folate vitamin b12

8/13/2019 Folate Vitamin B12

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Vitamin B12and Folate

Metabolism

Blood and Immunology

MDP 10307

Dr Zunika Amit

20.1.2014


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Objectives

List the sources of folic acid and vitamin B12 Describe the vitamins dependent enzymes

Describe the relationship between folic acid

and vitamin B12 Explain the absorption and transport of the

vitamins

Describe the diseases caused by thedeficiency of these vitamins


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Dietary sources of Vitamin B12

Synthesised by all types of bacteria and algae with afew exceptions.

Enters human food chain by being incorporated intofood of animal origin.

Incorporation mainly in GIT of herbivorous. B12 are absorbed and incorporated into the tissues of

the herbivorous.

Thus, omnivorus and carnivorous derive B12 from the

tissues or products from these animals.


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Vitamin B12


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Structure of Vitamin B12 Consists of cobalt called as cobamide or cobalamin

cobalt is in a coordination state of six

4 coordination position occupied pyrrole rings

5th coordination position occupied by a 5,6-dimethylbenzimidazole (DMB)

6th coordination position (R) by one of severaldifferent ligands; 5-deoxyadenosyl, methyl,

hydroxyl (OH), cyanide (CN)


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Different forms of B12

When isolated, the 6thcoordination state contains

cyanide called cyanocobalamin

Aquacobalamin or hydroxycobalamin is the formusually found in body tissue.

Two naturally/active occurring forms of B12:

5-deoxyadenosylcobalamin -account for 70% inthe liver

Methylcobalamin or methyl B12- major circulatingform


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Bhagavan,4thedition

Absorption, transport and cellular uptake of vitamin B12in humans


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Absorption, transport and cellular uptakeof B12in humans

Dietary B12released by gastric acid and bind tocobalophilins (R-protein) and intrinsic factor (IF).

At acid pH, R-protein bind B12stronger than IF(relative affinity of R-protein and IF for B

12

areabout 50:1)

In duodenum, pancreatic proteases partiallydegrade R-protein allowing more of B12to bind toIF.

Transfer of B12to IF is aided by bicarbonate

(more neutral pH) of pancreatic juice .


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IF- B12complex binds to ileal receptors on theileal mucosa cells in the presence of Ca2+ and atneutral pH.

As IF- B12

complex crosses the ileal mucosa, IF isreleased.

B12is transferred to plasma transport proteinTCII.

The TCII - B12

complex delivers B12

to all cell ofthe body

B12 is released and TCII is degraded in thelysosome.


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Vitamin B12Transport Protein

1. Cobalophilins (R-protein; R-binders), occurs in plasma, gastric juice, saliva, granulocyte and

other tissues and body fluids binds one B12 molecule per cobalophilin molecule. Include transcobalamin I, II and III (TCI, TCII and

TCII).

TCII- principal plasma binding protein for B12 newlyabsorbed from the intestine.

Responsible for transport of B12 to tissue Defect in B12release from lysosome also contribute to

inborn error of B12metabolism Congenital abnormality of TCII also result in

megaloblastic anemia


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2. Intrinsic factor (IF) from gastric parietal cells

binds one B12 molecule per IF molecule

necessary for the absorption of B12 later in the

terminal ileum. Lack of IF can cause poor absorption of dietaryB12 Pernicious anemia

Fewer rbc, rbc that are produced are

abnormally large and abnormal in shape. Causes of IF deficiency;

Chronic gastritis, gastrectomy, autoimmune attact


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3. Internal receptor for IF-B12 complex

Present on microvilli of ileal cells Defect in ileal receptor also contribute to B12

deficiency.


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B12 requiring reactions1. Conversion of methylmalonyl-CoA to succinyl-CoA

-lies in the pathway for degradation of the last C3ofodd-chain fatty acids together with the degradationof certain amino acids

Methylmalonyl-

CoAmutase

5-deoxyadenosylcobalamin

Methylmalonyl-CoA mutase

Methylmalonyl-CoA epimerase

-5-deoxyadenosyl cobalamin is the cofactor for Methylmalonyl-CoAmutase


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Defect in activity of methylmalonyl-CoA mutase

or synthesis of the deoxyadenosylcobalamincoenzyme causes L-methylmalonyl-CoAaccumulation methylmalonic acid causes

Severe acidosis (lowering of blood pH)

Damages the CNS

Mutation in methylmalonyl-CoA mutase cause a

condition called methylmalonic acidemia


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2. Conversion of homocysteine to methionineB12and folate are involved together in the conversion ofhomocysteine to methionine.

THF N5-methyl-THF

homocysteine Methionine

-methylcobalamin is , the cofactor for 5-methyltetrahydrofolate-

homocysteine methyltransferase or methionine synthase (MTR)


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Absence of B12inhibits the reaction and leads tobuild up of N5-methylTHF known as the THF trap.

Excess homocysteine (hyperhomocysteinemia) linkedto cardiovascular disease:

Elevated homocysteine levels promote oxidative damage,causing inflammation and endothelial dysfunction.


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Metabolic roles of folic acid and vitamin B12in one-carbon metabolism

MTR

B12

Methylenetetrahydrofolatereductase (MTHFR)


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Neurological disorder seen in B12 deficiency?

Due to progressive demyelination of nervous tissue.Possible explanation:

-Methylmalonyl-CoA compete with malonyl-CoAfor fatty acid synthesis-If residual fatty acid synthesis occur,methylmalonyl-CoA substitutes for malonyl-CoA inreaction sequence.-Thus, forming branched chain fatty acid causing

disruption of normal membrane structure


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Folic Acid

Sources :

Green leafy vegetables, fruits and liver

susceptible to heat destruction

Min. daily requirements

50 g for normal, nonpregnant adult

pregnant woman requires - 400 g/day


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Structure of folic acid

(pteroyl glutamic acid)


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Folate

Folic acid has a number of derivatives knowncollectively as folates.

Contains 3-8 (or more) glutamate residues This tail is split off to mono- (or di-)

glutamate form by conjugase duringabsorption in the small intestine (at thebrush border)

50% of the total body store is in polyglutamateform (in the liver)

folic acid is reduced to active formtetrahydrolate (THF) by DHF reductase


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Circulates in plasma primarily as 5-methyltetrahydrofolate.

Inside cell, 5-methyl THFA may be demethylatedto THFA, the active form participating in folate-dependent enzymatic reactions.

Monoglutamate the only form of folate that can

be transported across membranes.


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What does THF do?

Can accept so called C1 units from variousdonors and pass them on in variousbiosynthetic reactions.

It transfers and interconverts single carbon-units at the methyl, methylene and formyloxidation levels


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What does THF do? (continued)

Reactions with the methyl, methylene and formyloxidation levels involves:

Metabolism of certain N-containingcompounds Choline, serine, glycine, methionine and

histidine

Biosynthesis of purine nucleotides

Biosynthesis of methyl group of dTMP (therate limiting step in DNA synthesis)


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Causes of folate deficiencies:

Inadequate intake

Impaired absorption (anticonvulsants andoral contraceptives)

Increased demand

Impaired metabolism (oral contraceptive)


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Inhibition of DNA synthesis due to decreased

availability of purine and dTMP Failure or slow nuclear maturation and division

Effects of folate deficiency:


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Megaloblastic anemia associated with B12deficiency is related to effect of B12on

folate metabolism.

How?

When B12 is low, flux through methionine synthase

step decreases: 5-methylTHF accumulates

The other THF forms get depleted becausereduction of 5,10-methyleneTHF to 5-MethylTHF

does not stop (irreversible). Therefore, insufficient levels of the formyl and

methylene derivatives for the synthesis of nucleicacid precursors.


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Metabolic roles of folic acid and vitamin B12in one-carbon metabolism

B12

Methylenetetrahydrofolatereductase (MTHFR)

MTR


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Thank you

end

folate vitamin b12

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