O lufemi -A worinde k.J - PowerPoint Presentation

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Olufemi-Aworinde k.J mbbs,FMCpath,fwacpConsultant Haematologist/Senior LecturerBowen University, Iwo

Folic acid AND VITAMINB12 METABOLISM

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Chemistry of

Folic acid ( B9 )

The word folic acid is derived from

latin

word

Folium meaning leaf

Folic acid consists of

three components

-

Pteridine

ring

-PABA (p-amino benzoic acid)

-

Glutamic

acid residue (1 to 7 residues)

Hence it is known as

Pteroyl-glutamic acid

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Sources of Folic Acid Cereals (100-400 mcg), dark green vegetables (120-160 mcg), citrus fruits (50-100 mcg) Folic acid may also be found in supplements and multivitamin combinations sold at pharmacies

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daily requirementMen -100 µg/dayWomen -100 µg/dayPregnancy -400 µg/day

Lactation -150 µg/day

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N

H

H

H

N

I

H

H

2

N

N

N

H

I

N

- CH

2

– NH-

O

II

- C

H I - N

- CH –COO-

ICH2ICH2ICOO-

8

7

6

5

Folic Acid

Dihydrofolate

reductase

2NADPH + 2H

+

2NADP

5,6,7,8 –

Tetrahydrofolic

acid (THF)

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MetabolismAbsorption: Formation of monoglutamate form:

Most of the dietary folic acid exists as

polyglutamate with 3-7 glutamate residuesIt is not absorbed in the intestine

The glutamate side chains are cleaved by the enzyme

folate conjugase or

polylpolyglutamate

hydrolase

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Only monoglutamyl form of folic acid is absorbed from the intestineThe enzyme folate conjugase is present in duodenum & jejunumMucosal uptake & metabolism in mucosal cellFolate monoglutamate

is taken up by the

mucosal cellIn the mucosal cell, folate monoglutamate is reduced to tetrahydrofolate & methylated

to form N

5

methyl tetrahydrofolate (in circulation)

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N5 methyl tetrahydrofolate enters the circulationStorage:Inside the cells, tetrahydrofolates are found as

polyglumates

(with 5-6 amino acid residues)Which are biologically most potentPolyglutamate

is the storage form of folic acid

It is mainly stored in the liver

(10-20 mg)

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Biochemical functionsFolic acid is not biologically active

The active coenzyme forms of folic acid are

Tetrahydrofolic acid (FH4)

N

5

methyl

tetrahydrofolic

acid (N

5

FH

4

)

N

5

,N

10 methylene

tetrahydrofolic acidN10

formyl tetrahydrofolate(N10 formyl FH4

)N5 formimino tetrahydrofolate (N

5 formimino FH4)

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N5 formyl tetrahydrofolate (N5 formyl FH4)

N

5,10 methenyl tetrahydrofolate N5,10

methenyl

FH

4

)

N

5

formyl THF -CHO

N

10

formyl THF -CHO

N

5 formimino THF -CH=NH

N5,N10

methenyl THF = CHN5

,N10 methylene THF =CH2

N5 methyl THF - CH3

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The coenzymes of folic acid are actively involved in the one carbon metabolismTHF acts as an acceptor or donor of one carbon units (formyl, methyl etc.) in reactions involving amino acid & nucleotide metabolismThe

one carbon units bind with THF at position N5 or N10 or on both N5 &N10 of

pteroyl structure

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THF is a versatile coenzyme actively participates in one carbon metabolismTransfer of methyl groups from S-adenosylmethionineB

12

is also involved The one carbon units covalently binds with THF at position N5 or N10 or on both N5 &N10 of pteroyl

structure of

folate

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GlycineTryptophan

Formate

N

10

-Formyl THF

Purine

(C2)

Histidine

FIGLU

N

5

-FormiminoTHF

N

5

,N

10

-Methenyl THF

Serine

N

5

,N10

-Methylene THF

CholineBetaineN

5 Methyl THFB12

Methionine

S-Adenosyl MethionineHomocysteine

CH

3

-

Transmethylation

Formylmethionine

Purines

(C8)

Serine

Thymidylate

Major sources

Major Products

THF

THF

THF

THF

One Carbon Metabolism

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deficiencyDietary deficiency is the most common cause of folic acidDietary deficiencies are caused by -Inadequate intake seen in alcoholics-Overcooking of food resulting in loss of folic acid activity

-Impaired absorption due to small intestinal diseases,

-Drugs interfere with folic acid absorption-sulfamethaxazole, methotrexate

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-Increased demand of folic acid seen in pregnancy and Hemolytic anemia-Hence folic acid preparations are prescribed in pregnancy &hemolytic anemia-Loss of folic acid seen in patients undergoing dialysis

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Folic acid deficiency & neural tube defectsFolic acid supplementation during pregnancy helps to prevent neural tube defectsMainly involved in brain & spinal cord

Science, folic acid involved in

nucleic acid & amino acid metabolismDeficiency results in impaired & aberrant neural development

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CHEMISTRY OF VITAMIN B12

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Normal Vitamin B12 MetabolismVitamin B12 is composed ofA corrin nucleus which has 4 pyrrole rings bound to a central cobalt atomA 5,6 dimethylbenzimidazole group which is attached to the corrin ring and to the central cobalt atom

Important

cobalamins that are distinguished according to the ligand attached to the central cobalt atom are : cyanocobalamin, hydroxocobalamin, adenosylcobalamin and methylcobalamin

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Sources Liver, dairy products and seafish are major sourcesNatural formsProduced by microorganisms (bacteria/fungi)Plants do not produce or contain Vit B12 (except contamination)Colonic bacterial production occurs but their location is distal to the site of absorbtion

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Daily requirements

Age Amount/day

0 - 1 0.3 – 0.5 

g,

1 – 10 0.7 – 1.5



g

Adults

2



g .

Pregnancy (2



g + )

2

nd Trimestr 0.5

g 3

rd Trimestr 1

g Lactation 2.5 – 3 g

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Vit.B12Average diet contains 5 – 30 g Vit. B12 daily

The amount of Vit. B

12 in the body is about 2 – 5 mg.

Most of it is in the liver.

The store is sufficient for

3-

4

years in case of impaired absorbtion.

The storage form is mainly adenosylcobalamin.

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Absorption of Vitamin B122 mechanismActive (75%) – requires the presence of intrinsic factor ( a glycoprotein produced by gastric mucosa)Passive – absorption occurs by diffusion and works when pharmacological doses of vitamin B12 are ingested

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Vitamin B12 in foodR-Binder

B12-R-Binder complex

IF-B12 complex + Freed R-BinderIntrinsic Factor (IF)

Receptor-IF-B12

B12-TCII

Circulation

Receptor

TCII

IF

Degradation

Epithelial cell of

terminal

iIeum

Stomach

Duodenum

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Transport of Vitamin B12Following absorption by the ileal mucosal cells, vitamin B12 is carried in the plasma by various transporting proteins: Transcobalamin I

Transcobalamin II Transcobalamin III

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Transcobalamin I (TC I) is an alpha-globulin produced by granulocytes. It functions as a circulating reserve store of B12. TC I carries mostly methylcobalamin. Transcobalamin II (TC II) is a beta-globulin formed in the liver and is the dominant carrier of B12 immediately after absorption. It is the main agent for rapid transport of B12 to the body cells.

Transcobalamin

III (TC III) is an alpha-globulin. TC III may act as a defence mechanism by depriving pathogens of B12 at sites of infection

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Storage sites Total amount of vitamin in body is 2-5 mg ( adequate for 3 years ) Major site : liverExcreted through the bile and shedding of intestinal epithelial cells Most of the excreted vitamin B12 is again absorbed in the intestine (enterohepatic circulation)

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Functions of Vitamin B12Synthesis of methionine from homocysteineConversion of methyl malonyl CoA to succinyl CoA

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FH4

FH2

Methylene

FH4

Methyl FH4

Intestinal cell

Dietary

folates

Dihidrofolate

Redutase

Methionine

Homocysteine

Thymidylate

Synthase

DNA Synthesis

dTMP

dUMP

Role of Vitamin B12 and

Folate

in DNA synthesis

VitB12 (

Methylcobalamin

)

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Causes of Vit B12 deficiencyInsufficient dietary intake (very rare)Strict vegetarians Deficient absorptionPernicious anaemiaTotal or partial gastrectomyProlonged use of PPI or H2 blockersDiseases of small intestine

Fish tapeworm infestation

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THANK YOU