8/27/2014 Thiamine

http://www.angelfire.com/ak2/chemists/stan6.html 1/5

Thiamine
VITAMINE B1


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-soluble vitamin is 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]- 5-(2-
hydroxyethyl)-4-methylthiazolium. Thiamine consists 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.
BICHEMICAL FUNCTION OF THIAMINE
THIAMINE PRYOPHOSPHATE
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 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
Info Lowongan kerja 2014
berniaga.com/Lowongan-Kerja
Ratusan Ribu Lowongan Tersedia, Temukan Posisi Impianmu Sekarang!
8/27/2014 Thiamine
http://www.angelfire.com/ak2/chemists/stan6.html 2/5
a new ketose. All known TPP dependent enzymes also require a divalent cation, commonly Mg
2+
.
Thiamine in the Krebs Cycle
The Krebs cycle (also called the citric acid cycle and the tricarboxylic acid cycle) is very important in extracting energy from fuel molecules. TPP is the
coenzyme for alpha-ketoacid dehydrogenases which catalyze two reactions of the Krebs cycle.
The oxidative decarboxylation of pyruvate to acetyl CoA; The oxidative decarboxylation of alpha-ketoglutarate to succinyl CoA
In each of these reactions NAD+ is reduced to NADH and a molecule of CO2 is liberated. The first step in the Krebs cycle is the addition of a 2-carbon
acetyl group (from acetyl CoA) to the 4-carbon oxaloacetate to give the 6-carbon citric acid. The acetyl CoA is produced by the oxidative
decarboxylation of pyruvate (an alpha-ketoacid) and the covalent bonding of the decarboxylation product to CoA. This conversion of pyruvate to acetyl
CoA is catalyzed by a multiprotein assembly called pyruvate dehydrogenase complex. TPP is the cofactor for the pyruvate dehydrogenase component of
the complex. Pyruvate dehydrogenase catalyzes the oxidative decarboxylation of pyruvate. Other components of the complex complete the conversion of
pyruvate to acetyl CoA. After 3 steps in the Krebs cycle CO2 is released (TPP independent) to give alpha-ketoglutarate (another alpha-ketoacid). alpha-
Ketoglutarate's fate is similar to pyruvate's. alpha-Ketoglutarate is decarboxylated and the product is transferred to CoA to give succinyl CoA. alpha-
Ketoglutarate dehydrogenase complex, also a multiprotein complex, catalyzes the conversion of alpha-ketoglutarate to succinyl CoA. As with pyruvate
dehydrogenase complex, TPP is the coenzyme for the alpha-ketoglutarate dehydrogenase part of the complex.

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.
8/27/2014 Thiamine
http://www.angelfire.com/ak2/chemists/stan6.html 3/5
Thiamine in the Pentose Phosphate Pathway
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.
Cl ose Ad
8/27/2014 Thiamine
http://www.angelfire.com/ak2/chemists/stan6.html 4/5

Neurological Function of TPP
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. |

Thiamine Deficiency Diseases
Beri-beri
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
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 thePentose 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
8/27/2014 Thiamine
http://www.angelfire.com/ak2/chemists/stan6.html 5/5
Info Lowongan kerja
2014
berniaga.com/Lowongan-Kerja
Ratusan Ribu Lowongan Tersedia,
Temukan Posisi Impianmu
Sekarang!
(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.

Diet-Related Links
The Cyberdiet Page
Information on Thiamine and Alzheimers
What do the Mag Lab and Thiamine have to do with one another?
Project Links
Back to Project Page
Kim's Page - What is a Coenzyme?
Leah's Page - Niacin
Rod's Page -
How does this project relate to our previous learning?
Email: rld9881@garnet.fsu.edu

CKGSB MBA 2014
english.ckgsb.edu.cn
Learn from World-Class Faculty. Connect w/ China Top Executives!
Sponsored by