Thiamine, biosynthesis inhibition

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

Analogs and Inhibitors, When we use prototrophic microorganisms, production of repressors can be reduced by addition of end product analogs to the medium. Thus, all 10 histidine pathway enzymes are derepressed up to 30-fold by 2-thiazolealanine (Ames and Hartman, 1963). In a similar manner, adenine, which inhibits thiamine synthesis, derepresses the enzymes of thiamine biosynthesis (Kawasaki et al., 1969). 

C6H9N3O2, Mr 155.16, crystals (from methanol), mp. 175 °C. Thiamine antagonist isolated from culture filtrates of Bacillus megaterium and Streptomyces albus. B. is assumed to inhibit phosphorylation of the pyrimidine part in thiamine biosynthesis. 

Consider, for example, the biosynthesis of the amino acids valine, leucine, and isoleucine. A common intermediate, hydroxy ethyl thiamine pyrophosphate (hydroxy ethyl-TPP Section 17.1.1). initiates the pathways leading to all three of these amino acids. Hydroxyethyl-TPP can react with a-ketobutyrate in the initial step for the synthesis of isoleucine. Alternatively, hydroxyethyl-TPP can react with pyruvate in the committed step for the pathways leading to valine and leucine. Thus, the relative concentrations of a-ketobutyrate and pyruvate determine how much isoleucine is produced compared with valine and leucine. Threonine deaminase, the PLP enzyme that catalyzes the formation of a-ketobutyrate, is allosterically inhibited by isoleucine (Figure 24.22). This enzyme is also allosterically activated by valine. Thus, this enzyme is inhibited by the product of the pathway that it initiates and is activated by the end product of a competitive pathway. This mechanism balances the amounts of different amino acids that are synthesized. 

The pathway as presented in Table I shows that it is linear for the first 10 steps with no branch points before the pivotal IMP is formed. However, a branch point does exist for the synthesis of the pyrimidine moiety (Bi-pyrimidine) of thiamine. Convincing evidence has been obtained to indicate that AIR also serves as a precursor to Bi-pyrimi-dine [27]. This explains the concomitant growth requirement for thiamine for most of the mutants blocked in any one of the first five enzymes [27-29]. A complication in regulatory control is thus introduced in that any attempt to control purine biosynthesis at the first five steps would have dire consequences on the formation of thiamine. This has indeed been found in the often-reported cases where inhibition of growth by adenine and its derivatives can be reversed by thiamine or its pyrimidine moiety [29-31]. The situation is more complicated in a special class of adenine-sensitive mutants where the sensitivity appears to be related to disturbances in folic acid metabolism [32]. Mutations in the AICAR formyltransferase complex (steps 9 and 10) also create a pleiotropic thiamine requirement which is not due to a deficiency in the synthesis of thiamine but rather to an unexplained phenotypic... 

---