Thiamine

Thiamine- Chemistry, functions
and clinical significance
Biochemistry for Medics
http://www.namrata.co/
1Biochemistry for medics

Thiamine- Introduction
also known as vitamin B1, anti beriberi
factor or anti-neuritic vitamin
 is an important water-soluble vitamin
is involved in carbohydrate, fat, amino
acid, glucose, and alcohol metabolism.
is required as a coenzyme in enzymatic
reactions that involve the transfer of an
aldehyde group.
is essentially nontoxic.

Thiamine - Structure
Thiamine contains a substituted pyrimidine
ring (dimethyl 6-amino pyrimidine) connected
to a substituted thiazole ring (Methyl hydroxy
ethyl thiazole) by means of Methylene bridge.

Thiamine- Synthesis
Thiamine can be synthesized by plants
and some microorganisms, but not usually
by animals.
Human beings require thiamine from
diet, though small amounts may be
obtained from synthesis by intestinal
bacteria.
 Whole wheat flour, unpolished rice,
beans, nuts and yeast are the good
sources of thiamine
It is also present in liver, meat and eggs.
The body can only store up to 30 mg of
thiamine in its tissues.

Thiamine-Occurrence
It is present in large amounts in skeletal
muscle, heart, liver, kidney, and brain.
It has a widespread distribution in foods,
but there can be a substantial loss of
thiamine during cooking above 100°C
(212°F).
The half-life of thiamine is 9-18 days. It is
excreted by the kidney.

Activation of Thiamine
The active form of the coenzyme, thiamine
pyrophosphate (thiamine diphosphate, TPP), is
synthesized by an enzymatic transfer of a
pyrophosphate group from ATP to thiamine).

Recommended daily Allowance of
thiamine
Depends on calorie intake (0.5 mg/1000 cals)
 RDA is 1-1.5 mg/day
 Requirement increases with-
o increased carbohydrate intake
o Pregnancy
o Lactation
o Smoking
o Alcoholism
o Prolonged antibiotic intake
o Serious or prolonged illness

Metabolic role of Thiamine
Thiamine has a central role in energy-yielding
metabolism, and especially the metabolism of
carbohydrates
Thiamine pyrophosphate is an essential cofactor
for enzymes that catalyze the oxidative
decarboxylation of α-keto acids to form an acylated
coenzyme A (acyl CoA).
These include pyruvate dehydrogenase , α -keto
glutarate dehydrogenase and branched-chain α-
keto acid dehydrogenase. These three enzymes
operate by a similar catalytic mechanism.

Role of TPP in Pyruvate dehydrogenase
complex
The pyruvate dehydrogenase complex is a large,
highly integrated complex of three kinds of enzymes;
Pyruvate dehydrogenase, dihydrolipoyl transacetylase
and Dihydrolipoyl dehydrogenase.
At least two additional enzymes regulate the activity
of the complex and five coenzymes: thiamine
pyrophosphate (TPP), lipoic acid, CoASH, FAD and NAD+
participate in the overall reaction.

PDH Complex and role of TPP
Pyruvate is decarboxylated by the pyruvate dehydrogenase component of
the enzyme complex to a hydroxyethyl derivative of the thiazole ring of
enzyme-bound thiamine diphosphate, which in turn reacts with oxidized
lipoamide, the prosthetic group of dihydrolipoyl transacetylase, to form
acetyl lipoamide. In thiamine deficiency, glucose metabolism is impaired,
and there is significant (and potentially life-threatening) lactic and pyruvic
acidosis.

Role of TPP in α-Keto Glutarate
dehydrogenase complex
The enzyme complex is similar to that involved in the
oxidative decarboxylation of pyruvate. The α-
ketoglutarate dehydrogenase complex requires the
same cofactors as the pyruvate dehydrogenase
complex—thiamine diphosphate, lipoate, NAD+, FAD,
and CoA—and results in the formation of succinyl-CoA.

Role of TPP in branched-chain α-
keto acid dehydrogenase complex
Reaction 2 is catalyzed by α-keto acid dehydrogenase complex 12Biochemistry for medics

Role of TPP in branched-chain α-
keto acid dehydrogenase complex
Following transamination, all three -keto
acids of branched chain amino acids undergo
oxidative decarboxylation catalyzed by
mitochondrial branched-chain α-keto acid
dehydrogenase.
This multimeric enzyme complex of a
decarboxylase, a transacylase, and a
dihydrolipoyl dehydrogenase closely resembles
pyruvate dehydrogenase and α-keto glutarate
dehydrogenase complex.

Role of TPP in Transketolase
reaction
Thiamine pyrophosphate is also an important cofactor for
the Transketolase reactions in the pentose phosphate
pathway of carbohydrate metabolism.
These reactions are important in the reversible
transformation of pentoses into the glycolytic intermediates
fructose 6-phosphate and glyceraldehyde 3-phosphate.
Transketolase transfers the two-carbon unit comprising
carbons 1 and 2 of a ketose onto the aldehyde carbon of an
aldose sugar.
 It therefore effects the conversion of a ketose sugar into an
aldose with two carbons less and an aldose sugar into a ketose
with two carbons more.
The reaction requires Mg2+ and thiamine diphosphate
(vitamin B ) as coenzyme.

Role of TPP in Transketolase
reaction

Role of TPP in Tryptophan
Metabolism
Thiamine is also required for the metabolism of
Tryptophan( As a coenzyme for Tryptophan
pyrrolase)
Tryptophan oxygenase (tryptophan pyrrolase)
opens the indole ring, incorporates molecular
oxygen, and forms N-formyl kynurenine. 16Biochemistry for medics

Role of TPP in nerve conduction
Thiamine pyrophosphate has a role in nerve
conduction;
It phosphorylates, and so activates, a
chloride channel in the nerve membrane.
Thiamine appears to have a role in axonal
conduction particularly in acetyl cholinergic
and serotoninergic neurons.

Thiamine deficiency and
impaired reactions
A deficiency in thiamine will decrease the
efficiency of the enzymes for which TPP is
required as a cofactor.
Thus, the rate of conversion of pyruvate to
acetyl-CoA and the flow of acetyl-CoA through
the tricarboxylic acid cycle will be depressed
as a result of the inefficiency of the TPP-
requiring enzymes pyruvate dehydrogenase
and α-keto glutarate dehydrogenase.

impaired reactions (Contd.)
The production of the reduced electron carrier, NADH,
and the ATP produced from it via oxidative
phosphorylation is also decreased as a consequence.
Because nervous tissue and heart use at high rates
ATP synthesized from the oxidation of NADH produced
from pyruvate conversion to acetyl-CoA and from the
TCA cycle, these tissues are most affected by a
deficiency in thiamine.
When deficient in thiamine, the brain can no longer
efficiently metabolize pyruvate through the TCA cycle to
produce ATP and thus must convert it to lactate to
produce ATP.

impaired reactions (Contd.)
A deficiency in thiamine also adversely affects
the flux of glucose metabolized by the pentose
phosphate pathway.
When these reactions cannot proceed, precursor
metabolites build up, and the flow through the
pathway is decreased.
This results in a decreased production of NADPH
and decreased conversion of glucose to pentose,
including ribose.
This can lead to decreased regeneration of
reduced glutathione and susceptibility to oxidative
stress.

Thiamine deficiency(Beri-Beri)
Beriberi is observed in developed nations
in-
persons with alcoholism,
people on fad diets,
persons on long-term peritoneal dialysis
without thiamine replacement,
 persons undergoing long-term starvation,
or persons receiving intravenous fluids with
high glucose concentration.

Pathophysiology of Thiamine
deficiency (Beri-Beri)
Deficiency causes degeneration of peripheral
nerves, thalamus, mammillary bodies, and
cerebellum.
Cerebral blood flow is markedly reduced, and
vascular resistance is increased.
The heart may become dilated; muscle fibers
become swollen, fragmented, and vacuolized,
with interstitial spaces dilated by fluid.
Vasodilation occurs and can result in edema
in the feet and legs.
Arteriovenous shunting of blood increases.
Eventually, high-output heart failure may occur.

Classification of Beri-Beri
 Dry Beriberi
Cardiovascular
(Wet Beriberi)
Infantile Beriberi
Shoshin Beriberi
Wernicke-
Korsakoff syndrome

Dry Beriberi
Nervous system involvement is termed dry
beriberi.
The neurologic findings can be peripheral
neuropathy characterized by symmetric
impairment of sensory, motor, and reflex
functions of the extremities
These deficits are bilateral and roughly
symmetric, occurring in a stocking-glove
distribution.

Dry Beriberi (Contd.)
They affect predominantly the lower
extremities, beginning with paresthesias in the
toes, burning in the feet (particularly severe at
night), muscle cramps in the calves, pains in the
legs, and plantar dysesthesias.
Calf muscle tenderness, difficulty rising from a
squatting position, and decreased vibratory
sensation in the toes are early signs
Continued deficiency worsens polyneuropathy,
which can eventually affect the arms.

Dry Beriberi
Deficiency causes degeneration of peripheral nerves,
thalamus, mammillary bodies, and cerebellum.

Cardiovascular (wet) beriberi
Wet beriberi is the term used for the
cardiovascular involvement of thiamine deficiency.
The first effects are vasodilatation, tachycardia, a
wide pulse pressure, sweating, warm skin, and
lactic acidosis.
Later, heart failure develops, causing orthopnea
and pulmonary and peripheral edema.
Vasodilatation can continue, sometimes
resulting in shock.

Cardiovascular (wet) beriberi
"Pedal edema before and after the application of
pressure to the shin."

Infantile beriberi
Infantile beriberi
occurs in infants (usually
by age 3 to 4 wk) who
are breastfed by
thiamine-deficient
mothers.
Heart failure (which
may occur suddenly),
aphonia, and absent
deep tendon reflexes are
characteristic.

Shoshin beriberi
Shoshin beriberi A more rapid form of wet
beriberi is termed acute fulminant
cardiovascular beriberi, or Shoshin beriberi.
The predominant injury is to the heart, and
rapid deterioration follows the inability of the
heart muscle to satisfy the body's demands
because of its own injury.
 In this case, edema may not be present.
Instead, cyanosis of the hands and feet,
tachycardia, distended neck veins, restlessness,
and anxiety occur.

Wernicke-Korsakoff syndrome
Wernicke-Korsakoff syndrome, which
combines Wernicke's encephalopathy and
Korsakoff's psychosis occurs in some alcoholics
who do not consume foods fortified with
thiamine.
Wernicke's encephalopathy consists of
psychomotor slowing or apathy, nystagmus,
ataxia, ophthalmoplegia, impaired
consciousness, and, if untreated, coma and
death.

Korsakoff psychosis
Korsakoff psychosis
consists of mental
confusion, dysphonia,
and confabulation with
impaired memory of
recent events.
 It probably results
from chronic deficiency
and may develop after
repeated episodes of
Wernicke's
encephalopathy.

Causes of thiamine deficiency
Lack of thiamine intake
Food containing a high level of thiaminase,
including milled rice, raw freshwater fish, raw
shellfish, and ferns
Food high in anti-thiamine factor, such as tea,
coffee, and betel nuts
Processed food with a content high in sulfite,
which destroys thiamine
Alcoholic state
Starvation state

Causes of thiamine deficiency (
contd.)
Increased consumption states
Diets high in carbohydrate or saturated fat
intake
Pregnancy
Hyperthyroidism
Lactation
Fever - severe infection
Increased physical exercise

(contd.)
Increased depletion
Diarrhea
Diuretic therapies
Peritoneal dialysis
Hemodialysis
Hyperemesis gravidarum

(contd.)
Decreased absorption
Chronic intestinal disease
Alcoholism
Malnutrition
Gastric bypass surgery
Malabsorption syndrome -
Celiac and tropical sprue

Laboratory Studies in thiamine
deficiency
Diagnosis is usually based on a favorable
response to treatment with thiamine in a patient
with symptoms or signs of deficiency.
Electrolytes, including Mg, should be
measured to exclude other causes.
For confirmation in equivocal cases,
erythrocyte Transketolase activity and 24-h
urinary thiamine excretion may be measured.
Diagnosis of cardiovascular beriberi can be
difficult if other disorders that cause heart
failure are present.

Treatment of Thiamine deficiency
Supplemental thiamine, with dose based on
clinical manifestations
For mild polyneuropathy, thiamine 10 to 20
mg once/day is given for 2 wk.
For moderate or advanced neuropathy, the
dose is 20 to 30 mg/day; it should be
continued for several weeks after symptoms
disappear.
For edema and congestion due to
cardiovascular beriberi, thiamine 100 mg IV
once/day is given for several days.

Prognosis of Beriberi
The prognosis for beriberi is usually
good, unless patients have established
Korsakoff syndrome.
 When patients have progressed to this
stage, the degree of damage is only
minimally reversible.

Summary Beriberi
Thiamine deficiency (causing beriberi) is most common among
people subsisting on white rice or highly refined carbohydrates in
developing countries and among alcoholics.
Symptoms include diffuse polyneuropathy, high-output heart
failure, and Wernicke-Korsakoff syndrome.
Diagnosis is usually based on a favorable response to treatment
with thiamine in a patient with symptoms or signs of deficiency.
 For confirmation in equivocal cases, erythrocyte transketolase
activity and 24-h urinary thiamin excretion may be measured.
Because thiamine deficiency often occurs with other B vitamin
deficiencies, multiple water-soluble vitamins are usually given for
several weeks

Therapeutic uses of Thiamine
Thiamine deficiency
Thiamine is also used for digestive problems including
poor appetite, ulcerative colitis, and ongoing diarrhea.
also used for AIDS and boosting the immune system,
diabetic pain, heart disease, alcoholism, aging, vision
problems such as cataracts and glaucoma, motion
sickness, and improving athletic performance.
Other uses include preventing cervical cancer and
progression of kidney disease in patients with type 2
diabetes.

Thiamine

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