from protein and salts, which is indispensable to health
and the lack of which causes nutritional polyneuritis"
Vitamin B1 is also known as thiamine, thiamin and aneurin. Thiamine is the currently accepted name for vitamin B1 in the US. Aneurin is still widely used in Europe, especially in the United Kingdom. The chemical name for this water souble vitamin is 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]- 5-(2-hydroxyethyl)-4-methylthiazolium. Thiamine consist of a pyrimidine ring and a thiazole ring connected by a one carbon link. The nitrogen in the thiazole ring has a charge of +1. This nitrogen atom serves as an important electron sink in thiamine pyrophosphate mediated reactions (see below).
The history of thiamine begins with investigations into
the cause of the disease beri-beri. The first insight to the true cause
of beri-beri came in the 1880s when Dr. K. Takaki, at the time Director General
of the Japanese Naval Medical Services, noticed a correlation between the diet
of sailors and beri-beri. Takaki discovered "...that the nitrogenous
substances contained in the food were not sufficient to maintain nitrogen
metabolism...". Takaki ordered an increase of vegetables, barley,
fish and meat at the expense of rice in daily rations. The incidence of
beri-beri in the Japanese Navy dropped from 40% to 0% in six years. These
results were so convincing that the Japanese Army adopted the diet and by 1890
Takaki's diet was written into law.
While Dr. Takaki's findings did much to improve the health of the Japanese military, they did little to eradicate beri-beri in the rest of Asia. Due to Louis Pasteur's recent successes with the microbial causes of diseases, most of the medical community thought beri-beri was the result of a microbial infection or a toxin produced by a microorganism. The Dutch medical officer Dr. Christian Eijkman held this view as he began investigating beri-beri at a military hospital Batavia, Java in the Dutch East Indies (now Jakarta, Indonesia) in 1886. After months of searching for a toxic or microbial link to beri-beri he noticed certain chickens outside his laboratory were inflicted with a beri-beri like aliment. He named the disease polyneuritis gallinarum, and from pathological studies of myelin sheath degeneration of both human and fowl victims he concluded that polyneuritis gallinarum was an animal model for beri-beri. After consulting the hospital records and conducting experiments Eijkman discovered that chickens fed white (polished or milled) rice developed polyneuritis whereas red (partially polished) rice, unhusked rice (padi) and rice hulls prevented and even cured the disease. Eijkman and his colleague, Dr. Gerrit Grijns, showed that an "anti-polyneuritis factor" could be extracted from rice hulls with water or ethanol. Eijkman believed that this water soluble anti-polyneuritis factor was a "pharmacological antidote" to the "beri-beri microbe" present in the rice endosperm (white part of rice). Grijns, however, leaned toward the theory that white rice "lacked a certain substance of importance in the metabolism of the central nervous system".
In 1911 a young chemist at the Lister Institute in London named Dr. Casimir Funk crystallized an amine substance from rice bran. He was sure this was the anti-beri-beri factor and dubbed it "vitamine" for "vital amine". Though these crystals soon proved to have little antineuritic activity (it is now believed Funk crystallized nicotinic acid), the name stuck. About the same time U.S. Army Medical Officer Captain Edward B. Vedder became convinced by the work of Eijkman and Grijns and others that beri-beri was indeed caused by a nutritional deficiency. Vedder enlisted the help of Dr. Robert R. Williams of the Bureau of Science in Manila in isolating the anti-beri-beri factor. Though Williams worked diligently for over 25 years, often using his own money to fund the research, it was two Dutch chemists, Dr. B. C. P. Jansen and Dr. W. Donath, working in Eijkman's old laboratory, who finally crystallized vitamin B1 from rice bran in 1926. They named it aneurin for antineuritic vitamin. Unfortunately Jansen and Donath missed the sulfur atom, and their published incorrect formula for aneurin caused confusion for several years. It was Williams who published the first correct formula and synthesis for the vitamin in 1936. The American Medical Association did not accept any of the names by which it was known (anti-beriberi factor, anti-beri-beri vitamin, antineuritic vitamin, vitamin B, vitamin B1, etc.) for inclusion in their New and Non-Official Remedies list. Without inclusion in the list Williams' compound could not be advertised in reputable medical journals. The AMA asked Williams to come up with a new name and he choose "thiamin". To reflect the vitamin's amine nature the American Chemical Society added an "e" and the name "thiamine" is now accepted.
A major biologically active form of thiamine is thiamine pyrophosphate (TPP), sometimes called thiamine diphosphate (TDP) and cocarboxylase. In thiamine pyrophosphate the hydroxyl group of thiamine is replaced by a diphosphate ester group. The reaction site of TPP is carbon 2 of the thiazole ring. The proton on this carbon is rather acidic. When this proton dissociates a carbanion is formed which readily undergoes nucleophilic addition to carbonyl groups. TPP is a coenzyme for two types of enzymes, alpha-ketoacid dehydrogenases and transketolases, both of which cleave a C-C bond adjacent to a carbonyl group releasing either carbon dioxide or an aldehyde. The resulting product is then transferred to an acceptor molecule. alpha-Ketoacid dehydrogenases decarboxylate alpha-ketoacids. The decarboxylation product is then transferred to coenzyme A (CoA). Transketolases cleaves the C-C bond adjacent to the carbonyl group of an alpha-ketosugar to give an activated glycoaldehyde. The glycoaldehyde is then combined with an aldose to give a new ketose. All known TPP dependent enzymes also require a divalent cation, commonly Mg2+.
The mechanism is identical for both the conversion of pyruvate to acetyl CoA and the conversion of alpha-ketoglutarate to succinyl CoA. In the reaction, the proton on C2 of TPP dissociates to give a carbanion. Nucleophilic addition by the carbanion to the carbonyl group of the alpha-ketoacid (i. e. pyruvate or alpha-ketoglutarate) followed by protonation forms an activated alpha-hydroxyacid. The hydroxyacid then undergoes decarboxylation. The positively charged nitrogen of TPP serves as a critical electron sink during the decarboxylation step and contributes to the resonance stabilization of the hydroxyalkyl-TPP decarboxylation product. The hydroxyalkyl group is transferred by other proteins in the complex to CoA to produce acetyl CoA from pyruvate or succinyl CoA from alpha-ketoglutarate.
The pentose phosphate pathway harvests energy from fuel molecules and stores it in the form of NADPH. NADPH (reduced nicotinamide adenine dinucleotide phosphate) is an important electron donor in reductive biosynthesis. The pentose phosphate pathway also produces 5-carbon sugars such as ribose which is used in the synthesis of DNA and RNA. TPP is the coenzyme for the enzyme transketolase. Transketolase transfers a 2-carbon unit from an alpha-ketose (a sugar with a carbonyl group at position 2) to an aldose. In the reaction below a 2-carbon unit from the 5-carbon alpha-ketose xylulose 5-phosphate is transferred to the 4-carbon aldose erythrose 4-phosphate to make the 6 carbon alpha-ketose fructose 6-phosphate. Glyceraldehyde 3-phosphate results from the 3-carbon fragment that is cleaved from xylulose 5-phosphate. Note that fructose 6-phosphate and glyceraldehyde 3-phosphate (the products of the forward reaction) are an alpha-ketose and an aldose and that the reaction is reversible.
In the reaction, a carbanion at C-2 of TPP is first produced. This carbanion attacks the carbonyl carbon of the alpha-ketose to give an addition product. After deprotonation of the appropriate hydroxyl group an aldose (in this case glyceraldehyde 3-phosphate) is released and an activated glycoaldehyde bound to TPP is produced. As with the decarboxylation mechanism discussed above, the thiazole nitrogen serves as electron sink in the reaction and contributes to resonance stabilization of the resulting product (activated glycoadehyde). This glycoaldehyde is said to be activated because it is also a carbanion and readily undergoes nucleophilic addition to the carbonyl group of an aldose (erythrose 4-phosphate here). Following another deprotonation the nascent alpha-ketose is released from TPP.
|Transketolase from baker's yeast (Saccharomyces cerevisiae) is shown to the right. The coloring scheme highlights the secondary structure and reveals that transketolase is a dimer In this structure TPP has been substituted by 2,3'-deazo-thiamin diphosphate which is shown as a CPK colored space filling model. Ca2+ (blue-gray) can be seen complexed with the diphosphates.|
It is evident from the neurological disorders caused by thiamine deficiency that this vitamin plays a vital role in nerve function. It is unclear, however, just what that role is. Thiamine is found in both the nerves and brain. The concentration of thiamine in the brain seems to be resistant to changes dietary concentration. Electrical or chemical (e.g., acetylcholine) stimulation of nerves results in the release of thiamine monophosphate and free thiamine into the medium with accompanying decrease of cellular thiamine pyrophosphate and thiamine triphosphate. This observation suggest that thiamine has a role in the nervous system independent of its coenzyme roles. One theory is that thiamine triphosphate is involved with nerve impulses via the Na+ and K+ gradient.
"A certain very troublesome
affliction, which attacks men,
is called by the inhabitants Beri-beri (which means sheep).
I believe those, whom this same disease attacks, with their
knees shaking and legs raised up, walk like sheep. It is a
kind of paralysis, or rather Tremor: for it penetrates the
motion and sensation of the hands and feet indeed
sometimes the whole body..."
Jacobus Bonitus, Java, 1630
Thiamine deficiency usually causes weight loss, cardiac
abnormalities, and neuromuscular disorders. The classic thiamine
deficiency syndrome in humans is beri-beri (sometimes called Kakke).
Thiamine is abundant in whole grains, usually in the scutellum (the thin
covering of the starchy interior endosperm), but is scarce in the endosperm.
Unfortunately beri-beri is still common in parts of southeast Asia where
polished rice is a staple and thiamine enrichment programs are not fully in
place. Beri-beri is characterized by anorexia (loss of appetite) with
subsequent weight loss, enlargement of the heart, and neuromuscular symptoms
such as paresthesia (spontaneous sensations, such as itching, burning, etc.),
muscle weakness, lassitude (weariness, general weakness), and foot and wrist
droop. There are three main types of beri-beri: (1) dry (also
neuritic, paraplegic, and pernicious) beri-beri; (2) wet (also edematous or
cardiac) beri-beri; (3) and infantile (also acute) beri-beri.
Dry beri-beri usually inflicts older adults and affects mainly the peripheral nerves with little cardiac involvement. It is characterized by atrophy (wasting away) and peripheral neuritis (inflammation of nerves) of the legs and paraplegia (paralysis of the lower extremities). In contrast wet beri-beri displays substantial cardiac involvement especially tachycardia (rapid heart beat) in addition to peripheral neuropathy. Edema progresses from the feet upwards to the heart causing congestive heart failure in severe cases. Infantile beri-beri is usually seen in breast-feeding infants whose mothers are thiamine deficient (but not necessarily showing signs of beri-beri). These infants are usually anoretic and often have trouble keeping the milk down. Once the disease begins it moves rapidly causing heart failure in a matter of hours.
Wernicke-Korsakoff Syndrome or Wernicke's encephalopathy is the thiamine deficient disease seen most often in the Western hemisphere. It mainly affects alcoholics due to three reasons: (1) the diets of alcoholics are usually poor; (2) diets rich in carbohydrates (e.g., alcohol or rice) increase the metabolic demands of thiamine; and (3) alcohol inhibits intestinal ATPase which is involved in the uptake of thiamine. Two observations suggest a genetic invovlement with Wernicke-Korsakoff Syndrome: (1) it is much higher in among Europeans than non-Europeans; and (2) transketolase (see above under " Thiamine in the Pentose Phosphate Pathway") from Wernicke-Korsakoff Syndrome patients binds TPP 10 time less strongly than normal transketolase. The symptoms of Wernicke-Korsakoff syndrome include confusion, sixth nerve damage resulting in ophthalmoplegia (paralysis of an eye motor nerve) and nystagmus (rhythmical oscillation of the eyes), psychosis, confabulation, and impaired retentive memory and cognitive function. In severe cases the patient may slip into a coma. A congenital defect in transketolase which causes a low binding affinity for TPP increases the chances of acquiring Wernicke-Korsakoff syndrome.
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Gerald F. Combs, Jr., The Vitamins: Fundamental Aspects in Nutrition and
Health, Academic Press, Inc. New York, 1992.
Wilhelm Friedrich, Vitamins, Walter de Gruyter, New York, 1988.
Handbook of Vitamins, second edition, Lawrence J. Machlin Ed., Marcel Dekker, Inc. New York, 1991.
Stedman's Medical Dictionary, 24th edition, Williams & Wilkins, Baltimore, 1982.
Lubert Stryer, Biochemistry, third edition, W. H. Freeman and Company, New York, 1988.
Robert R. Williams, Toward the Conquest of Beriberi, Harvard University Press, Cambridge. Mass. 1961.