

TRANSPORT & STORAGE

• • • •

The IF is digested inside the mucosal and B 12 circulation.

is transported to the In the blood predominant.

methyl B 12 form is Transcobalamin II, a glycoprotein, is the specific carrier.

It is stored in the liver cells, as ado-B form, in Transcobalamin I.

combination 12 with

•

Generally, B complex vitamins are not stored in the body, B 12 is an exception.

•

Whole liver contain about 2 mg of B 12

•

Which is the sufficient requirement for 2 – 3 years.

for the

•

So, B 12 deficiency is seen only years after gastrectomy.

BIOCHEMICAL FUNCTIONS

•

Synthesis of Methionine from homocystine:

N 5 METHYL THF THF

Homocysteine METHIONINE Methyl Coblamin B 12

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 FUNCTIONS

•

ISOMERISATION OF METHYL MALONYL COA TO SUCCINYL COA

DEFICIENCY MANIFESTATIONS

• • • • • • •

Adult pernicious anemia Mucosal atrophy of stomach Glossitis, hypersegmented neutrophils Stomatitis Pharyngitis Achlorhydria Folate Trap

DEFICIENCY MANIFESTATIONS

•

Damage to nervous system, the sub acute combined degeneration.

•

Demyelination and neural death.

•

Mild deficiency may cause depression, confusion and less alertness

.

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

Megaloblastic anemia

CAUSES OF B12 DEFICIENCY

•

NUTRITIONAL: Vitamin B 12 deficiency is very common in India, especially among vegetarians of low socioeconomic group.

•

The only source for B 12 in vegetarian diet is curd/ milk and lower income group may not able to afford it.

CAUSES 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 lesions are aggravated.

nervous Hence all generally vitamin B12.

macrocytic treated with anemia's Folate are and 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 factor Lactis R pteroyl glutamic acid (PGA).

(SLR)

FOLIC ACID CHEMISTRY

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

• • •

Pteridine nucleus Para Amino Benzoic Acid Glutamic Acid

RDA

• • •

Adults Infants Children : 400 – 500 μg/ day : 50 μg/ day : 100 – 300 μg/ day

• •

Requirement increases in pregnancy & lactation Pregnant women : 800 Lactating women: 600 μg/ day μg/ day

DIETARY SOURCES

•

Folic nature.

acid is widely distributed in

•

Rich sources are green leafy vegetables, whole grains, cereals, liver, kidney, yeast and eggs. Milk is rather poor source of folic acid.

ABSORPTION, TRANSPORT AND STORAGE

• •

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

•

The enzyme folate conjugase present in duodenum and glutamate residues.

jejunum split the Only the monoglutamate of folic acid is absorbed 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 synthesis.

acid deficiency, decreased production of purines and dTMP is observed which impairs DNA

•

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.

Folic Acid Deficiency and Homocysteinimia

HOMOCYS.

– A RISK FACTOR FOR CHD

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

CHOLINE

•

Choline is ethanolamine.

trimethyl hydroxy

•

Best and Huntsman (1934) found that, Choline deficiency in rats produced fatty liver and established its nutritional importance.

STRUCTURE OF CHOLINE

CH 3 H 3 C N +

CH2 CH2 OH

CH3

BIOCHEMICAL FUNCTIONS

• • •

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

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

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

INOSITOL

•

Inositol is hexahydroxy – cyclohexane.

•

It is also known as myo – Inositol or meso – inositol.

STRUCTURE OF INOSITOL

BIOCHEMICAL FUNCTIONS

•

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

is a

•

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

BIOCHEMICAL FUNCTIONS

•

For some hormones, inositol act as a second messenger at the membrane level for the release of Ca 2+ ions.

LIPOIC ACID

•

Lipoic acid is a sulphur containing fatty acids.

•

It exists in an oxidized and reduced form.

•

Lipoic acid is fat as well as water soluble.

STRUCTURE OF LIPOIC ACID

BIOCHEMICAL FUNCTIONS

•

Lipoic acid is involved in the decarboxylation reactions along with other vitamins.

•

The conversion of pyruvate to acetyl CoA and α – ketogluterate to succinyl CoA require LIPOIC ACID.

PARA AMINO BENZOIC ACID

•

Para amino benzoic acid (PABA) is a structural constituent of folic acid.

•

The deficiency of PABA was first found to be associated with failure of lactation graying of black hair in rats.

PARA AMINO BENZOIC ACID

PARA AMINO BENZOIC ACID

•

PABA is synthesized by the bacteria and is essential for their growth.

•

The sulfa drug sulfonilamide structural analogue of PABA.

is a

BIOFLAVONOIDS

• •

Szent (1936) – Gyorgi and his associates 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 FUNCTIONS

•

Bioflavonoids act as antioxidant and protect ascorbic acid from being destroyed.

•

It is suggested that, this antioxidant property may be responsible for maintenance of capillary permeability.