Abstract
This paper is a brief review of the detailed mechanism of action of thiamine enzymes, based on metal complexes of bivalent transition and post-transition metals of model compounds, thiamine derivatives, synthesized and characterized with spectroscopic techniques and X-ray crystal structure determinations. It is proposed that the enzymatic reaction is initiated with a V conformation of thiamine pyrophosphate, imposed by the enzymic environment. Thiamine pyrophosphate is linked with the proteinic substrate through its pyrophosphate oxygens. In the course of the reaction, the formation of the “active aldehyde” intermediate imposes the S conformation to thiamine, while a bivalent metal ion may be linked through the N1' site of the molecule, at this stage. Finally, the immobilization of thiamine and derivatives on silica has a dramatic effect on the decarboxylation of pyruvic acid, reducing the time of its conversion to acetaldehyde from 330 minutes for the homogeneous system to less than 5 minutes in the heterogenous system.
Highlights
Thiamine pyrophosphate (TPP) is the cofactor of many enzymes, including carboxylase, transketolase, phosphoketolase, and so forth [1]
Thiamine pyrophosphate can undertake three conformations, depending on the relative orientations of the two rings of pyrimidine and thiazolium, determined by the torsional angles ΦT = C(5 )−C(3, 5 )−N(3)−C(2), ΦP = N(3)−C(3, 5 )−C(5 )−C(4 ). These conformations are the common F, found in all derivatives of free thiamine, with ΦT = 0◦ and ΦP = ±90; the S conformation, constantly found in all 2-substituted derivatives of thiamine, with ΦT = ±100◦ and ΦP = ±150◦, and the most rare V conformation with ΦT = ±90◦ and ΦP = ±90◦, where the C4−NH2 group approaches the C2−H of thiazolium [2]
Bivalent metals are required for the action of thiamine enzymes (e.g., Mg2+, Ca2+ in vivo) or transition or post-transition metals (e.g., Ni2+, Co2+, Zn2+, Cd2+, etc., in vitro)
Summary
Thiamine pyrophosphate (TPP) is the cofactor of many enzymes, including carboxylase, transketolase, phosphoketolase, and so forth (see Scheme 1) [1]. It catalyzes the decarboxylation of α-ketoacids and the formation of α-ketols. Thiamine pyrophosphate can undertake three conformations, depending on the relative orientations of the two rings of pyrimidine and thiazolium, determined by the torsional angles ΦT = C(5 )−C(3, 5 )−N(3)−C(2), ΦP = N(3)−C(3, 5 )−C(5 )−C(4 ). The accepted mechanism of action of thiamine in its enzymes was proposed by Breslow [3] and involves the addition of pyruvic acid to the C2 atom of thiazolium, following its deprotonation and the ylide formation (see Scheme 2).
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