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11

 

 

Water soluble vitamins function as coenzymes, 

 

is essential for haloenzyme activity.

 

apoenzymes

for an 

 

coenzyme

affinity of the 

 

The

 
 

 

 

The free vitamin occurs in the plasma, but the 

 

, predominates in the cellular

, TPP

coenzyme
component

 

 

 

Absorption 

The phosphorylated vitamin is dephosphorylated by (membrane-bound alkaline 
phosphatase) in the intestinal mucosa. The dephosphorylated vitamers are absorbed in 
small intestine by two mechanisms.

 

1)  Active transport (thiamin transporter): 

Carrier mediated as long as intake is less than 5mg/day. 

2)  Simple passive diffusion: 

When the intakes higher than 5mg/day. 
Percentage absorption diminished with increased dose  

 

 

Food Sources 

•  Excellent sources are liver, heart, kidney, egg yolk and unrefined grains.   
•  Milk, sea foods, fruits, and vegetables are not good sources of thiamine. 

 

 

Tissue distribution and storage 

•  High concentrations are found in skeletal muscles, heart, liver, kidneys, and brain.  
•  About 50% of the total thiamine is distributed in the muscles.  
•  In spinal cord & brain, the thiamine level is about double that of the peripheral nerves.  

 

 

Transport 

•  Thiamine is carried to the liver by portal circulation; the free vitamin found in the 

plasma but the coenzyme (TPP) is primary cellular component.  

•  The transport of thiamine into erythrocytes by a facilitated diffusion process, where as 

it enters other cells by an active process, (leukocytes have a 10fold higher thiamin 
concentration than erythrocytes) why. 

•  Thiamine transport across the blood brain barrier involves the saturable mechanism 

which depends on membrane-bound phosphatase enzyme. why   

 
 
 
 


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Role thiamin pyrophosphate (TPP);  

1)  Biochemical functions: 

The oxidative decarboxylation of pyruvate and α-ketoglutarate, plays 
a key role in energy metabolism of most cells, particularly in 
nervous system. 

 

 

activity of these two enzymes is

the 

In thiamine deficiency

of ATP and, thus, 

 

decreased production

decreased, resulting in a 
impaired cellular function.

 

 

1.  Oxidative decarboxylation by dehydrogenase complex. 

A.  The conversion of α-ketoglutarate to succinyl CoA  release CO

2

 and produce 

the NADH in the  TCA cycle.  

B.  The conversion of Pyruvate (end product of aerobic glycolysis) to acetyl coA. 

 

 

2.  Formation of α –ketoses catalyzed by transketolase 

unit of a ketose 

carbon 

-

transfers the two

Transketolase 
onto the aldehyde carbon of an aldose sugar (the conversion 
of a ketose sugar into an aldose with 2 carbons less)

 

[Note: Thiamine deficiency is diagnosed by an increase in 
erythrocyte transketolase activity.]

 

 

n pentose phosphate pathway

I

 

  The metabolic significance of the pentose phosphate pathway is not to obtain 

energy from the oxidation of glucose. 

  Its primary purpose is to generate NADPH, which serves as a hydrogen and 

electron donor in reductive biosynthetic reactions, including the biosynthesis of 
fatty acids  

 

2)  Neurophysiologic functions 

  Involve in metabolism of four types of neurotransmitters (acetylcholine, 

catecholamine, serotonin, and amino acids) 

  Abnormal metabolism of 4 types of neurotransmitters  has been reported in 

thiamine deficiency. 


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Deficiency (clinical sings) 

  Caused by inadequate intake, decreased absorption, and defective transport of 

thiamine, impaired biosynthesis of TPP, increased requirement, and increased loss of 
thiamine.  

  result in three syndromes: 

1)  Chronic peripheral neuritis (beriberi): which may or may not be associated with 

heart failure and edema; 

2)  Acute pernicious (shoshin beriberi): heart failure without peripheral neuritis; 
3)  Wernicke’s- Korsakoff’s syndrome : 

•  As consequences of failure of energy metabolism, affects neurons functions & 

CNS as a result of thiamin deficiency on neurotransmitter function & nerve 
conduction. 

•  This is because brain cells are unable to produce sufficient ATP (via the TCA 

cycle) for proper function if pyruvate dehydrogenase is inactive. 

 

 

Toxicity 

Excess thiamine is easily cleared by the kidneys.

 

Although there is some evidence of toxicity from large doses given parenterally, 
there is no evidence of thiamine toxicity by oral administration. why

 

 

 
 

 

Vitamin B6 includes six vitamer: Pyridoxine (alcohol) (principal form), pyridoxal 
(aldehyde), pyridoxamine (amine) & their 5- phosphates;

 

 They have equal biological activity.

 

 

 

Absorption & transport 

•  Intestinal mucosal cells have (pyridoxine kinase)  

so that there is net accumulation of pyridoxal phosphate by metabolic trapping.  

•  Tissue concentrations of pyridoxal phosphate are controlled by the balance between 

phosphorylation and dephosphorylation. 

 

 

 

Reaction type

  

1)  Transamination 

The presence of the α-amino group keeps amino acids away 
from oxidative breakdown, therefore removing the α-amino 
group is essential for producing energy from any amino acid, 

.

and is an obligatory step in the catabolism of all amino acids

 

2)  Deamination 

glutamate → α-ketoglutarate  + NH

3

 

3)  Decarboxylation 

Histidine → histamine + CO

2

 

4)  Condensation 

succinyl CoA → aminolevulinic acid

 

Glycine + 


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•  The metabolically active coenzymes are: 

a)  Flavin mononucleotide (FMN). (By flavokinase ) 
b)  Flavin adenine dinucleotide (FAD). (By FAD synthetase.) 

•   They are reversibly accepting two hydrogen atoms, forming FMNH2 or FADH2 & 

have a central role as a coenzyme in oxidation- reduction reaction.  

•  The conversion of riboflavin to coenzymes occurs within the cellular cytoplasm of 

most tissue. 

  

 

Food sources 

•  Milk, dairy products, liver and green leafy vegetables.  
•  Intestinal bacteria synthesize riboflavin, and fecal losses of the vitamin may be 5-6 

folds higher than intake.  

•  The vitamin is readily destroyed by UV components of sunlight (photodegradation). 

 

 

Absorption 

•  free riboflavin , absorbed in the small intestines by a saturable transport mechanism; 
•  Riboflavin is phosphorylated in the intestinal mucosa by flavokinase ; this metabolic 

trapping is essential for concentrative uptake of riboflavin into enterocytes . 

 

 

Excretion 

•  Once metabolic requirements have been achieved, riboflavin are excreted by  kidney, 

so that any excess absorbed is excreted  in urine & riboflavin does not accumulate in 
the body even when oral intake is very high. 

•  When dietary deficiency is present, any riboflavin present in the body can be 

efficiently conserved & reutilized. 

 

 

With the onset of riboflavin deficiency, an adaptation occurs through: 

1)  Fall in the hepatic free riboflavin metabolism to undetectable levels, with a sparing of 

FMN and FAD for critical metabolic functions. 

2)  In early stages of deficiency, there is an increase in the synthesis of reduced 

glutathione, 

  In response to the decrease conversion of oxidized glutathione to reduced glutathione, 

as a results of decreasing activity of glutathione reductase (require FAD as coenzyme) 

 


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Metabolic function of Riboflavin  

An electron carrier in oxidation - reduction rx.   

1)  In the mitochondrial electron transport chain.  

       FAD reversibly accepting 2H atoms, forming FADH2 

2)  In TCA: Succinate dehydrogenated to fumarate by succinate dehydrogenase, 

producing the reduced coenzyme FADH2. 

 

 

 

 

•  In plasma, the major vitamen is methylcobalamin accounting for 80% of plasma 

vitamin B12. 

•  In tissues, the major vitamen is adenosylcobalamin (70% in liver). 

 

 

Sources 

1)  Cobalamin is synthesized by certain microorganisms in SI. 
2)  Diets: essentially of animal origin & not found in plant.  

 

 
 
 
 
 


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Absorption  

•  Vit.B12 released from food in the stomach by action of gastric acid and pepsin which 

release the vitamin from protein binding and to make it available for 
absorption.  

•  Liberated vit. B12 binds to intrinsic factor IF (is a glycoprotein produced 

from gastric mucosa by parietal cells). 

•  vit.B12 –IF complex in small intestine, bound to receptors on mucosal 

cells & enter the cells (enterocytes). 

•  The absorption of vitamin B12 is limited by the number of vit.B12 –IF 

complex binding sites. 

•  Inside the enterocytes the complex is dissociated,& vit.B12 is then bound 

with transcobalamin II (Tc-II) [a vitamin B12 binding protein 
synthesized in the enterocytes].  

•   B12-TcII complex is then transported across the cell membrane & then 

released into the plasma of mucosal capillaries & into portal vein. 

  

 

Metabolic roles of vit.B12   

1)  There are 2 vitamin B12-dependent enzymes:  

a. Methionine synthetase,   b. Methyl malonyl CoA mutase. 

 
 

 

 
 

2)  Vitamin B12 has a role in the metabolism of cyanide, forming Cyancobalamin, lead to 

prevent the binding of cyanide to cytochrome oxidase. 

 

 

Cobalamin deficiency 

 

•  Have many underlying causes: 

a) Inadequate dietary intake. 
b) Increased metabolic requirements ( pregnancy)  
c)  Impaired vitamin activation or utilization in tissues. 
d) Pernicious anemia.  
an autoimmune disease in which chronic atrophic gastritis results from antibodies 
to gastric parietal cells & IF, directed against parietal cell .

 

•  The effects of cobalamin deficiency are most pronounced in rapidly dividing cells, 

such as the erythropoietic tissue of bone marrow and the mucosal cells of the intestine  


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•  Vit.B12 deficiency induces 2 clinical complexes:  

1)  The Megaloblastic anemia. 
2)  Characteristic neuropathy 

 

•  The Megaloblastic anemia:  due to  

a) Cobalamin deficiency: respond to cobalamin therapy. 
b) Folate deficiency: respond to folic acid therapy.  

o  Folic acid can partially reverse the hematological abnormalities of B12 deficiency 

and, therefore, can mask a cobalamin deficiency. 

o  Rapidly dividing cells need both the N5-N10-methylene tetrahydrofolate and N10-

formyl tetrahydrofolate for the synthesis of nucleotides required for DNA 
replication, resulting in the symptoms of megaloblastic anemia.  

o  In vitamin B12 deficiency, the utilization of the  
o   N5-methyl tetrahydrofolate is impaired, because the methylated form cannot be 

converted directly to other forms of tetrahydrofolate, so that folate is trapped as N5-
methyl tetrahydrofolate, which accumulates & the levels of the other forms decrease. 

 
 
 

 

•  Niacin (B3) describes 2 compounds:                                 

1- Nicotinic acid  2- Nicotinamide. 
They have equal biological activity.  

•  The biologically active forms (coenzymes): 

1)  Nicotinamide adenine dinucleotide (NAD).  
2)  Nicotinamide adenine dinucleotide phosphate (NADP) 

 

 

Absorption 

•  Once absorbed (Passive diffusion) into the enterocytes, nicotinamide may be converted 

to NAD or released into the portal circulation.  

•  Can be synthesized in the body from the essential amino acid tryptophan (not consider 

as a vitamin, since it can be synthesized in the body )  

 

 

Food content 

1)  In plant: Niacin is mainly in the form of nicotinic acid.  
2)  In animal: contain mainly NAD and NADP coenzymes. 

 

 

Distribution and excretion 

Liver plays an important role in the preparation of niacin for urinary excretion, 

on the 

 

products, depending

producing a variety of methylation and hydroxylation 

.

niacin status

 

 

 

Metabolic function niacin

 (NAD as cofactors in Redox reactions) 

NAD coenzymes reactions are the basis for hydrogen transfer reactions (NAD+ is 

oxidative decarboxylation 

 

glycolytic reactions,

reduced to NADH), important in 

.

of pyruvate & oxidation of acetate in the TCA cycle

 


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Pellagra (disease of tryptophan & niacin deficiency). 

•  Characterized by a photosensitive dermatitis, like severe sunburn, typically with a 

butterfly-like pattern of distribution over the face, affecting all parts of the skin that 
are exposed to sunlight.  

•  Similar skin lesions may also occur in areas not exposed to sunlight, but subject to 

pressure, such as the knees, elbows & ankles.  

 

 
 

 

Food sources 

•   Liver, kidney, yeast, egg yolk .  
•  About 85% of dietary Pantothenic acid is as CoA. 

 

 

Deficiency (Why its deficiency has not been reported?) 

Because, its widely distributed in foods, and it is absorbed throughout the small 
intestine so that deficiency has not been reported in human except in specific 
depletion studies.

 

 

 

Metabolic role  

1)  Part of Co-enzyme A:  

•  CoA is the major carrier of acyl groups in an acyl transfer reactions ex:  

a)  In ketogenesis.  b) In β-oxidation of FFA. 

•  Coenzyme A is synthesized in a 5-step process 

from Pantothenic acid & cysteine. 

•  Coenzyme A contains a thiol group that carries 

acyl compounds as activated thiol esters 

 

2)  Prosthetic group  of Fatty acid Synthase :  

  Phosphopantetheine is covalently linked via a phosphate ester to a serine OH of 

the acyl carrier protein domain of Fatty Acid Synthase. 

  Fatty acid synthase is a multi-enzyme protein that catalyzes 

fatty acid synthesis

.  

  It is not a single 

enzyme

 but a whole enzymatic system composed of two 

identical multifunctional 

polypeptides

, in which 

substrates

 are handed from one 

functional domain to the next  


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Four of the B vitamins are essential in the citric acid cycle and therefore in 
energy-yielding metabolism:

 

1)  Riboflavin (B2): FAD a cofactor in the succinate dehydrogenase; 
2)  Niacin (B3): NAD coenzyme for 3 dehydrogenas  

1.  isocitrate dehydrogenase,  
2.  α-ketoglutarate dehydrogenase, 
3.  malate dehydrogenase; 

3)  Thiamin (vitamin B1):  

reaction.

 

ketoglutarate dehydrogenase

-

α

in the 

 

coenzyme for decarboxylation

 

The

 

4)  Pantothenic acid (B5): as part of coenzyme A, the cofactor attached to “active” 

carboxylic acid residues such as acetyl-CoA and succinyl-CoA. 

 
 
 

 
 


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Food source

 

•  The major source of folate is green vegetables, bread, citrus fruits and juices, meat, 

and fish.  

•  Reduced folates are less stable than folic acid and large losses in food folate can occur 

during food preparation such as heating. 

 
 
 
 
 
 
 
 
 
 
•  Most dietary folate is metabolized to 5-methyl-tetrahydrofolate mono glutamate 

during its passage through the intestinal mucosa.  

•  This metabolism in depend on the amount  of folate ingested, so that when dose of 

folic acid is high , most of the folate appears unchanged in the portal circulation. 

•  A folate binding receptor (folate receptor) has been detected in the intestine, which 

has been shown to mediate endocytosis of folate in the kidney and other tissues.  

 

 

Transport  

Methyl-tetrahydrofolate (the main vitamer) from the intestinal mucosa circulates 
in plasma protein bound to albumin for uptake by extrahepatic tissues. 

 

 

 

Source of folate in RBCs ? 

•  RBC s contain higher levels of folate (a several-hundred-fold) higher than plasma, 

incorporated during erythropoeisis rather than taken up from the circulation, as 
polyglutamates bound to hemoglobin because mature red cells do not transport  folate 
and their folate stores are formed during erythropoiesis and are retained  due to 
binding to hemoglobin, through the life span of the human RBC. 

•  Red cell folate levels are often used as a measure of long-term folate status.  

 

 

Biochemical roles: 

•  Folic acid is itself not biologically active, but its biological importance is due to 

tetrahydrofolate

 and other derivatives after its conversion to dihydrofolate in the liver. 

•  Folates act serve as acceptors and donors of one-carbon units in a variety of 

reactions in amino acid and nucleotide metabolism.  

•  The C-3 of serine is the major source of one-carbon units for folate metabolism.  
•  Other sources include formate, which is derived from serine metabolism in the 

mitochondria, and the C-2 of histidine.  


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Deficiency

•  Folate deficiency symptoms are usually due to a dietary deficiency. 
•  The classical symptom of folate deficiency is a Megaloblastic anemia that cannot be 

distinguished from that caused by vit. B12 deficiency. WHY?  

•  Many of the clinical effects of folate deficiency can be explained by the metabolic 

role of folate coenzymes in pathways leading to nucleotide synthesis of DNA .  

•  Because of this role, symptoms of deficiency are expressed in rapidly growing tissues.  

 

1)  Megaloblastic Anemia 

Characterized by large immature red blood cells, it is a reflection of disturbed 
DNA synthesis in blood cells characterized by enlarged red cells and 
hypersegmentation of the nuclei with reduced cell number, the condition is usually 
detected clinically by the anemia.

 

2)  Vitamin B12 interactions 

•  Vitamin B12 deficiency is identical to that observed in folate deficiency, these 

vitamins are cofactors for the methionine synthase reaction [a block in this enzyme 
lead to accumulation of folate in form of 5-CH3- THF which cannot be 
metabolized by other mechanism]. 

•  this would result in the trapping of folate in a nonfunctional form with a associated 

reduction in the level of other folate coenzymes required for other reactions. 

  Hyperhomocysteinemia and Folate concentration 

  Genetic disease includes methylenetetrahydrofolate reductase deficiency. 
   Fasting homocysteine levels have been inversely correlated with both plasma 

folate levels and food folate intake.  

   Increased folate intake lowers the mean homocysteine of groups, and the lowering 

effect is greatest in subjects with the highest plasma homocysteine levels.  


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•  Biotin is a coenzyme in carboxylation reactions, in which it serves as a carrier of 

activated carbon dioxide.  

•   The biotin-dependent enzymes (biotin-dependent carboxylase) are cytosolic and 

mitochondrial. They catalyze a two-step reaction:   

1)  enzyme-biotin + ATP + HCO3− →enzyme-biotin-COOH + ADP + Pi 
2)  Enzyme-biotin-COOH+ acceptor → enzyme-biotin + acceptor-COOH. 

•  Biotin is linked to the enzyme by an amide bond between the terminal carboxyl of the 

biotin side chain and the Enz-amino group of a lysine residue.  

•   This combination act as a long flexible arm that allows the biotin ring to translocate 

between the 2 active sites.  

•  Only d-biotin is enzymatically active. 

o  It's bound covalently to enzymes by the formation of a peptide bond between the 

carboxyl group of the side chain and the ε-amino group of a lysine residue. 

o  This combination act as a long flexible arm that allows the biotin ring to 

translocate between the 2 active sites.  

 

1- Biotin carboxylase,  
Which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-
dependent reaction. 
2- Biotin carrier protein:  
Has the long, flexible biotin arm carries the activated CO2 from the biotin 
carboxylase site to the transcarboxylase active site. 
3- Biotin transcarboxylase, which transfers activated CO2 from biotin to acetyl-
CoA, producing malonyl-CoA  

 
 


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Defeciency 

•  Biotin deficiency does not occur naturally because the vitamin is widely distributed in 

food. 

•  Also, a large percentage of the biotin requirement in humans is supplied by intestinal 

bacteria. 

•  Consequences of def. 

:

all in deficiency, resulting in

f

 

dependent carboxylases

-

biotin

The activities of 

 

1)  Impaired gluconeogenesis, with accumulation of lactate, pyruvate, and alanine. 
2)  Impaired lipogenesis, with accumulation of acetyl CoA.  

 

 
 

Dehydroascorbic acid and dehydroascorbate are the oxidized form of ascorbic acid, 
both of which have vitamin activity because they can be reduced to ascorbate.

 

 

 

 

 

Sources 

Ascorbic acid occurs in significant amounts.

 

1)  In plants: In vegetables, and fruits.  
2)  In animal organs: such as liver, kidney, and brain.  

 

 

Absorption &Tissue uptake of Vitamin C 

•  Ascorbic acid absorbed by  

1)  Sodium-dependent active transport at low concentration. 
2)  Simple diffusion at high concentrations. 

•  Absorption of vitamin C depend largely on the amount ingested, so that 90% of 

dietary ascorbate is absorbed at intakes up to about 100 mg / day; the absorption 
decreased to 50% of a 1.5-g dose & to 25% of a 6-g dose, and 16% of a 12g dose .  

•  The absorbed ascorbic acid moves rapidly from the intestinal cell into blood by 

facilitated diffusion.  

•  Ascorbate uptake by cells is mediated by sodium-dependent transporters SVCT 

1& SVCT 2. 

•  Dehydroascorbate uptake mediated by glucose transportes GLUT 1, 2 &3.  
•  Many cells accumulate ascorbic acid against a concentration gradient (up to 40-fold 

higher than plasma concentrations). 

•  The normal physiological conc. of glucose will inhibit uptake of dehydroascorbate. 
•  Functional signs of deficiency may develop in poorly controlled diabetes mellitus, 

despite an adequate intake and adequate plasma concentrations, suggesting that 


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hyperglycemia and insulin insensitivity and thus uptake of dehydroascorbate in 
competition with glucose. 

•  Some of the adverse effects of poor glycemic control in diabetes mellitus may be 

related to this impairment of vitamin C uptake, and supplements of vitamin C maybe 
beneficial to decrease diabetic complication. 

•  There is no specific storage organ for ascorbate; the only tissues showing a significant 

conc. of the vitamin are the adrenal and pituitary glands. 

 

 

Metabolic functions 

A.  Ascorbate involved in 

1)  Synthesis of adrenal hormones via dopamine B-hydroxylase. 
2)  Biosynthesis of corticosteroids & aldosterone. 
3)  Folate metabolism & leukocyte functions. 
4)  Hydroxylation of cholesterol in the formation of bile acids.  

 

B.  Role of Ascorbate in iron absorption & metabolism 

  Ascorbic acid in the intestinal lumen will both maintain iron in the reduced state 

and also chelate it, thus increasing absorption.  

  A dose of vitamin C taken together with a meal increases the absorption of iron 

65%.  

  Ascorbate is also active in the reduction of Fe3+ in the plasma transport 

protein (transferrin) to Fe2+ for storage in the liver or for heme synthesis. 

 

C.  Antioxidant roles of Ascorbate 

1)  A radical-trapping antioxidant, reacting with superoxide and a proton to yield 

hydrogen peroxide. 

2)  With the hydroxyl radical to yield water.  

 

 

 

Deficiency – (Scurvy) 

Most of the clinical signs of scurvy can be accounted by effects of deficiency on 

impaired proline and lysine hydroxylase activity

collagen synthesis as a result of 

 

Characterized by hypercholesterolemia & fatigue. 

 

Clinical signs of scurvy such as delayed in wound healing.

 
 




رفعت المحاضرة من قبل: Mostafa Altae
المشاهدات: لقد قام 6 أعضاء و 170 زائراً بقراءة هذه المحاضرة








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