Lipothiamide

Lipothiamide pyrophosphate, LTPP (reduced) LTPP (oxidized) -0.42... 

Lipothiamide pyrophosphate (LTPP) is a compound postulated by Reed (26) to account for the biological activity of a-lipoic acid. It is not certain that such a compound does exist however, a-lipoic acid and thiamine pyrophosphate do act in oxidation-reduction reactions. 

Reed and De Busk have suggested that the true coenzyme form of lipoic acid is a conjugate of a-lipoic acid and thiamine pyrophosphate, given the name lipothiamide. The bond between the two is presumed to be a peptide bond between the amino group on Ci of the pyrimidine moiety of thiamine and the carboxyl group of a-lipoic acid. The true coenzyme is reported to be the lipothiamide pyrophosphate. 

The function of the amino group in TPP is, therefore, still an open question. However Reed and De Busk suggest that a-lipoic acid is connected to thiamine through a peptidic linkage between the carboxyl of a-lipoic acid and the amino group of thiamine to form lipothiamide. This finding would account for the essential nature of the amino group as far as oxidative decarboxylation is concerned. 

Karrer and Viscontini have found that the thiol form of TPP is as active as TPP in the yeast carboxylase assay. Evidence for the open-ring form of thiamine in nature also is at hand. Approximately 50% of the thiamine in milk has long been known to be present in a form which is released only upon treatment with a proper proteolytic enzyme. In the light of present-day knowledge this bound form is suggestive of a thiamine-protein-S-S complex or of lipothiamide. Bonvicino and Hennessey have prepared a complex of the former type and found it to be biologically active to the extent of 90 %. Myrback and his co-workers have evidence to the effect that well-aerated baker s yeast contains what is probably the disulfide form of TPP. 

Recently Reed and DeBusk have isolated from natural materials a bound form of lipoic acid which seems to be somewhat closer to the coenzyme form. Analysis of this compound as well as its preparation from synthetic materials indicates that it is the amide of thiamine and lipoic acid (lipothiamide). This important discovery may eventually cast some light upon the mechanism of action of lipoic acid. It is significant that lipothiamide can restore pyruvate oxidation to deficient cells, and the authors conclude that lipothiamide may be part of the coenzyme for the oxidative decarboxylation of a-keto acids. 

Even more recently, Reed and DeBusk have observed that lipothiamide pyrophosphate is required for pyruvate dismutation and a-keto-glutarate oxidation by soluble enzyme preparations from an E. coli mutant. They suggest that the initial step in the oxidative decarboxylation of a-keto acids is the formation of an acyl lipothiamide pyrophosphate complex. In a subsequent step, they assume that the acyl group is transferred to CoA. These observations cast considerable light on the mechanism of the oxidative decarboxylation of a-keto acids and certainly may explain some of the difficulties already discussed in the section on TPP. However it remains to be seen whethei lipothiamide pyrophosphate carries the acyl group as a thioester as in CoA, and whether it acts exclusively as an acyl carrier and not also as a hydrogen carrier. One point which is still not clear is whether the oxidation and decarboxylation occur simultaneously or in an orderly sequence. 

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