Thiamin (Vitamin B1)

Structure
Functions
Metabolism
Sources
Requirements
Deficiency
Toxicity

I.  Structure

II.  Functions

1. Energy transformation
   1. TDP is a coenzyme necessary for oxidative decarboxylation of pyruvate and alpha-keto glutarate
      1. These reactions instrumental in generating ATP
      2. Inhibition of these reactions prevents synthesis of ATP and acetyl CoA
      3. Needed for synthesis of fatty acids and cholesterol among others
      4. Pyruvate and a-ketoglutarate accumulate in the blood
   2. Oxidative decarboxylation of pyruvate requires a multienzyme complex, pyruvate dehydrogenase complex
      1. TDP dependent pyruvate decarboxylase
      2. Lipoic acid-dependent dihydrolipoyl transacetylase (Lipoic acid, a sulfur-containing fatty acid, functions as a prosthetic group but is not considered a vitamin)
      3. FAD-dependent dihydrolipoyl dehydrogenase
   3. Four vitamins involved in this decarboxylation process can be identified
      1. Thiamin (TDP)
      2. Riboflavin (FAD)
      3. Niacin (NAD⁺)
      4. Pantothenic acid (CoA)
   4. Decarboxylation of a-ketoglutarate to form succinyl CoA is similar to decarboxylation of pyruvate
   5. Decarboxylation of branched-chain a -ketoacids which arise from transamination of valine, isoleucine and leucine requires thiamin as TPD
      1. Failure to oxidize the a-ketoacids results in their accumulation in body fluids
      2. Deficiency of the branched-chain a-ketoacid dehydrogenase enzyme complex results in maple syrup urine disease (MSUD), an inborn error of metabolism
      3. Individuals with MSUD must avoid meat, poultry, fish, and dairy products in order to limit intakes of valine, isoleucine, and leucine
2. Synthesis of NADPH and Pentoses
   1. TDP functions as a prosthetic group of transketolase, a key cytosolic enzyme in the hexose monophosphate shunt
      1. Pathway in which sugars of varying chain lengths are interconverted
      2. Generation of pentoses for nucleic acid synthesis
      3. Generation of NADPH
   2. TDP forms a carbon ion that acts to transfer an activated aldehyde from a donor ketose substrate to an acceptor
      Xylulose 5-P + ribose – 5P¬^Mg+2® sedoheptulose 7-P + glyceraldkehyde 3-P
                                                                        ^{transketolase}
      Xylulose 5-P + erythrose – 4-P¬^Mg+2® glyceraldehyde 3-P + fructose 6-P
                                                                              ^{transketolase}
   3. Membrane and nerve conduction
      1. Thiamin triphosphate (TTP) may be the form involved
      2. It is believed to exert its action in some manner other than as a coenzyme
      3. Possible causes of aberrations in nerve function
         1. Lack of energy (thiamin necessary for energy transformation)
         2. Decreased amount of acetylcholine (TDP required for synthesis of acetylcholine)
         3. Reduced nerve impulse transmission (TDP or TPP occupying a site on the nerve membrane may regulate nerve impulse transmission

III.  Metabolism

1. Absorption and transport
   1. Intestinal phosphatases hydrolyze phosphates from thiamin prior to absorption
   2. Free thiamin is absorbed from the intestine
      1. At low concentrations, thiamin absorption is active and Na dependent
      2. When intake is high, absorption is predominately passive
   3. Within the mucosal cells, thiamin may be phosphorylated
   4. Thiamin transport across the basolateral membrane is Na and energy dependent
   5. Thiamin appearing on the serosal side is not initially bound to phosphates
   6. In the blood, thiamin is in the form of thiamin monophosphate (TMP)
   7. Thiamin may be bound to albumin for transport in plasma
   8. Only free thiamin or TMP is thought to cross cell membranes in tissues
   9. Distribution of thiamin
      1. About half is distributed throughout skeletal muscle
      2. About 80% of total thiamin in body exists as TDP
      3. About 10% is TTP
2. Excretion
   1. Thiamin in excess of need and storage capacity is metabolized for urinary excretion
      1. Thiamin is degraded by thiazole cleavage
      2. At low intake excretion is primarily as the metabolites
      3. As intake increases, excretion of free thiamin increases

IV.  Sources

1. Yeast, lean pork, legumes, whole grains
2. Thiamin in cereal grains is found especially in the outer layers
3. Form of thiamin in foods
   1. Free thiamin in vegetable products
   2. Phosphate or pryophosphate in animal tissues
4. Beriberi is a disease in countries in which a large part of the population depend on polished rice or cassava for a main source of calories

V.  Requirements

1. Factors which increase thiamine requirement
   1. Thiaminases which catalyze cleavage of thiamin, destroying its activity
      1. Present in several species of fish. Foxes fed raw fish develop a paralysis (Chastex paralysis)
      2. Horses fed feed containing large amounts of bracken fern (Pteris aquilina) develop signs of polyneuritis which can be cured with thiamin
      3. Cerebrocortical necrosis or polioencephalomalacia in cattle fed large quantities of grain.  Microorganisms may produce thiaminases during abnormal rumen fermentation
   2. Tannic and caffeic acids found in coffee, tea, betel nuts, blueberries, black currants, brussels sprouts, red cabbage
   3. Ca⁺² and Mg⁺² assist in precipitation of thiamin by tannic acid
   4. Destruction of thiamin can be prevented by reducing agents such as vitamin C and citric acid
   5. Ethanol interferes with absorption of thiamin
2. Physiological factors affecting thiamin requirement
   1. Body size
   2. Thyroid status
   3. Pregnancy and lactation
   4. Fever, infection, chronically ill
   5. Heavy work if extra carbohydrate is metabolized
3. Recommended allowance
   1. Human...........0.25-.5 mg/100 Kcal intake
   2. Pigs................0.6 mg/lb feed
   3. Chickens........0.8 mg/lb feed

VI.  Deficiency

1. Deficiency conditions result primarily from insufficient utilization of glucose. (Thiamine is important for pyruvate to enter the TCA cycle.)
   1. GI tract: anorexia, indigestion, severe constipation
   2. Nervous system:
      1. Impaired neuronal activity, diminished alertness and reflexes
      2. Lipogenesis is retarded so myelin sheaths of nerves degenerate causing nerve irritation, pain, prickly or deadening sensations, paralysis
   3. Cardiovascular system:
      1. Weakened heart muscle and cardiac failure
      2. Edema in extremities
2. Deficiency symptoms
   1. Humans
      1. Infantile beriberi - sudden onset of symptoms - rigidity of the body, whining, constipation, weakness, edema, cardiac enlargement, rapid and irregular pulse and cyanosis, sudden death if undetected
      2. Adult, chronic dry type - muscle tenderness, burning feet, diminished reflexes, muscle atrophy, mental confusion, peripheral neuritis or neuropathy
      3. Adult, wet type - Edema, congestive heart failure with enlargement of the heart, high cardiac output with ultimate cardiac failure
   2. Birds
      1. Loss of appetite, emaciation, impairment of digestion
      2. Polyneuritis, convulsions, head retraction
   3. Other species
      1. Anorexia, emaciation
      2. Slowed pulse rate, lowered body temperature
      3. Polyneuritis

VII.  Toxicity

1. Certain metabolic diseases may respond to large doses of thiamin
   1. Maple syrup urine disease
   2. Thiamin-responsive megaloblastic anemia
   3. Thiamin-responsive lactic acidosis
2. Thiamin toxicity associated with oral intake of large amounts is unlikely (500 mg/day for one month)
3. 100 times recommendation by parenteral route has been associated with headache, convulsions, cardiac arrhythmia, and anaphylactic shock

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