Thiamine action mechanism

Breslow R (1958) On the mechanism of thiamine action. IV. Evidence from studies on model systems. J Am Chem Soc 80 3719 Breuer K (1997) PhD thesis. RWTH Aachen University Brodesser S, Sawatzki P, Kolter T (2003) Bioorganic chemistry of ceramide. Eur J Org Chem 11 2021-2034... 

Mizuhara S, Tamura R, Arata H (1951) The mechanism of thiamine action II. Proc Jpn Acad 27 302... 

Breslow RJ (1958) On the mechanism of thiamine action. IV. Evidence from studies on model systems. J Am Chem Soc 80 3719-3726... 

Breslow, R. (1958). On the Mechanism of Thiamine Action. IV.l Evidence from Studies on Model Systems. Journal... 

The oxidation of p3Tnvate demonstrates the variety of oxidation reactions that can be found for the metabolism of a given substrate, and emphasizes the danger in attempting to carry over information from one system to another. All of the pyruvate oxidases, however, have one outstanding feature in common they all require cocarboxylase and a divalent cation. These cofactors presumably play the same role both in the non-oxidative carboxylase reaction and in pyruvate oxidation, but the mechanism of thiamine action remains conjectural. 

Ultimately, then, all of the peraminoethylene syntheses from dipolar halves have depended upon the acidity of the central proton of a formamidinium ion. Thus all were foreshadowed by the pioneering work of Breslow on the mechanism of thiamine action and, more remotely, by Hammick s study of the decarboxylation of certain heterocyclic acids The Hammick reaction, illustrated in equation (4), led its discoverer to conclude that decarboxylation yields dipolar... 

Breslow, R., Mechanism of thiamine action participation of a thiazolium zwitterion, Chem. Ind., 1957, 893-894. 

Breslow, R., The mechanism of thiamine action evidence from studies on model systems, CIBA Foundation Study Group II, J.A. Churchill Ltd., London, 1961, p. 65. 

Based on the action of thiamine pyrophosphate in catalysis of the pyruvate dehydrogenase reaction, suggest a suitable chemical mechanism for the pyruvate decarboxylase reaction in yeast ... 

Some kinds of fish and Crustacea contain thiaminases. These enzymes cleave thiamin and thus inactivate the vitamin. Some plant phenols, e.g., chlorogenic acid, may possess antithiaminic properties, too, though their mechanism of action is so far not well understood. 

The next coenzyme for which a mechanism was established was thiamin pyrophosphate [3]. Ronald Breslow used nmr spectroscopy to show that the hydrogen atom at C-2 of a thiazolium salt rapidly exchanges with deuterium in even slightly alkaline solutions (6), so that the coenzyme offers an anionic centre for catalysis (Breslow, 1957). With this established, Breslow could confidently offer the pathway shown in Scheme 2 for the action of the... 

Mechanism of action of the pyruvate dehydrogenase complex. TPP = thiamine pyrophosphate L = lipoic acid. 

A reaction that is related to that of transketolase but is likely to function via acetyl-TDP is phosphoketolase, whose action is required in the energy metabolism of some bacteria (Eq. 14-23). A product of phosphoketolase is acetyl phosphate, whose cleavage can be coupled to synthesis of ATP. Phosphoketolase presumably catalyzes an a cleavage to the thiamin-containing enamine shown in Fig. 14-3. A possible mechanism of formation of acetyl phosphate is elimination of HzO from this enamine, tautomerization to 2-acetylthiamin, and reaction of the latter with inorganic phosphate. 

Mechanism of thiamine pyrophosphate action. Intermediate (a) is represented as a resonance-stabilized species. It arises from the decarboxylation of the pyruvate-thiamine pyrophosphate addition compound shown at the left of (a) and in equation (2). It can react as a carbanion with acetaldehyde, pyruvate, or H+ to form (b), (c), or (d), depending on the specificity of the enzyme. It can also be oxidized to acetyl-thiamine pyrophosphate (TPP) (e) by other enzymes, such as pyruvate oxidase. The intermediates (b) through (e) are further transformed to the products shown by the actions of specific enzymes. 

In the thiazolium cation the proton in the 2-position is acidic and its removal gives rise to the ylide/carbene 227. This nucleophilic carbene 227 can add, e.g., to an aldehyde to produce the cationic primary addition product 228. The latter, again via C-deprotonation, affords the enamine-like structure 229. Nucleophilic addition of 229 to either an aldehyde or a Michael-acceptor affords compound(s) 230. The catalytic cycle is completed by deprotonation and elimination of the carbene 227. Strictly speaking, the thiazolium salts (and the 1,2,4-triazolium salts discussed below) are thus not the actual catalysts but pre-catalysts that provide the catalytically active nucleophilic carbenes under the reaction conditions used. This mechanism of action of thiamine was first formulated by Breslow [234] and applies to the benzoin and Stetter-reactions catalyzed by thiazolium salts [235-237] and to those... 

During the last two decades, the mechanisms of many enzymic processes have been established, and model systems have been developed that effectively mimic their action. In particular, the roles of thiamin, NAD, pyridoxal, flavins, Bl2, ferridoxin, and metals in many enzymic processes now are understood. Model systems have been developed to imitate the action of decarboxylases and esterases, to imitate the action of enzymes in binding their substrates, and to approach the stereospecificity of enzymes. Our laboratory recently has found phosphorylating agents that release monomeric methyl metaphosphate, which in turn carries out phosphorylation reactions, including some at carbonyl oxygen atoms, that suggest the actions of ATP. The ideas of biomimetic chemistry are illustrated briefly in terms of the processes mentioned above. 

Another early success in biomimetic chemistry concerns reactions promoted by thiamin. In 1943, more than 35 years ago, Ukai, Tanaka, and Dokowa (12) reported that thiamin will catalyze a benzoin-type condensation of acetaldehyde to yield acetoin. This reaction parallels a similar enzymic reaction where pyruvate is decarboxylated to yield acetoin and acetolactic acid. Although the yields of the nonenzymic process are low, it is clearly a biomimetic process further investigation by Breslow, stimulated by the early discovery of Ugai et al., led to an understanding of the mechanism of action of thiamin as a coenzyme. 

TWo analogs of thiamin, oxythiamin and pyrithiamin, are potent antimetabolites and have been widely used to induce thiamin deficiency in experimental animals. The mechanisms of action of pyrithiamin, oxythiamin, and thiaminases found in foods are discussed in Section 6.4.7. 

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