Thiamine (Vitamin B1)

• Also called Aneurine or anti-beriberi factor

• It is a sulphur containing, water soluble, B-complex vitamin
• Contains substituted pyriding ring connected to substituted
thiazole ring
• Two phosphates are added to form active coenzyme TPP
 Coenzyme functions of TPP

Pyruvate dehydrogenase
 Pyruvate ----------------------------------Acetyl CoA
TPP
dehydrogenase
 Alpha keto glutarate---------------------- Succinyl CoA
TPP
 Transketolase in pentose phosphate pathway of
carbohydrates
Pyruvate decarboxylase
 Pyruvate ----------------------------- Acetaldehyde (yeast)
TPP
Pyruvate dehydrogenase complex
 Dietary source

Unpolished rice, cereals, pulses, whole grains,

yeast,bread, green peas. Animal sources - milk,
pork, liver
Recommended daily allowance (RDA)

 1 – 1.5 mg/day

 Requirement increases during pregnancy & lactation

 Deficiency manifestations

 Beriberi

 Wernicke-Korsakoff Syndrome

 Polyneuritis
 Reasons for Beriberi

 People whose diet consists mainly of polished

white rice.

 Anti-thiamine factors (tea, coffee, betel nuts).

 Chronic alcoholics with inadequate diet.

 Baby is mainly fed on the milk of a mother who

suffers from thiamine deficiency.
 Symptoms of Beriberi

 Weight loss

 Emotional disturbances

 Impaired sensory perception

 Weakness and pain in the limbs

 Edema (swelling of bodily tissues) is common.

 Types of Beriberi

 Wet beriberi – CVS manifestations are prominent

edema, heart failure.
 Dry beriberi – CNS manifestations are prominent
progressive muscle wasting – difficulty in walking
Peripheral neuritis with sensory disturbance - paralysis

 Infantile beriberi - infants of thiamine-deficient mothers.

restlessness
sleeplessness
bouts of screaming
 Wernicke-Korsakoff syndrome

 Also known as cerebral beriberi

 Encephalopathy
• Nystagmus
• Ophthalmoplegia
• Cerebellar ataxia

 Psychosis
 Polyneuritis

 Chronic alcoholics

 Motor and sensory defects

 Increased requirement of thiamine

 Less nutritive food

 Laboratory diagnosis

 Estimation of RBC transketolase activity.

 Activityis reduced
 Which becomes normal after addition of the
cofactor

 Rarely indicated
 RIBOFLAVIN

 Water-soluble vitamin.
 Also known as vitamin B2.
 Not stored in the body.
 Major part excreted in urine.
 Exists in tissues tightly bound with enzymes.
 CHEMISTRY

 Has dimethyl
isoalloxazine ring.
Ribitol

 Ribitol is attached to
it.

Dimethyl isoalloxazine
 Coenzyme forms

 Flavin mononucleotide (FMN), and

 Flavin adenine dinucleotide (FAD).

FAD
Acceptance of hydrogen by FAD

 FAD accepts two hydrogen atoms from

substrate during oxidation.

 FAD is reduced to FADH2.

 The two nitrogen atom of isoalloxazine

accepts the hydrogen atom
 BIOCHEMICAL FUNCTIONS OF
COENZYMIC FORMS OF RIBOFLAVIN

 FAD takes part in oxidation reduction reactions.

 FMN mostly takes part in reductive biosynthesis

 FAD dependent enzymes
• Succinate
dehydrogenase

• Acyl CoA
dehydrogenase
 FMN dependent enzymes
 Amino acid Oxidase
During amino acid oxidation FMN is reduced .
L-amino acid L-imino acid

FMN FMNH2

Ketoacid

 In respiratory chain NADH dehydrogenase

contains FMN.
 Riboflavin deficiency

Causes:

 Natural deficiency is uncommon

 Accompanies diseases like Pellagra, Beri beri and
Kwashiorkar.
Manifestations:
• Angular cheilosis.
• Oral pain, ulceration,
ulcerative gingivitis.

• Glossitis.
• Tip of tongue is red &
swollen.
• Vascularization of the
cornea followed by
ulceration and
secondary infection.
Sources:
• Liver, dried yeast, egg and
whole milk are rich sources.

• Fish, whole cereals, legumes and

green leafy vegetables are good
sources.
RDA:
• Adults : 1.5mg / day

• During pregnancy & lactation

additional 0.2 to 0.4 mg/day is
required
 NIACIN
• Water-soluble vitamin.

• Also known as nicotinic acid or vitamin B3.

• Nicotinamide is the derivative of niacin and

used by the body to form the coenzymes.
 CHEMISTRY
Niacin is Pyridine–3–Carboxylic acid
 Coenzyme forms

• Nicotinamide adenine dinucleotide (NAD+)

• Nicotinamide adenine dinucleotide phosphate

(NADP+).

• Niacin is attached to ribose phosphate to form a

mononucleotide.

• It is then attached to AMP to form dinucleotide.

Adenine mononucleotide
Nicotinamide mononucleotide

Nicotinamide Adenine Dinucleotide (NAD+)

In oxidised form:
• The nitrogen of nicotinamide residue has
positive charge.
• Hence written as NAD+

In reduction Process:
• NAD accepts one hydrogen atom and one
electron to form NADH
• H+ ion is released
 BIOCHEMICAL FUNCTIONS OF COENZYMIC
FORMS OF NIACIN

• NAD+/NADH takes part in oxidation

reduction reactions.

• NADPH mostly takes part in reductive

biosynthesis.
NAD+ Dependent Enzymes
• Lactate dehydrogenase (Lactate Pyruvate)

• Glyceraldehyde 3 phosphate dehydrogenase

• Pyruvate dehydrogenase (Pyruvate Acetyl CoA)

• Beta hydroxy acyl CoA dehydrogenase

• Glutamate dehydrogenase

• Mitochondrial isocitrate dehydrogenase

• During this NADH is generated which is
oxidised in Respiratory chain to generate ATP
NADPH Generating Reactions
• Glucose 6 phosphate dehydrogenase

• 6-phospho gluconate dehydrogenase

 NADPH Utilizing Reactions
• Fatty acid synthase complex

• HMG CoA Mevolanate

• Met hemoglobin Hemoglobin

• Phenylalanine Tyrosine

• Folate Dihydrofolate Tetrahydrofolate

Synthesis of Niacin or NAD from Tryptophan

Tryptophan

Several steps Pyridoxal Phosphate

(PLP)
3-Hydroxyanthranilate

Several steps

Quinolinate

Several steps
NAD
 Niacin Deficiency
• Deficiency of niacin leads to PELLAGRA
Causes for deficiency:

(1) Dietary deficiency of Tryptophan (Trp):

• Pellagra is common in people whose staple diet is Maize or

Sorghum.

• In maize niacin is in bound form and hence not available.

• In sorghum, Leucine is present which inhibits QPRT enzyme

and hence niacin is not converted to NAD+
(2) Vitamin B6 deficiency:

• In Pyridoxal deficiency Tryptophan can not be converted to

niacin.

(3) Use of Isoniazid (INH):

• Anti TB drug that inhibits Pyridoxal phosphate.

• Thus no conversion of Trp to niacin or NAD+.

(4) Hartnup Disease:

• Tryptophan absorption is defective.

• Increased excretion of Tryptophan in urine.

• Thus leading to deficiency of Tryptophan and niacin.

(5) Carcinoid Syndrome:

• Tumor which utilizes Trp for Serotonin synthesis.

• Leads to Trp deficiency and thus niacin deficiency

Clinical features
of Pellagra:3D’s
(1) Dermatitis:

• Erythema in feet,
ankles and face.

• Increased
pigmentation
around neck.
(2) Diarrhea:

• Mild or severe with blood and mucus.

• Leads to weight loss

(3) Dementia:

• Irritability, Inability to concentrate and poor

memory.
• Ataxia and Spasticity occurs rarely.
Sources:
• Dried yeast, liver, peanut, cereals, legumes,
meat and fish.

• Most of the requirement is met by

conversion of tryptophan to niacin.

• 60mg of tryptophan yields 1gm of niacin.

RDA :
• 20 mg/day.

• During pregnancy additional 2mg/day.

• During lactation additional 5mg/day.

Therapeutic use:

• Vasodilatation and histamine release.

• Nicotinamide safer than nicotinic acid.

• Lowers serum cholesterol level by inhibiting flux of

FFA from adipose tissue
PANTOTHENIC ACID
 Pantothenic acid (vitamin B5 )

 Greek word “pantos” meaning "everywhere”

 Widely distributed in nature

 Chick antidermatitis factor

 Structure

Pantoic acid Beta alanine

 Functions of Pantothenic acid

 Synthesis of Coenzyme A

 Synthesis of Acyl carrier protein (ACP)

 Metabolism and synthesis of carbohydrates, proteins

and fats for energy release.

 Secretion of hormones, such as cortisone

Coenzyme function of Pantothenic acid

Component of coenzyme-A (CoA)

CoA has pantothenic acid and ß-mercaptoethanol
 Coenzyme A

 Synthesis of essential fats, cholesterol, and steroid

hormones

 Synthesis of the neurotransmitter, acetylcholine and

the hormone, melatonin.

 Metabolism of a number of drugs and toxins by the

liver.

 Heme synthesis.
 Function - as Acyl group carrier

List of coenzyme A activated acyl groups

 Acetyl- CoA

 Propionyl-CoA

 Acetoacetyl-CoA

 Malonyl-CoA

 Succinyl-CoA

 HMG-CoA

 Butyryl -CoA
 Sources and RDA

 RDA: about 10 mg/day

 Whole grain cereals, legumes, eggs, yeast, liver

 Synthesized by normal bacterial flora in intestines

 Deficiency symptoms

 Exceptionally rare

 Burning foot syndrome – paresthesia, staggering

gait, sleep disturbance

 In experimental animals – anemia, reduced

steroidogenesis, dermatitis, fatty liver, adrenal
necrosis
Pyridoxine (B6)
4- substituted 2- methyl 3- hydroxyl 5- hydroxymethyl pyridines

Pyridoxine Pyridoxal
O
CH2O

=
H C-H
HO CH2O
H HO CH2O
H3 H
+
C N H3 +
H C N
H
CH2N
H2
Pyridoxamine HO CH2O
H
H3 +
C N
H
 Pyridoxal Pyridoxal 5’phosphate
O O

=
=

C-H C-H

HO CH2O HO CH2O-P-
O-

=
Kinase
H O- P
H3 ATP H3 +
+
C N C N
H H
 Transaminase

H
R -C -
Threonine aldolase COOH
N Decarboxylase

=
C-H

HO CH2-O - P -
Enz
H3 +
C N
H
Functions:
Transamination

Decarboxylation

Glycogen phosphorylase

Steroid hormone action

 Transamination

NH3+ O

=
R1 CH COO - R1 C COO -

PLP

O NH3+
=

R2 C COO - R2 CH COO -

All aminoacids undergo transamination except

Threonine, Lysine, Proline, Hydroxyproline,
Tryptophan and Histidine.
 Pyruvate  - AA

Alanine Transaminase

L - Alanine  - KA

Oxaloacetate  - AA

Aspartate Transaminase

L - Aspartate  - KA
 Decarboxylation

Glutamate GABA(Inhibitory Neurotransmitter)

Histidine Histamine (mediator of

allergy,anaphylaxis)

5 hydroxy tryptophan Serotonin

Cysteine Taurine

Serine Ethanolamine
Tyrosine

DOPA
PLP DOPA decarboxylase
CO2
Dopamine

Norepinephrine

Epinephrine
 Methionine metabolism
(Trans sulfuration reaction)

Homocysteine + Serine

PLP Cystathionine β synthase

Cystathionine

PLP Cystathionase

Cysteine + Homoserine
 Heme synthesis: ALA synthase is a PLP depended enzyme

Niacin synthesis:

Tryptophan (60mg)

Kynureninase
3 hydroxy kynurenine 3 hydroxy anthranillic acid
PLP

Xanthurenic acid (excreated in urine)

NIACIN
(1mg)
 PLP
Palmitoyl CoA + Serine 3Ketodihydrosphingosine

Sphinganine

Ceramide

Various Sphingolipids & Gangliosides

 Serine dehydratase
Serine Pyruvate + NH3
PLP

Serine hydroxymethyl transferase

Serine Glycine
PLP
THF N5,N10 methylene THF

Threonine dehydratase
Threonine α-keto butyrate + NH3
PLP
PLP is required for the release of steroid hormone
receptor complex from its DNA binding site

Deficiency causes increased sensitivity to the hormones

 Drugs and B6

Isoniazid (INH) –INH combines with PLP and form inactive

hydrazone derivative

Alcohol –Acetaldehyde inactivates PLP resulting in neuritis

Penicillamine (β dimethyl cysteine)-reacts with PLP to form

inactive thiazolidine

Oral contraceptives increases the requirement

Cycloserine - B6 antagonist
Deficiency-

Children – convulsions (decreased GABA)

Adults – irritability,nerousness depression in mild

deficiency. In severe deficiency Peripheral
neuritis due to demylination of nerves
Skin changes due to niacin deficiency
anemia
Metabolic – homocystinuria,Xanthurenic aciduria

Excess – sensory neuropathy in 2-7g/day intake

RDA – 1.3 to 1.7 mg / day for an adult consuming
100g of protein
Requirement increases in Pregnancy and lactation

Sources – meat vegetables,whole grain cereals banana

and egg yolk
BI TIN
 Biotin (vitamin H or B7)

 Water-soluble B-complex vitamin

 Anti-egg white injury factor.

 Present in liver as biocytin.

 Coenzyme for carboxylation reaction

Structure

imidizalone ring

thiophene ring

Valeric acid
 Functions of biotin

 Synthesis of fatty acids

 In gluconeogenesis.

 Metabolism of leucine.
Coenzyme function of biotin
Carbon dioxide fixation

Biotin
Carbon dioxide fixation
Carbon dioxide fixation
 Sources and RDA

 Normal bacterial flora of the gut will provide

adequate quantities of biotin.

 Liver, yeast, peanut, soybean, milk, egg yolk are rich

sources

 RDA – 200 – 300 µg / day

 Biotin antagonist

 Avidin is a protein found in the egg white

 Heat labile – boiling neutralizes its activity

 Avidin has a very strong affinity for biotin.

(one molecule binds with 4 biotin)

 Streptavidin (Streptomyces avidinii) used in ELISA

techniques
 Biotin deficiency

 Rare, since the daily requirements of biotin are low,

many foods contain adequate amounts.
 Intestinal bacteria can synthesize significant amount.

 Excessive consumption of raw egg-white over a long

period (high levels of avidin).
 Prolonged use of antibiotics (destroys intestinal flora)
 Leiner’s disease – breast fed infants with persistent
diarrhoea
 Symptoms of Biotin deficiency

 Dermatitis
 Atrophic glossitis
 Anorexia
 Hyperasthesia
 Hallucination
 Muscle pain
 Folic Acid (vitamin B9)

 Folium: leaf
 Other names: folinic acid, folacin, pteroyl glutamic
acid
 Readily absorbed by the upper part of jejunum.
Transported in blood by β-globulins
Structure of folic acid
 Sources and RDA of folic acid

Green leafy vegetables, cereals, pulses,

oil seeds, yeast, liver, egg
RDA: Adults 200g
Pregnancy 400g, Lactation 300g
 Functions of folic acid

 Prevention of cancer
 Reduce levels of homocysteine in blood
 Prevents birth defects
 Crucial for proper brain function and plays an
important role in mental and emotional health
 Production of DNA and RNA
 Regulate the formation of red blood cells
 Folate in one carbon metabolism

 Coenzyme - Tetra hydro folic acid (THFA)

 THFA- carrier of one carbon groups
 Folic acid functions as a methyl donor
 Synthesis of active methionine – transmethylation
reactions
 One carbon transfer reactions --biosynthesis of serine,
methionine, glycine, choline, purine nucleotides,
epinephrine etc.
THFA - One carbon carrier
Folate trap
 Folate deficiency

 Causes- pregnancy, defective absorption, anemia,

anticonvulsant drugs, low dietary intake (rare)

 Manifestations
 Weakness, Fatigue, Lightheadedness, Forgetfulness, Irritability,
Pale appearance (pallor), Lack of appetite and weight loss.

 Macrocytic anemia: immature looking nucleus in the bone

marrow cells, macrocytic RBCs in peripheral blood,
reticulocytosis, hemolysis

 GIT manifestations- vomiting, diarrhoea, abdominal pain

 Assessment of folate deficiency

 Normal serum level 20 ng/ml, ~200g/ml of packed

cells, measured by RIA

 Measurements of folic acid and vitamin B12 levels.

 Histidine load test- excretion of FIGLU
 Complete blood count (CBC)
 Folate Antagonists
• Sulphonamides, 5-fluorouracil, Methotrexate,
Aminopterin, trimethoprim
• Antibacterial, antimalarial and anticancer agents
 Vitamin B12

 Synonyms: cobalamin, antipernicious anemia factor,

extrinsic factor of Castle
 C63N14CO( cobalt vitamin)

 Forms- cyano cobalamin, methyl cobalamin, hydroxy

cobalamin

 “Deoxyadenosyl cobalamin (Ado-B12)” is the major

storage form in liver (whole liver contains ~2mg,
sufficient for 2-3 years)
 Structure of cobalamin

R = -CN, -OH, -adenosyl or -methyl groups

 Sources and RDA of B12
Only animal sources
Liver is the richest
source
Meat, fish and egg are
good sources
Curd is a good source
because lactobacillus
can synthesize B12
RDA: Adults 1 - 2g
Pregnancy & Lactation 2 - 4g
Vitamin B12 absorption
 Coenzymic role of Vitamin B12

CH3Cbl

Homocysteine Methionine

AdoCbl

D-methyl malonyl CoA Succinyl CoA

 Methyl Folate trap

B12

Leads to associated folic acid scarcity and

B12 deficiency
 Causes of B12 deficiency

 Nutritional deficiency
 Defective absorption
 Old Age
 Addisonian pernicious anemia (autoantibody to IF)
 Atrophy of gastric epithelium
 Fish tapeworm infection
 Pregnancy (increased requirement)
 Inherited defects in formation of ado-B12
 Deficiency manifestations of B12
 Causes simultaneous folate deficiency
 Homocystinuria
 Megaloblastic/ pernicious anemia
 Megaloblasts & immature RBC in peripheral blood
 Damage to nervous system, demyelination and
neuronal death, alteration in deep senses &
reflexes, unsteady gait
 Positive Romberg’s & Babinski’s sign
 Dementia, confusion, delusion
 Assessment of B12 deficiency

 Serum B12 quantitated by RIA or ELISA

 Schilling test
 Methyl malonuria
 FIGLU excretion test
 Peripheral blood and bone marrow morphology