Haemopoietic Functions- Related Vitamins HMIM224.

Haemopoietic Functions- Related Haemopoietic Functions- Related VitaminsVitamins

HMIM224HMIM224

Objectives of the LecturesObjectives of the Lectures

1. Introduction to the role of vitamins2. Types of vitamins3. Biochemistry of water soluble vitamins4. Importance of water soluble vitamins in red blood

cells formation5. Biochemistry of the fat soluble vitamins6. Role of vitamin K in blood coagulation

VitaminsVitamins are chemically unrelated organic compounds that cannot be synthesized by humans & therefore must be supplied by diet

Nutritional deficiency of many vitamins may lead to different types of anemia

Types of water-soluble vitamins:Types of water-soluble vitamins:

• Non B – Complex Non B – Complex :: Vitamin CVitamin C

• B-ComplexB-Complex:: Thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6),

biotin (B7), cobalamin (Bcobalamin (B1212) & folic acid) & folic acid

Water-soluble vitamins:Water-soluble vitamins:

• NotNot significantly stored in the body• MustMust be supplied regularly in the diet• Excess than need is excreted in urine excreted in urine

.

Water-soluble vitaminsWater-soluble vitamins

B-Complex vitaminsB-Complex vitamins

• Available in small quantities in different types of food

• Important for growth & good health

• Help in various biochemical processes in cell as many of them are precursors of coenzymesprecursors of coenzymes

• Folic acidFolic acid• Cobalamin (vitamin B12)Cobalamin (vitamin B12)• Ascorbic Acid (vitamin C)Ascorbic Acid (vitamin C)

Water-soluble vitamins Water-soluble vitamins related to the haemopoeitic systemrelated to the haemopoeitic system

Biochemistry of Folic AcidBiochemistry of Folic Acid

• Synthesized bySynthesized by: microorganisms (notnot synthesized synthesized by humans)

• Active form Active form : Tetrahydrofolate (activation occurs in human cellsactivation occurs in human cells)

• FunctionFunction:

Active form of folic acid receives one-carbon fragments from donors

such as serine, glycine, and histidine & transfers them to intermediates

This function is required in synthesis of purinespurines & TMPTMP.

Purines & TMP are required for DNA synthesis DNA synthesis that is essential

for cell division.

So, folic acid is essential for cell division including haemopoeticSo, folic acid is essential for cell division including haemopoetic

cells (as RBCS)cells (as RBCS)

Folic acidFolic acid

Folic acid Folic acid is synthesized by microorganisms (as bacteria)Humans can notnot synthesize folic acid.Humans obtain folic acid by diet & converts it to the active form tetrahydrofolate.TetrahydrofolateTetrahydrofolate is required for synthesis of purines & TMPPurines & TMP are required for DNA synthesis (required during cell division)

Inadequate serum levels of folic acid is caused by:Inadequate serum levels of folic acid is caused by:

• increased demand increased demand (pregnancy & lactation)• poor absorption poor absorption caused by pathology of the small intestine• drugsdrugs for example, methotrexate (inhibit activation of folic acid)• A folate-free diet (rarerare) can cause a deficiency within a few weeks.

Effect of folic acid deficiency:Effect of folic acid deficiency:

A primary result of folic acid deficiency is megaloblastic anemia megaloblastic anemia caused by

diminished synthesis of purines & TMP (required for DNA molecules synthesis in

the nucleus & hence no division of cells)

Folic Acid & AnemiaFolic Acid & Anemia

• It is important to evaluate the cause of the megaloblastic anemia evaluate the cause of the megaloblastic anemia prior to instituting therapy because also vitamin B12 deficiency indirectly causes symptoms of this disorder.

• Deficiency of folic acid leads to neural tube defects neural tube defects in fetus.

Folic Acid & Anemia Folic Acid & Anemia (cont.)

Biochemistry of Vitamin B12 Biochemistry of Vitamin B12 (Cobalamin)(Cobalamin)

Vitamin B12 (Cobalamin)Vitamin B12 (Cobalamin)

•Cyanocobalamin (commercial preparation)Cyanocobalamin (commercial preparation)

•HydroxycobalaminHydroxycobalamin

•AdenosylcobalaminAdenosylcobalamin (major storage form in the liver)

•MethylcobalaminMethylcobalamin (mostly found in blood circulation)

Forms of vitamin B12Forms of vitamin B12

• Adenosylcobalamin Adenosylcobalamin • MethylcobalaminMethylcobalamin

• Body can convert other forms of cobalamins into active coenzymes

Coenzyme forms of B12Coenzyme forms of B12

Vitamin B12 is NotNot synthesized in the body (synthesized only by microorganism)

Humans obtain vitamin B12Humans obtain vitamin B12:

- performed by natural bacterial flora bacterial flora

- or/ supplied in the dietdiet (animal sources of diet – not in plants)

Vitamin B12 binds to intrinsic factor and absorbed by intestine.

Intrinsic factor is a protein secreted by cells in the stomach

Sources & absorption of vitamin B12 Sources & absorption of vitamin B12

Sources & absorption of vitamin B12 Sources & absorption of vitamin B12 (cont.)

Two reactions require B12

Reaction 1:Reaction 1:

Conversion of methylmalonyl-CoA to succinyl-CoA

Methylmalonyl CoA is produced during the degradation of fatty acids with odd numbers of carbon atoms.

When vitamin B12 is deficient, abnormal fatty acids accumulate & become incorporated to cellmembranes including those of nervous system leading to neurological manifestations. neurological manifestations.

Functions of vitamin B12Functions of vitamin B12

Reaction 2Reaction 2::

Conversion of homocysteine to methionine

Methionine synthase requires B12 in converting homocysteine to methionine.

When vitamin B12 is deficient, homocysteine accumulates leading to neurological manifestations.neurological manifestations.

Also, tetrahydrofolate will not be available for formation of purine & TMP leading to megaloblastic anemiamegaloblastic anemia.

Functions of vitamin B12 Functions of vitamin B12 (cont.)

Causes of vitamin B12 deficiency:Causes of vitamin B12 deficiency:

1- Deficiency of vitamin B12 in dietdiet (rare)

2- Deficiency of absorptionabsorption of vitamin B12 from intestine, called pernicious anemia (more common) due to: - Autoimmune destruction of gastric parietal cells (that synthesizes intr. f). - Partial or total gastrectomy

N.BN.B. As liver stores 4-5 mg of vitamin B12 (in contrast to other water soluble

vitamins), clinical symptoms develop in several years after gastrectomy.

Vitamin B12 DeficiencyVitamin B12 Deficiency

Block of reaction 1 & 2Block of reaction 1 & 2::

B12 deficiency causes accumulation of homocysteine and methylmalonic acid which are harmful for nervous tissue leading to neurological manifestationsneurological manifestations

Block of reaction 1Block of reaction 1::

Methyl tetrahydrofolate cannot be converted to tetrahydrofolate

Hence folate is trapped as N5-methyltetrahydrofolate (folate trap)

This leads to folate deficiency (notnot available for purine synthesis).

So, vitamin B12 deficiency (indirectly) causes So, vitamin B12 deficiency (indirectly) causes megaloblastic anemiamegaloblastic anemia..

TREATMENT OF THIS CASE BY FOLIC ACID ONLY CURES ANAEMIA TREATMENT OF THIS CASE BY FOLIC ACID ONLY CURES ANAEMIA ONLYONLY BUT NERVOUS BUT NERVOUS MANIFESTATIONS ARE MANIFESTATIONS ARE NOTNOT CURED (masking of B12 def.) CURED (masking of B12 def.)

Clinical manifestations of vitamin B12 deficiencyClinical manifestations of vitamin B12 deficiency

DemyelinationDemyelinationMyelin sheath of neurons is chemically unstable and damaged

NeuropathyNeuropathyPeripheral nerve damage

Causes of neurological manifestations:Causes of neurological manifestations:

Deficiency of vitamin B12 leads to accumulation of methylmalonyl CoAHigh levels of methylomalonyl CoA is used instead of acetyl CoA for fatty acid synthesis resulting in synthesis of abnormal fatty acids.Myelin sheath is synthesized with these abnormal fatty acids is unstable and degraded causing neuropathyneuropathy

Neurological manifestations of vitamin B12 deficiencyNeurological manifestations of vitamin B12 deficiency

Treatment of vitamin B12 deficiencyTreatment of vitamin B12 deficiency

CautionCaution:

Administration of high levels of folic acid can mask vitamin B12 deficiency. So, therapy is initiated with folic acid and vitamin B12 folic acid and vitamin B12 until the cause of the anemia can be determined (either due to folic acid def. or vit.B12 def.).

Therapy with vitamin B12Therapy with vitamin B12 ::

1 -RouteRoute : Oral: High doses

or/ IM injection of cyanocobalamin )

2 -DurationDuration: must be continued life-long

Biochemistry of Vitamin C Biochemistry of Vitamin C

(Ascorbic Acid)(Ascorbic Acid)

Function of ascorbic acidFunction of ascorbic acid::

1- Reducing agent Reducing agent in several different reactions

2- Coenzyme in hydroxylation reactionsCoenzyme in hydroxylation reactions: as hydroxylation of lysine & proline amino acids of collagen. Thus, vitamin C is required for the maintenance of normal connective tissue & wound healing.

3- Helps absorption of dietary iron absorption of dietary iron from the intestine.

4- One of the antioxidantsantioxidants available in diet Consumption of diets rich in vitamin C (& other antioxidants as vitamin E & -carotenes) is associated with a decreased incidence of some chronic diseases as coronary heart disease & certain cancers.

Vitamin C (Ascorbic acid)Vitamin C (Ascorbic acid)

Proline is hydroxylated by Proline is hydroxylated by prolyl hydroxylase enzyme prolyl hydroxylase enzyme

which requireswhich requires

ascorbic acid (vitamin C) ascorbic acid (vitamin C) as a coenzymeas a coenzyme


Deficiency of ascorbic acid (Scurvy)Deficiency of ascorbic acid (Scurvy)

Hydroxylation of collagen is deficient resulting in weakness of collagen weakness of collagen present in connective tissue & blood vessels.This results in fragile blood vessels that causes hemorrhage which if severe & prolonged may lead to anemiaanemia. Also, absorption of iron is low which may end in iron deficiency anemia.

Clinical manifestations:Clinical manifestations:

•Sore, spongy gums•Loose teeth•Fragile blood vessels•Swollen joints•Anemia


Bruises in lower limb in a case of scurvy

Fat Soluble VitaminsFat Soluble Vitamins

They are vitamin A, vitamin D, vitamin K & vitamin EThey are vitamin A, vitamin D, vitamin K & vitamin E

Characteristics of fat-soluble vitaminsCharacteristics of fat-soluble vitamins::

Absorbed & transported with fat with fat of diet.

NotNot excreted in the urine (but excreted in bile)

Significant quantities are storedstored in the liver & adipose tissue.

ToxicityToxicity due to overdose is more common than water-soluble vitamins.

Fat Soluble VitaminsFat Soluble Vitamins

Biochemistry of Vitamin K Biochemistry of Vitamin K

Types of vitamin KTypes of vitamin K

Vitamin K occurs in several forms:

•Vitamin K1 (Phylloquinone)Vitamin K1 (Phylloquinone)

•Vitamin K2 (Menaquinone)Vitamin K2 (Menaquinone)

•Vitamin K3 (Menadione)Vitamin K3 (Menadione)

Sources of vitamin KSources of vitamin K

Vitamin K1 (PhylloquinoneVitamin K1 (Phylloquinone):):Vitamin K1 is available in green leafy vegetablesgreen leafy vegetables

Vitamin K2 (MenaquinoneVitamin K2 (Menaquinone):): Vitamin K2 is produced by intestinal bacteriaintestinal bacteria. Intestinal bacterial synthesis meets the daily requirement of vitamin K even without dietary supplement

Vitamin K3 (MenadioneVitamin K3 (Menadione): ): SyntheticSynthetic form (for therapy)

Function of vitamin K Function of vitamin K (cont.)

Vitamin K is a CoenzymeCoenzyme essential for the carboxylase enzyme involved

for the synthesis of prothrombin & blood clotting factors in the liver

Synthesis of prothrombin & clotting factors II, VII, IX, X require

carboxylation of their glutamic acid (Glu) at -carbon by carboxylase Ɣ

enzyme .

Prothrombin & clotting factors that get -carboxyglutamate are capable of Ɣ

subsequent activation ending in coagulation (formation of blood clot).

Prothrombin – platelets interaction:Prothrombin – platelets interaction:

– Carboxylated prothrombin contains two carboxylate groups (COO–)– These groups bind to Ca2+ forming prothrombin-calcium complex– The complex then binds to phosholipids on the surface of platelets

(important for blood clotting) – This will convert prothrombin to thrombin and thus blood coagulation

process is proceeded ending in blood clot formation.

Functions of vitamin K Functions of vitamin K (cont.)

Anticoagulant drugs Anticoagulant drugs (warfarin & dicoumarol) are structural

analogs of vitamin K.

Hence, prothrombin and clotting factors are notnot carboxylated

resulting in stopping of the coagulation process (no blood clot

formation).

Blood coagulation time increases upon injuryBlood coagulation time increases upon injury

Analogs of vitamin KAnalogs of vitamin K

Functions of vitamin K in other proteinsFunctions of vitamin K in other proteins

Synthesis of -carboxyglutamate in osteocalcin:

– Osteocalcin is a bone protein– May have a role in bone formation & mineralization– -carboxyglutamate is required for its binding to hydroxyapatite (a

mineral) in the bone– The function of bone osteocalcin is unclear

Causes of vitamin K deficiency:Causes of vitamin K deficiency:

1- Actual deficiencies Actual deficiencies are rarerare as it is synthesized by the intestinal bacteria in addition to being obtained by diet.

2- Malabsorption of lipids Malabsorption of lipids leads to vitamin K deficiency

3- Deficiency most common in newborns most common in newborns (first month of life) as: Newborns lack intestinal flora Human milk cannot provide enough vitamin K.So, supplements are given by single IM injection of vitamin K to all newborns to protect them against hemorrhagic diseases

other causes are in next slide….other causes are in next slide….

Vitamin K DeficiencyVitamin K Deficiency

Causes of vitamin K deficiency Causes of vitamin K deficiency (cont.):

4- Destruction of the normal bacterial flora Destruction of the normal bacterial flora due todue to: - Prolonged antibiotic therapy - Gastrointestinal infections with diarrhea

Both of above cause destroy the bacterial flora and can also lead to vitamin K deficiency.

5- Second generation cephalosporins Second generation cephalosporins cause warafarin-like action

Vitamin K Deficiency Vitamin K Deficiency (cont.)

Effects of vitamin K deficiencyEffects of vitamin K deficiency::

1- HypoprothrombinemiaHypoprothrombinemia: increased blood coagulation time

2- Deficiency may affect bone growth and mineralization


Clinical manifestations of vitamin K deficiency:Clinical manifestations of vitamin K deficiency:

•Hemorrhagic disease of the newborn

•Bruising tendency, ecchymotic patches, mucus membrane hemorrhage

•post-traumatic bleeding

•Internal bleeding

•Prolongation of the prothrombin time


ReferencesReferences

• Lippincott’s Illustrated BiochemistryLippincott’s Illustrated Biochemistry• Harper’s BiochemistryHarper’s Biochemistry

Haemopoietic Functions- Related Vitamins HMIM224.

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