Thiamin oxidative cleavage

The oxidative cleavage of an a-oxoacid is a major step in the metabolism of carbohydrates and of amino acids and is also a step in the citric acid cycle. In many bacteria and in eukaryotes the process depends upon both thiamin diphosphate and lipoic acid. The oxoacid anion is cleaved to form C02 and the remaining acyl group is combined with coenzyme A (Eq. 15-33). 

Thiaminolytic enzymes are found in a variety of microorganisms and foods, and a number of thermostable compounds present in foods (especially polyphenols) cause oxidative cleavage of thiamin, as does sulfite, which is widely used in food processing. The products of thiamin cleavage by sulfite and thiaminases are shown in Figure 6.1. 

Tire enzyme does not require lipoic acid. It seems likely that a thiamin-bound enamine is oxidized by an iron-sulfide center in the oxidoreductase to 2-acetyl-thiamin which then reacts with CoA. A free radical intermediate has been detected318 321 and the proposed sequence for oxidation of the enamine intermediate is that in Eq. 15-34 but with the Fe-S center as the electron acceptor. Like pyruvate oxidase, this enzyme transfers the acetyl group from acetylthiamin to coenzyme A. Cleavage of the resulting acetyl-CoA is used to generate ATR An indolepyruvate ferredoxin oxidoreductase has similar properties 322... 

All biochemical reactions with participation of thiamine start with C-C-bond cleavage of 2-oxo carbonyl-compound and proceed with formation of an activated aldehyde , TPP catalyzes decarboxylation of a-keto acids, oxidative decarboxylations together with lipoic acid, and trans-ketolase reactions. 

Thiamin diphosphate (TDP) functions as a cofactor to overcome a chemically difficult problem in carbon-carbon formation and cleavage (77). Editor s note Thiamin diphosphate-dependent decarboxylation is discussed in Chapter 6 by O Leary.) The reaction pattern is exemplified by the decarboxylation of pyruvate to give acetaldehyde (or a more oxidized species) and carbon dioxide. In this reaction, the bond that is broken is not inherently activated toward the reaction. The bond that is to be cleaved is between two carbonyl functions. Since these groups are similarly polarized, heterolytic cleavage is not a likely process. Non-enzymically, the direct cleavage of such a bond involves a homolytic (radical) process. 

Confirmation of the structure of the pyrimidine part of the vitamin soon followed when Grewe synthesized 2-methyl-4-amino-5-aminomethylpyrimi-dine (V, see p. 8), a product obtained by Windaus et al. upon oxidizing thiamine with barium permanganate. From (V) Grewe was able to prepare a sulfonic acid derivative (IV), which proved to be identical with Williams s primary cleavage product A. 

---