Water soluble vitamins -B1

WATER SOLUBLE VITAMINS
VITAMIN-B1 (THIAMINE)
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VITAMINS
Vitamins may be regarded as organic
compounds required in the diet in small
amounts to perform specific biological
functions for normal maintenance of
optimum growth and health of the
organism.
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WATER SOLUBLE VITAMINS
MRIMS
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DEFICIENCY OF VITAMINS MAY OCCUR DUE TO
a. Reduced intake
b. Impaired absorption
c. Impaired metabolism
d. Additional requirements
e. Increased losses.
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THIAMINE (VITAMIN B1)
Thiamine is also called as vitamin B1
Aneurine (it can relieve neuritis) or antiberberi
factor.
Christian Eijkman produced beriberi in chicken by
feeding polished rice .
Adolf Windaus elucidated the structure of the
vitamin.
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SOURCES
Aleurone layer of cereals (food grains) is a rich
source of thiamine.
whole wheat flour and unpolished handpound rice
have better nutritive value than completely
polished refined foods.
When the grains are polished, aleurone layer is
usually removed.
 Yeast is also a very good source.
Thiamine is partially destroyed by heat.
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STRUCTURE OF THIAMINE
Thiamine contains a substituted pyrimidine ring
connected to a substituted thiazole ring by
means of methylene bridge.
The vitamin is then converted to its active co-
enzyme form by addition of two phosphate
groups, with the help of ATP .
 It is catalyzed by thiamine pyrophospho
transferase.
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Vitamin B1
It is required for the essential decarboxylation
reactions catalyzed the pyruvate and 2-
oxoglutarate by omplexes.
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Chemistry
 The structure of thiamine [3-(4-amino-2-methyl-pyrimidyl-5-
methyl)-4-methyl-5-(β-hydroxyethyl)thiazole] is that of a
pyrimidine ring, bearing an amino group, linked by a
methylene bridge to a thiazole ring .
 The thiazole has a primary alcohol side chain at C5, which can
be phosphorylated in vivo to produce thiamine phosphate
esters, the most common of which is TPP (also known as
thiamine diphosphate [cocarboxylase]).
 Monophosphate and triphosphate esters also occur.
 The basic vitamin is isolated or synthesized and handled as a
solid thiazolium salt (eg, thiamine chloride hydrochloride).
 Thiamine is somewhat heat labile, particularly in alkaline
solutions, where base attacks occur at C2 of the thiazolium
ring.
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Dietary Sources
Small amounts of thiamine and its phosphates
are present in most plant and animal tissues,
but more abundant sources include unrefined
cereal grains, liver, heart, kidney, and lean cuts
of pork.
The enrichment of flour and derived food
products, particularly breakfast cereals, has
considerably increased the availability of this
vitamin.
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tranketolase
• (0-15% normal, 15-25% deficiency, >25%
severe deficiency)
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2-methyl 4 –amino,5 methyl (pyrimidine),2-methyl,3-ethyl
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PHYSIOLOGICAL ROLE OF THIAMINE
i. Pyruvate dehydrogenase: The co-enzyme for is
thiamine pyrophosphate(TPP).
 It is used in oxidative decarboxylation of alpha
keto acids, e.g. pyruvate dehydrogenase
catalyzes the breakdown of pyruvate, to acetyl
CoA, and carbon dioxide.
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(a) TPP is the coenzyme form of
vitamin B1 (thiamine). The reactive
carbon atom in the thiazolium ring of
TPP is shown in red. In the reaction
catalyzed by pyruvate decarboxylase,
two of the three carbons of pyruvate
are carried transiently on TPP in the
form of a hydroxyethyl, or “active
acetaldehyde,” group.
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(b), which is subsequently
released as acetaldehyde.
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The thiazolium ring of TPP
stabilizes carbanion
intermediates by providing an
electrophilic (electrondeficient)
structure into which the
carbanion electrons can be
delocalized by resonance.
Structures with this property,
often called “electron sinks,” play
a role in many biochemical
reactions—here, facilitating
carbon–carbon bond cleavage.
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ii. Alpha ketoglutarate dehydrogenase: An
analogousbiochemical reaction that requires TPP is
the oxidative decarboxylation of alpha
ketoglutarate to succinyl CoA and CO2 (See citric
acid cycle).
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iii. Transketolase: The second group of enzymes that
use TPP as co-enzyme are the transketolases, in the
hexose monophosphate shunt pathway of glucose .
iv. The main role of thiamine (TPP) is in carbohydrate
metabolism. So, the requirement of thiamine is
increased along with higher intake of
carbohydrates.
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DEFICIENCY MANIFESTATIONS OF THIAMINE
A. Beriberi
B. Wet beriberi
C. Dry beriberi
D. Inantile beriberi
E. Wenicke-Korsakoff syndrome (cerebral beriberi)
F. Polyneuritis
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BERIBERI
Deficiency of thiamine leads to beriberi.
It is a Singhalese word, meaning “weakness”.
The
early symptoms are anorexia, dyspepsia,
heaviness
and weakness. Subjects feel weak and get
easily
exhausted.
4/3/2020 40

BERIBERI continue…………..
B. Wet beriberi: Here cardiovascular manifestations
are prominent. Edema of legs, face, trunk and
serous cavities are the main features.
Palpitation, breathlessness and distended neck
veins are observed. Death occurs due to heart
failure.
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BERIBERI continue…………..
C. Dry beriberi: In this condition, CNS manifestations
are the major features.
Walking becomes difficult.
Peripheral neuritis with sensory disturbance leads
to complete paralysis.
D. Infantile beriberi: It occurs in infants born to
mothers suffering from thiamine deficiency.
Restlessness and sleeplessness are observed.
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E. Wernicke-Korsakoff syndrome:
It is also called as cerebral beriberi.
Clinical features are those of encephalopathy
(ophthalmoplegia, nystagmus, cerebellar ataxia)
plus psychosis.
It is seen only when the nutritional status is
severely affected.
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Wernicke-Korsakoff Syndrome Is Exacerbated by a
Defect in Transketolase continue….
alcoholism than in the general population, because
chronic, heavy alcohol consumption interferes with
the intestinal absorption of thiamine.
 The syndrome can be exacerbated by a mutation in
the gene for transketolase that results in an enzyme
with a lowered affinity for TPP—an affinity one-
tenth that of the normal enzyme.
This defect makes individuals much more sensitive
to a thiamine deficiency.
The result is a slowing down of the whole pentose
phosphate pathway.
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WERNICKE ENCEPHALOPATHY &
KORSAKOFF SYN DROME
 Wernicke encephalopathy i s characterized b y confusion, ataxia,
and nystagmus leading to ophthalmoplegia (lateral rectus muscle
weakness, conjugate gaze palsies) ;
 peripheral neuropathy may also be present. It is due to thiamine
deficiency and in the patients with alcoholism.
 It may also occur in patients with AIDS or hyperemesis
gravidarum, and after bariatric surgery.
 In suspected cases, thiamine ( 1 00 mg) is given intravenously
immediately and then intramuscularly on a daily basis until a
satisfactory diet can be ensured.
 Korsakoff syndrome occurs in more severe cases; it includes
anterograde and retrograde amnesia and sometimes
confabulation, and may not be recognized until after the initial
delirium has lifted.4/3/2020 45

WKS
Glucose administration increases the thiamine
requirement and can precipitate Wernicke-
Korsakoff syndrome if thiamine is not co
administered.
Parenteral nutrition without thiamine causes
severe refractory lactic acidosis from deranged
pyruvate metabolism.
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F. Polyneuritis:
It is common in chronic alcoholics.
Alcohol utilization needs large doses of
thiamine.
Alcohol inhibits intestinal absorption of
thiamine, leading to thiamine deficiency.
Polyneuritis may also be associated with
pregnancy and old age.
 Thiamine deficiency in alcoholism may cause
impairment of conversion of pyruvate to acetyl
CoA.
Increased plasma concentration of pyruvate and
lactate, leading to lactic acidosis.4/3/2020 47

Biochemical Parameters
blood thiamine is reduced, but pyruvate, alpha
ketoglutarate and lactate are increased.
Erythrocyte transketolase activity is reduced.
Erythrocyte transketolase levels may be reduced in
comatose patients, alcoholics, chronic renal failure,
malnutrition as well as in elderly patients.
A lipid soluble acylated derivative (benfotiamine) is
now being recommended for diabetic patients to
decrease glycation of proteins (AGE) and to improve
diabeteic neuropathy.
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ANTITUMOR DRUG
The thiamine analog oxythiamine, which blocks the
action of a transketolase-like enzyme that converts
xylulose 5-phosphate to glyceraldehyde 3-
phosphate is in preclinical trials as an antitumor
drug.
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Absorption, Transport, Metabolism, and
Excretion
 proximal smallintestine by a saturable (thiamine transporter)
process at a low concentration (≤1 μmol/L) and by simple passive
diffusion beyond that, although percentage absorption diminishes
with an increased dose.
 Absorbed thiamine undergoes intracellular phosphorylation,
mainly to the pyrophosphate, but at the serosal side, 90% of
transferred thiamine is present in the free form.
 Thiamine uptake is enhanced by thiamine deficiency and is
reduced by thyroid hormone, diabetes, and ethanol ingestion.
 Thiamine is carried by portal blood to the liver.
 The free vitamin is present in plasma, but the coenzyme, TPP, is
the primary cellular component. Approximately 30 mg is stored in
the body, with 80% as pyrophosphate, 10% as triphosphate, and
the rest as thiamine and its monophosphate.
 About half of body stores are found in skeletal muscle, with much
of the remainder in the heart, liver, kidneys, andnervous tissues
(including the brain, which contains most of the triphosphate).4/3/2020 51

Absorption, Transport, Metabolism, and Excretion
continue………………..
 The three tissue enzymes known to participate in the formation of
phosphate esters are (1) thiaminokinase (a pyrophosphokinase),
which catalyzes formation of TPP and adenosine monophosphate
(AMP) from thiamine and adenosine triphosphate (ATP).
 (2) TPP-ATP phosphoryltransferase (cytosolic 5′-adenylic kinase),
which forms the triphosphate and adenosine diphosphate from
TPP and ATP.
 (3) thiamine triphosphatase, which hydrolyzes TPP to the
monophosphate.
 Although thiaminokinase is widely distributed in the body,
phosphoryl transferase and the membrane-associated
triphosphatase are found mainly in nervous tissue.
 With the use of labeled thiamine probes, a study of thiamine
metabolism at normal loads produced an estimated half-life of
thiamine of 9.5 to 18.5 days, and showed a large number of
breakdown products in the urine.
 Several of these urinary catabolites are shown in Fig.4/3/2020 52

Functions
 Thiamine is required by the body as the pyrophosphate (TPP) in two
general types of reactions: (1) the oxidative decarboxylation of 2-oxo
acids catalyzed by dehydrogenase complexes; and
 (2) the formation of α-ketols (ketoses) as catalyzed by transketolase
and as the triphosphate (TTP) within the nervous system.
 TPP functions as the magnesium (Mg)-coordinated coenzyme for the
active aldehyde transfers in multienzyme dehydrogenase complexes
that affect decarboxylative conversion of α-keto (2-oxo) acids to acyl-
coenzyme A (acyl-CoA) derivatives, such as pyruvate dehydrogenase
and α-ketoglutarate dehydrogenase.
 These are often localized in the mitochondria, where efficient use in
the Krebs tricarboxylic acid (citric acid) cycle follows.
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Functions
Three types of subunit proteins constitute such
dehydrogenase complexes: (1) a TPP-dependent
decarboxylase, which converts the 2-oxo acid to an α-
hydroxyalkyl–TPP complex;
(2) a transacylase core, which contains lipoyl residues
that are acylated by the α-hydroxyalkyl–TPP.
 (3) a flavin adenine dinucleotide (FAD)-dependent
dihydrolipoyl dehydrogenase, which re-oxidizes the
reduced lipoyl residues produced after transfer of their
acyl functions to reduced CoA.
 the initial pyruvate dehydrogenase–catalyzed step
provides acetyl-CoA as a biosynthetic precursor to lipids
and acetylcholine of the parasympathetic nervous
system.4/3/2020 56

Functions
Transketolase is a TPP-dependent enzyme found in
the cytosol of many tissues, especially liver and
blood cells, in which the principal carbohydrate
pathways exist.
 In the pentose phosphate pathway, which
additionally supplies reduced nicotinamide-adenine
dinucleotide phosphate (NADPH) necessary for
biosynthetic reactions.
 this enzyme catalyzes the reversible transfer of a
glycoaldehyde moiety from the first two carbons of a
donor ketose phosphate to the aldehyde carbon of
an aldose phosphate.
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Functions
 thiamine as its pyrophosphate contributes to nervous system
composition and function in such essential reactions as
energy production and biosynthesis of lipids and
acetylcholine, a further specific, non-cofactor role for
thiamine has been proposed in excitable cells.
 TTP is believed to be involved in the regulation of ion
channels, specifically, chloride channels of large unitary
conductance (the “maxi-chloride channels”).
 TTP may also have more basic metabolic functions, including
acting as a phosphate donor for the phosphorylation of
proteins, suggesting a potential role in cell signaling.
 A subacute necrotizing encephalomyelopathy has been seen
in patients with Leigh syndrome, resulting from the presence
of an inhibitor of TPP-ATP phosphoryl transferase and a
consequent reduction in TTP concentration.4/3/2020 58

Requirements and Reference Nutrient
Intakes
 Thiamine is necessary mainly for the metabolism of
carbohydrates, fats, and alcohol, a direct correlation has been
noted between physiologic requirements and the amount of
metabolizable food intake.
 A greater requirement is present under situations in which
metabolism is increased (eg, in normal conditions of
increased muscular activity, pregnancy, and lactation, and in
abnormal cases of protracted fever, posttrauma, and
hyperthyroidism).
 Clinical signs of deficiency in adults can be prevented with
intakes of thiamine of more than 0.15 to 0.2 mg/1000 kcal,
but 0.35 to 0.4 mg/1000 kcal may be closer to a
concentration necessary to maintain urinary excretion and
TPP-dependent erythrocyte transketolaseactivity within
normal reference intervals.
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RDA
1.2 mg/day for men 19 years and older and 1.1 mg/day
for women 19 years and older.
The requirement for pregnant women increases early in
pregnancy and then remains constant; 1.4 mg/day is
recommended.
 The lactating woman secretes 0.1 to 0.2 mg of
thiamine/day in milk, so 1.4 mg/day is suggested.
 Based on the thiamine content of human milk and with
an increment considered to provide a margin of safety,
0.2 mg/day is the allowance for infants up to 6 months,
and 0.3 mg/day for infants 7 to 12 months.
 For children, due to growth, 0.5 mg/day is suggested
for up to 3 years of age, and between 4 and 8 years, 0.6
mg/day is suggested.4/3/2020 60

Intravenous Supply
Traditionally, the intravenous recommendation was
3 mg/ day for adults, usually provided as thiamine
hydrochloride, but also as thiamine mononitrate or
tetrahydrate.
this was increased to 6 mg/ day, with recognition of
the likelihood of increased demands for thiamine
caused by hypercatabolism in such patients and the
serious potential complications o deficiency.
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Deficiency
 Inadequate intake caused by diets largely dependent
on milled, nonenriched grains such as rice and wheat.
Raw fish containing thiaminases, which hydrolytically
destroyt the vitamin in the gastrointestinal tract.
Tea may also contain anti-thiamine factors.
 Chronic alcoholism often leads to thiamine deficiency
caused by reduced intake, impaired absorption,
impaired use, and reduced storage, and may lead
clinically to the Wernicke-Korsakoff syndrome.
 who receive parenteral nutrition without adequate
thiamine supplementation, older adult patients taking
diuretics,and patients undergoing long-term renal
dialysis.
4/3/2020 62

DEFICIENCY
 In infants symptoms appear suddenly and severely, often involving cardiac
failure and cyanosis.
 Commonly, the distinction between wet (cardiovascular) and dry (neuritic)
manifestations of beriberi relate to duration and severity of the deficiency,
the degree of physical exertion, and caloric intake.
 The wet or edematous beriberi results from severe physical exertion and
high carbohydrate intake.
 the dry or polyneuritic beriberi stems from relative inactivity with caloric
restriction during a long-term deficiency.
 cardiovascular system are peripheral vasodilatation leading to a high-output
state, biventricular myocardial failure, and retention of sodium (Na) and
water, leading to edema.
 Nervous system involvement includes peripheral neuropathy, Wernicke
encephalopathy, and the amnesic psychosis of Korsakoff syndrome.
 More rarely, but especially in seriously ill patients in hospitals, an acute
form of cardiac failure has been described (Shoshin beriberi), which may be
fatal, but can be successfully and rapidly reversed with high-dose
intravenous thiamine.4/3/2020 63

DEFICIENCY
Beriberi (origin: Sinhalese from a word meaning
weakness) is the disease that results from thiamine
deficiency.
Clinical signs of thiamine deficiency primarily
involve the nervous and cardiovascular systems. In
the adult, the most frequently observed symptoms
include mental confusion, anorexia, muscular
weakness, ataxia, peripheral paralysis,
ophthalmoplegia, edema (wet beriberi),.
muscle wasting (dryberiberi), tachycardia, and an
enlarged heart.
4/3/2020 64

DEFICIENCY
 In thiamine-responsive megaloblastic anemia, the gene has
been mapped and cloned, and designated as SLC19A2 as a
member of the solute carrier gene superfamily.
 Mutations of this gene, the product of which is a membrane
protein that transports thiamine with submicromolar affinity,
have been found in all thiamine-responsive megaloblastic
anemia kindreds studied.
 Thiamine-responsive pyruvate dehydrogenase complex
deficiency, which presents with lactic acidosis, can be caused
by a point mutation within the TPP-binding region .
 and a thiamine-responsive, branched-chain keto acid
dehydrogenase complex deficiency, which presents as a form
of maple syrup urine disease, is caused by mutations in the E1
α-subunit of the enzyme complex.
 Therapeutic doses of 5 to 20 mg/day of thiamine have proved
beneficial in these cases.
4/3/2020 65

Toxicity
stimulators of transketolase enzyme synthesis, such
as thiamine, support the high rate of nucleic acid
ribose synthesis necessary for tumor cell survival,
chemotherapy resistance, and proliferation.
4/3/2020 66

Laboratory Assessment of Status
A rapid HPLC method for measuring both
thiamine and its phosphate esters .
Measurements of certain urinary metabolites,
thiamine acetic acid, have been suggested as
reflecting thiamine status but are not
routinely requested.
4/3/2020 67

Preanalytical Variables
 Whole blood collected into containers with the
preservatives Li heparin or ethylenediaminetetraacetic acid
(EDTA) is recommended.
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Reference Intervals
(1) erythrocytes, whole blood, or plasma is used as a
sample; (2) cellular concentrations are expressed per
liter of packed red cells or grams of Hb.
 erythrocyte transketolase activity, 0.75 to 1.30 U/g Hb
(48.4–83.9 kU/ mol Hb) is used.
 Percent TPP effect (activation), 0% to 15% is normal,
16% to 25% is marginally deficient, and more than 25%
is severely deficient with clinical signs.
For direct TPP : 173 to 293 nmol/L for erythrocytes and
90 to 140 nmol/L for whole blood, 280 to 590 ng/g Hb
in erythrocytes, and 275 to 675 ng/g Hb in whole blood
with less than 150 ng/g Hb indicating clinical deficiency.
4/3/2020 69

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