Thiamine pyrophosphate
Encyclopedia
Thiamine pyrophosphate or thiamine diphosphate (ThDP), is a thiamine
(vitamin B1) derivative
which is produced by the enzyme
thiamine pyrophosphatase. Thiamine pyrophosphate is a coenzyme that is present in all living systems, in which it catalyzes several biochemical
reactions. It was first discovered as an essential nutrient
(vitamin
) in humans through its link with the peripheral nervous system
disease
Beriberi
, which results from a deficiency of thiamine in the diet
.
TPP works as a coenzyme in many enzymatic reactions, such as:
Chemically, TPP consists of a pyrimidine
ring which is connected to a thiazole
ring, which is in turn connected to a pyrophosphate
(diphosphate) functional group
.
The part of TPP molecule that is most commonly involved in reactions is the thiazole ring, which contains nitrogen
and sulfur
. Thus, the thiazole ring is the "reagent portion" of the molecule. The C2 of this ring is capable of acting as an acid
by donating its proton
and forming a carbanion
. Normally, reactions that form carbanions are highly unfavorable, but the positive charge on the tetravalent nitrogen just adjacent to the carbanion stabilizes the negative charge, making the reaction more favorable. (A compound with positive and negative charges on adjacent atoms is called an ylid
or ylide, so sometimes the carbanion form of TPP is referred to as the "ylid form".
or an alcohol
). It achieves this in four basic steps:
Thiamine
Thiamine or thiamin or vitamin B1 , named as the "thio-vitamine" is a water-soluble vitamin of the B complex. First named aneurin for the detrimental neurological effects if not present in the diet, it was eventually assigned the generic descriptor name vitamin B1. Its phosphate derivatives are...
(vitamin B1) derivative
Derivative (chemistry)
In chemistry, a derivative is a compound that is derived from a similar compound by some chemical or physical process. In the past it was also used to mean a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms, but modern...
which is produced by the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
thiamine pyrophosphatase. Thiamine pyrophosphate is a coenzyme that is present in all living systems, in which it catalyzes several biochemical
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
reactions. It was first discovered as an essential nutrient
Essential nutrient
An essential nutrient is a nutrient required for normal body functioning that either cannot be synthesized by the body at all, or cannot be synthesized in amounts adequate for good health , and thus must be obtained from a dietary source...
(vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
) in humans through its link with the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
Beriberi
Beriberi
Beriberi is a nervous system ailment caused by a thiamine deficiency in the diet. Thiamine is involved in the breakdown of energy molecules such as glucose and is also found on the membranes of neurons...
, which results from a deficiency of thiamine in the diet
Diet (nutrition)
In nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...
.
TPP works as a coenzyme in many enzymatic reactions, such as:
- Pyruvate dehydrogenasePyruvate dehydrogenasePyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
complex - Pyruvate decarboxylasePyruvate decarboxylaseNot to be confused with pyruvate dehydrogenase, the enzyme which catalyses the link reaction.Pyruvate decarboxylase is a homotetrameric enzyme that catalyses the decarboxylation of pyruvic acid to acetaldehyde and carbon dioxide in the cytoplasm. It is also called 2-oxo-acid carboxylase,...
complex in ethanol fermentationEthanol fermentationEthanol fermentation, also referred to as alcoholic fermentation, is a biological process in which sugars such as glucose, fructose, and sucrose are converted into cellular energy and thereby produce ethanol and carbon dioxide as metabolic waste products... - Alpha-ketoglutarate dehydrogenase complex
- Branched-chain amino acid dehydrogenase complex
- 2-hydroxyphytanoyl-CoA lyase2-hydroxyphytanoyl-CoA lyase2-Hydroxyphytanoyl-CoA lyase is a peroxisomal enzyme involved in the catabolism of phytanoic acid by α-oxidation. It requires thiamine diphosphate as cofactor.It is classified under EC number 4.1.400px...
- TransketolaseTransketolaseTransketolase, an enzyme of both the pentose phosphate pathway in animals and the Calvin cycle of photosynthesis, catalyzes two important reactions, which operate in opposite directions in these two pathways...
Chemistry
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
ring which is connected to a thiazole
Thiazole
Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen; the term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular formula C3H3NS...
ring, which is in turn connected to a pyrophosphate
Pyrophosphate
In chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Any salt or ester containing two phosphate groups is called a diphosphate. As a food additive, diphosphates are known as E450.- Chemistry :...
(diphosphate) functional group
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
.
The part of TPP molecule that is most commonly involved in reactions is the thiazole ring, which contains nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
and sulfur
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
. Thus, the thiazole ring is the "reagent portion" of the molecule. The C2 of this ring is capable of acting as an acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
by donating its proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
and forming a carbanion
Carbanion
A carbanion is an anion in which carbon has an unshared pair of electrons and bears a negative charge usually with three substituents for a total of eight valence electrons. The carbanion exists in a trigonal pyramidal geometry. Formally a carbanion is the conjugate base of a carbon acid.where B...
. Normally, reactions that form carbanions are highly unfavorable, but the positive charge on the tetravalent nitrogen just adjacent to the carbanion stabilizes the negative charge, making the reaction more favorable. (A compound with positive and negative charges on adjacent atoms is called an ylid
Ylide
An ylide or ylid is a neutral dipolar molecule containing a formally negatively charged atom directly attached to a hetero atom with a formal positive charge , and in which both atoms have full octets of electrons. Ylides are thus 1,2-dipolar compounds...
or ylide, so sometimes the carbanion form of TPP is referred to as the "ylid form".
Reaction mechanisms
In several reactions, including that of pyruvate decarboxylase, alpha-ketoglutarate dehydrogenase, and transketolase, TPP catalyses the reversible cleavage of a substrate compound at a carbon-carbon bond connecting a carbonyl group to an adjacent reactive group (usually a carboxylic acidCarboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
or an alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
). It achieves this in four basic steps:
- The carbanion of the TPP ylid nucleophilically attacks the carbonyl group on the substrate. (This forms a single bond between the TPP and the substrate.)
- The target bond on the substrate is broken, and its electrons are pushed towards the TPP. This creates a double bond between the substrate carbon and the TPP carbon and pushes the electrons in the N-C double bond in TPP entirely onto the nitrogen atom, reducing it from a positive to neutral form.
- In what is essentially the reverse of step two, the electrons push back in the opposite direction forming a new bond between the substrate carbon and another atom. (In the case of the decarboxylases, this creates a new carbon-hydrogen bond. In the case of transketolase, this attacks a new substrate molecule to form a new carbon-carbon bond.)
- In what is essentially the reverse of step one, the TPP-substrate bond is broken, reforming the TPP ylid and the substrate carbonyl.