Thiazole pyrophosphate

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... 

The mechanism of action of cocarboxylase is still very obscure. The suggestion has been offered that the thiol and disulfide forms of thiamine might constitute an oxidation-reduction system. Subsequently, it has been shown in enzyme experiments with yeast that the isomeric thiazole pyrophosphate exhibited full cocarboxylase activity, whereas the disulfide... 

Buchman, Heegard, and Bonner (48) observed a very interesting inhibition of the activity of a carboxylase system by the pyrophosphate of the vitamin thiazole (4-methyl-5-/3-hydroxyethyl-thiazole pyrophosphate). This inhibition was explained as due to a competition between cocarboxylase (thiamin pyrophosphate) and the thiazole pyrophosphate, for the carboxylase protein, the thiazole pyrophosphate giving an inactive enzyme analogue. On the other hand, Niven and Smiley (272a) found that co-carboxylase was 40% more active than intact thiamin for Streptococcus salivarius. (See also Sarett and Cheldelin, addl. ref., 325a). 

As shown in Eigure 18.17, thiamine is composed of a substituted thiazole ring joined to a substituted pyrimidine by a methylene bridge. It is the precursor of thiamine pyrophosphate (TPP), a coenzyme involved in reactions of carbo-... 

Assisted decarboxylation of pyruvic acid by thiamine pyrophosphate (only the thiazole portion of the coenzyme is shown)... 

Hydrogen exchange of thiazole and thiazolium ions has received much attention since Breslow s observation that thiamine (12), which in the form of its pyrophosphate, cocarboxylase, is the coenzyme for a... 

Thiamin (vitamin B 6.16) consists of two heterocyclic rings (substitued pyrimidine and substituted thiazole), linked by a methylene bridge. Thiamin acts as a co-enzyme in the form of thiamin pyrophosphate (TPP 6.17)... 

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... 

Commercial thiamine dietary supplements are prepared by synthesis Pyrimidine + thiazole nuclei synthesized separately and then condensed also build on pyrimidine with acelaiiudiiie. Precursors in the biosynthesis of thiamine include thiazole and pyrimidine pyrophosphate, with thiamine phosphate as an intermediate. In plants, production sites arc found in grain and cereal germ. 

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... 

Branching of pathways is relevant in several cases. Thus, intermediates of the porphyrin biosynthetic pathway serve as precursors for chlorophyll (17, Fig. 2) and for the corrinoid ring systems of vitamin B12 (20, Fig. 2) (17). 1-Deoxy-D-xylulose 5-phosphate (43) serves as an intermediate for the biosynthesis of pyridoxal 5 -phosphate (39, Fig. 5), for the terpenoid precursor IPP (86) via the nonmevalonate pathway (Fig. 11), and for the thiazole moiety of thiamine pyrophosphate (46, Fig. 4). 7,8-Dihydroneopterin triphosphate (29, Fig. 3) serves as intermediate in the biosynthetic pathways of tetrahydrofolate (33) and tetrahydrobiopterin (31). The closely related compound 7,8-dihydroneopterin 2, 3 -cyclic phosphate is the precursor of the archaeal cofactor, tetrahydromethanopterin (34) (58). A common pyrimidine-type intermediate (23) serves as precursor for flavin and deazaflavin coenzymes. Various sulfur-containing coenzymes (thiamine (9), lipoic acid (7), biotin (6), Fig. 1) use a pyrosulfide protein precursor that is also used for the biosynthesis of inorganic sulfide as a precursor for iron/sulfur clusters (12). 

The thiamin phosphate synthase-catalyzed formation of thiamin phosphate from 4-amino-5-(hydroxymethyl)-2-methylpyrimidine pyrophosphate and 4-methyl-5-( 1 -hydroxyethyl)thiazole phosphate has been studied. A mechanism was proposed, and the substituent effects of the pyrimidine ring upon the TS discussed <2001B10095>. 

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. 

Biosynthesis of pyrophosphate (5) from pyrimidine phosphate (47) and thiazole phosphate (48) depends on the activity of five enzymes, four of them kinases (87). In yeasts and many other organisms, including humans, pyrophosphate (5) can be obtained from exogenous thiamine in a single step catalyzed by thiamine pyrophosphokinase (88). 

A. form a hydroxyethyl derivative of the thiazole ring of enzyme-bound thiamine pyrophosphate... 

Addition of thiamine. The conversion of pyruvate to acetyl CoA begins by reaction of pyruvate with thiamine pyrophosphate, a derivative of vitamin Bj. The hydrogen on the heterocyclic (thiazole) ring of thiamine pyrophosphate is weakly acidic and can be removed by reaction with base to yield a nucleophilic ylide much like the phosphorus ylides used in Wittig reactions (Section 19.12). This nucleophilic ylide adds to the ketone carbonyl group of pyruvate to yield a tetrahedral intermediate. 

Thiamine pyrophosphate has two important coenzyme roles, both of which focus mostly on carbohydrate metabolism (Figs. 8.26 and 8.27). The active portion of the coen- rae is the thiazole ring. The first step in the oxidative decarboxylation of a-keto acids requires TPP. The two most common examples are pyruvate and a-ketoglutarate, oxidatively decarboxyatedto acetyl CoA and succinyl CoA, respectively. The same reaction is found in the metabolism of the branched-chain amino acids valine, isoleucine, leucine, and methionine. In all cases, TPP is a coenzyme in a mitochondrial multienzyme complex, consisting of TPP, lipoic acid, coenzyme A, FAD, and NAD. Note the number of vitamins required for the oxidative decarboxylation of a-keto acids thiamine (TPP), pantothenic acid (coenzyme A), riboflavin (FAD),and niacin (NAD). 

Transketolase Reaction. Transketolase contains a tightly bound thiamine pyrophosphate as its prosthetic group. The enzyme transfers a two-carbon glycoaldehyde from a ketose donor to an aldose acceptor. The site of the addition of the two-carbon unit is the thiazole ring of TPR Transketolase is homologous to the Ej subunit of the pyruvate dehydrogenase complex (p. 478) and the reaction mechanism is similar (Figure 20.21). 

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. 

Thiamine pyrophosphate is also an important cofactor for the transketolase reactions in the pentose phosphate pathway of carbohydrate metabolism (Fignre 15-3). These reactions are important in the reversible transformation of pentoses into the glycolytic intermediates fructose 6-phosphate and glyc-eraldehyde 3-phosphate. Again, it is the reactive carbon on the thiazole ring of TPP that reacts with a ketose phosphate (xylnlose 5-phosphate) to canse the release of an aldose phosphate with two fewer carbons (glyceraldehyde 3-phosphate). The TPP-bonnd glycoaldehyde unit is then transferred to a different aldose phosphate (ribose 5-phosphate or erythrose 4-phosphate) to produce a ketose phosphate that has two carbons more (sedoheptulose 7-phosphate or fructose 6-phosphate). 

A very important naturally occuring thiazole derivative is thiamine pyrophosphate (473). It is the prosthetic group in a variety of enzymes which catalyze decarboxylation (decarboxylase) and aldol-type condensation (aldolase) reactions. The catalytic active site of the molecule is at C-2 of the thiazole ring . The same activity of (473) is shown by other thiazolium salts and therefore these compounds have been widely exploited as catalysts in reactions of importance such as the benzoin condensation (see Section 3.06.12.2). 

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