Abstract
Phosphoribosylamine (PRA) is an intermediate in the biosynthetic pathway that is common to thiamine and purines. Glutamine phosphoribosyl pyrophosphate (PRPP) amidotransferase is the product of the purF gene in Salmonella enterica and catalyzes the synthesis of PRA from PRPP and glutamine. Strains lacking PurF require exogenous addition of purines for growth. However, under some growth conditions or with specific secondary mutations these strains grow in the absence of exogenous thiamine. Mutant alleles of hisA, which encodes 1-(5-phosphoribosyl)-5-[(5-phosphoribosylamino) methylideneamino] imidazole-4-carboxamide (ProFAR) isomerase, allowed PurF-independent PRA formation. The alleles of hisA that suppressed the requirement for exogenous thiamine resulted in proteins with reduced enzymatic activity. Data presented here showed that decreased activity of HisA altered metabolite pools and allowed PRA formation from ProFAR. Possible mechanisms of this conversion were proposed. The results herein emphasize the plasticity of the metabolic network and specifically highlight the potential for chemical syntheses to contribute to network robustness.
Highlights
Discrete biochemical pathways define the framework of metabolism
We have shown that thiamine biosynthesis in S. enterica is amenable to in vivo analyses, making it a powerful system to query an organism about the characteristics of the naturally occurring metabolic network and dissect its potential
This study described a new metabolic link between histidine and thiamine biosynthesis in S. enterica
Summary
Discrete biochemical pathways define the framework of metabolism. Superimposed on this framework is a network of interactions mediated by metabolites. Our understanding of the metabolic framework has been achieved through decades of biochemical and genetic studies, many of them in bacterial systems. Efforts to identify the network of interactions mediated by metabolites and define the significance of these interactions to the fitness of the organism are in the early stages. Thiamine biosynthesis in Salmonella enterica has proven to be a productive model system to study metabolic integration and robustness (reviewed in [1]). We have shown that thiamine biosynthesis in S. enterica is amenable to in vivo analyses, making it a powerful system to query an organism about the characteristics of the naturally occurring metabolic network and dissect its potential
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