Thiazoles diphosphate

Thiamin, structure of, 530, 1045 thiazolium ring in, 530 Thiamin diphosphate, p/Ca of, 1151 reaction with pyruvate, 1151-1153 structure of. 1151 ylide from. 1151 Thiazole, basicity of. 948 thio-, thioester name ending, 787 Thioacetal, synthesis of, 743 Thioanisole, electrostatic potential map of. 777... 

Biosynthesis of Thiamine Diphosphate from Thiazole and Pyrimidine... 

Thiamine is present in cells as the free form 1, as the diphosphate 2, and as the diphosphate of the hydroxyethyl derivative 3 (Scheme 1) in variable ratio. The component heterocyclic moieties, 4-amino-5-hydroxymethyl-2-methylpyrimidine (4) and 4-methyl-5-(2-hydroxyethyl)thiazole (5) are also presented in Scheme 1, with the atom numbering. This numbering follows the rules of nomenclature of heterocyclic compounds for the ring atoms, and is arbitrary for the substituents. To avoid the use of acronyms, compound 5 is termed as the thiazole of thiamine or more simply the thiazole. This does not raise any ambiguity because unsubstituted thiazole is encountered in this chapter. Other thiazoles are named after the rules of heterocyclic nomenclature. Pyrimidine 4 is called pyramine, a well established name in the field. A detailed account of the present status of knowledge on the biosynthesis of thiamine diphosphate from its heterocyclic moieties can be found in a review by the authors.1 This report provides only the minimal information necessary for understanding the main part of this chapter (Scheme 2). 

Thiamine can be considered to be the product of the quatemization of 4-methyl-5-(2-hydroxymethyl)thiazole (5) by an active derivative of 4-amino-5-(hydroxymethyl)-2-methyl pyrimidine (4) (Scheme 2). In living cells, pyramine can be activated by conversion into the diphosphate 7, via monophosphate 6, and the substrate of the enzyme responsible for the quatemization is not the thiamine thiazole, but its phosphate 8. The product of the condensation, thiamine phosphate (9), is finally converted into diphosphate 2—the biochemically active derivative—by hydrolysis to free thiamine, followed by diphosphorylation, or more directly, in some cases. Enzymes are known for all of the steps depicted in Scheme 2, and adenosine triphosphate (ATP) is, as usual, the phosphate donor. 

Thiamine was biosynthesized by resting cells of S. typhimurium strain thilO/T-ath-383, which can synthesize thiamine from exogenous glucose, AIRs, and thiazole.54 Derepression was achieved by conventional means. The organism was cultivated in the presence of a suboptimal amount of thiamine (20 nM), the washed cells were resuspended in a minimal medium containing glucose (10 mM), thiazole (1-2 mM), and labeled AIRs (10 p,M). During the incubation (1.5 hours 37°C), the level of thiamine diphosphate in the cells had risen from about 0.04 to 0.5 nmol/mg. In work with molecules labeled with stable isotopes, thiamine was extracted and cleaved by ethanethiol to 4-amino-5-(ethyl-... 

Thiamine diphosphate, biosynthesis, from thiazole and pyrimidine precursors, 269-271... 

Thiamine diphosphate (TPP, 3), in cooperation with enzymes, is able to activate aldehydes or ketones as hydroxyalkyl groups and then to pass them on to other molecules. This type of transfer is important in the transketo-lase reaction, for example (see p. 152). Hydroxyalkyl residues also arise in the decarboxylation of 0x0 acids. In this case, they are released as aldehydes or transferred to lipoamide residues of 2-oxoacid dehydrogenases (see p. 134). The functional component of TPP is the sulfur- and nitrogen-containing thiazole ring. 

In nature, an enzyme requiring two co-factors, thiamine diphosphate 2 and flavin adenine dinucleotide, accomplishes the oxidation of pyruvate to acetyl phosphate. The thiazole ring in thiamine condenses at the 2-position with pyruvat eliminating carbon dioxide to give an activated species that is oxidised by the flavin. An enzymatic oxidation process then reactivates the reduced flavin. The redox... 

Thiamin is synthesized in bacteria, fungi, and plants from 1-deoxyxylulose 5-phosphate (Eq. 25-21), which is also an intermediate in the nonmevalonate pathway of polyprenyl synthesis. However, thiamin diphosphate is a coenzyme for synthesis of this intermediate (p. 736), suggesting that an alternative pathway must also exist. Each of the two rings of thiamin is formed separately as the esters 4-amino-5-hydroxy-methylpyrimidine diphosphate and 4-methyl-5-((i-hydroxyethyl) thiazole monophosphate. These precursors are joined with displacement of pyrophosphate to form thiamin monophosphate.92b In eukaryotes this is hydrolyzed to thiamin, then converted to thiamin diphosphate by transfer of a diphospho group from ATP.92b c In bacteria thiamin monophosphate is converted to the diphosphate by ATP and thiamin monophosphate kinase.92b... 

As shown in Figure 6.1, thiamin consists of pyrimidine and thiazole rings, linked by a methylene bridge the alcohol group of the side chain can be esterified with one, two, or three phosphates, yielding thiamin monophosphate, thiamin diphosphate (also known as thiamin pyrophosphate, the metabolically active coenzyme), and thiamin triphosphate. The vitamin was originally named aneurine, the antineuritic vitamin, because of its function in preventing or... 

The thiazole biosynthetic enzyme (THIl), produced using heterologous expression in bacteria, is unexpectedly bound to 2-carboxylate-4-methyl-5-/3-(ethyladenosine 5-diphosphate)thiazole, a potential intermediate of thiazole biosynthesis in eukaryotes. The 3-D structure of this complex was determined by single-wavelength anomalous X-ray diffraction to l.bA resolution <2006JBC30957>. 

Vitamin Bj Vitamin Bj was discovered in 1926 by Jansen and Do-NATH, who synthesized it in its crystalline form from rice bran. It was initially called aneurine due to its antipolyneuropathic effect. Because it contains sulphur, Windaus correctly renamed it thiamine in 1932, a term by which it is still known today. The stixicture of this vitamin was described by Williams and Grewe in 1936. It is made up of pyrimidine and thiazole. Thiamine occurs in nature as free thiamine and in the form of thiamine monophosphate, diphosphate and triphosphate. A maximum amount of 8 — 15 mg is absorbed daily in the proximal portion of the small intestine. In the case of oversupply, thiamine is neither stored nor intestinally absorbed. A regular intake, with a daily requirement of about 1 mg, is necessary. The major coenzyme is thiamine pyrophosphate (TPP). Thiamine deficiency may be caused by malnutrition, impaired absorption, alcoholism, antithiamines or a lack of magnesium. Magnesium is an important cofactor for the coenzyme thiamine pyrophosphate. 

Thiamine is absorbed in the intestine by both active transport mechanisms and passive diffusion. The active form of the cofactor, thiamine pyrophosphate (thiamine diphosphate, TPP), is synthesized by an enzymatic transfer of a pyrophosphate group from ATP to thiamine (Figure 15-1). The resulting TPP has a reactive carbon on the thiazole ring that is easily ionized to form a carbanion, which can undergo nucleophilic addition reactions. 

Vitamin Bi is an essential co-factor for several enzymes of carbohydrate metabolism such as transketolase, pyruvate dehydrogenase (PDH), pyruvate decarboxylase and a-ketoglutarate dehydrogenase. To become the active co-factor thiamin pyrophosphate (TPP), thiamin has to be salvaged by thiamin pyrophosphokinase or synthesized de novo. In Escherichia coli and Saccharomyces cerevisiae thiamin biosynthesis proceeds via two branches that have to be combined. In the pyrimidine branch, 4-amino-5-hydroxymethy-2-methylpyrimidine (PIMP) is phosphorylated to 4-amino-2-methyl-5-hydroxymethyl pyrimidine diphosphate (PIMP-PP) by the enzyme HMP/HMP-P kinase (ThiD) however, the step can also be catalyzed by pyridoxine kinase (PdxK), an enzyme also responsible for the activation of vitamin B6 (see below). The second precursor of thiamin biosynthesis, 5-(2-hydroxyethyl)-4-methylthiazole (THZ), is activated by THZ kinase (ThiM) to 4-methyl-5-(2-phosphoethyl)-thiazole (THZ-P), and then the thia-zole and pyrimidine moieties, HMP-PP and THZ-P, are combined to form thiamin phosphate (ThiP) by thiamin phosphate synthase (ThiE). The final step, pyrophosphorylation, yields TPP and is carried out by thiamin pyrophosphorylase (TPK). 

EC 2.5.1.3 Thiamin-phosphate pyrophosphorylase 2-Methyl-4-amino-5-hydroxymethylpyrimide diphosphate + 4-methyl-5-(2-phosphono-oxyethyl)-thiazole pyrophosphate + thiamine monophosphate FGM... 

Although thiamine, a thiazolium salt, contains a pyrimine ring, it is the thiazole ring that is responsible for its biological action, thiamine dihosphate being the coenzyme of decarboxylases. The mechanism of the catalytic decarboxylation (e.g. of pyruvic acid to acetaldehyde) was interpreted by Breslow in 1958. The active species is the N-ylide 12 formed from thiamine diphosphate and basic cell components ... 

Chemical structure (Figure 6). Pyrimidine and thiazole moiety linked by methylene bridge - phos-phorylated forms thiamine monophosphate (TMP), thiamine diphosphate (TDP), thiamine triphosphate (TTP). 

Thiamin (vitamin Bi) is a complex nitrogenous base containing a pyrimidine ring joined to a thiazole ring. Because of the presence of a hydroxyl group at the end of the side chain, thiamin can form esters. The main form of thiamin in animal tissues is the diphosphate ester, commonly known as thiamin pyrophosphate (TPP).The vitamin is very soluble in water and is fairly stable in mildly acidic solution but readily decomposes in neutral solutions. 

The biologically active form of thiamine (vitamin Bi) is thiamine diphosphate (ThDP), in which a diphosphate group is attached to the thiazole ring of thiamine. ThDP was formally known as cocarboxylase , which is required for the decarboxylation reaction of pyruvate decarboxylase (PDC) from yeast. In 1937, Lohmann and Schuster established that the coenzyme cocarboxylase is ThDP (Lohmann and Schuster 1937). Enzymes requiring ThDP as a cofactor... 

Vitamin Bi (also called thiamine) is a water-soluble vitamin of B complex present in many foods as a natural nutrient. It is a biologically and pharmaceutically important compound containing a pyrimidine and a thiazole moiety such as 4-amino-5-hydroxymethyl-2-methyl-pyrimidine and 5-(2-hydroxyethyl)-4-methylthiazole linked by a methylene bridge (Figure 15.1). It is necessary for carbohydrate metabolism and for the maintenance of neural activity because most of the humans and mammals cannot synthesize vitamin Bi. Nerve cells need vitamin BI for their normal function because vitamin Bi has diphosphate-active sites which serve as a cofactor for several enzymes (Leopold et al. 2005). Vitamin Bi is employed for the prevention and treatment of beriberi, neuralgia, etc. and played a vital role in enzymatic mitochondrial... 

Thiamine is a relatively simple compound consisting of a pyrimidine and a thiazole ring. It exists naturally in most types of foods as free thiamine and phosphorylated forms including thiamine monophosphate (TMP), thiamine diphosphate or pyrophosphate (TPP), and thiamine triphosphate (TTP) (Tanphaichitr 2001) (Figure 17.1). Although all forms exist in animal and plant foods, thiamine as the free (non-phosphorylated) form is mainly found in plant-based foods whereas, in animal products, 80% of thiamine is represented by TPP and lesser amounts by TMP and triphosphate TTP. 

Thiamine, thiamine diphosphate. Humans are not able to synthesize the thiazol ring, the key element of thiamine. Therefore thiamine must be supplied from the diet (daily allowance is 1.0-1.5 mg). It is converted to the active compound thiamine diphosphate (vitamin Bi) by thiamine kinases present in all tissues. 

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