Thiamine biosynthesis can be used to dissect metabolic integration

Abstract

The emergence of systems biology has re-emphasized the advantages of understanding biological processes with a global perspective. One biological process amenable to global approaches is microbial metabolism. This review describes a model system that contributes to the goals of systems biology by experimentally defining metabolic integration found in a bacterial cell and thus providing data needed for implementation and interpretation of systems approaches. We have taken a largely unbiased in vivo approach centered on thiamine biosynthesis to identify new metabolic components and connections, and to explore uncharacterized paradigms of the integration between them. This article summarizes recent results from this approach that include the identification of the function of unknown genes, connections between cofactors biosynthesis and thiamine biosynthesis, and how metabolites from one biosynthetic pathway can be used in thiamine biosynthesis.

Figure 1. The joint thiamine-purine biosynthesis pathway

(a) Schematic representation of the purine-thiamine biosynthetic pathways in S. enterica. Relevant gene products are noted above the step they catalyze. Not all steps are shown. (b) Schematic representation of the mechanisms for PRA formation that are distinct from PurF. (i) The non-enzymatic breakdown of PR-anthranilate to anthranilate and R5P allows for the non-enzymatic formation of PRA [21]. (ii) High levels of R5P generated when ribose is the sole carbon source allows for non-enzymatic formation of PRA [19]. (iii) R5P can be diverted for non-enzymatic PRA formation when PrsA activity is reduced [19]. (iv) TrpD (bifunctional glutamine amidotransferase/anthranilate phosphoribosyltransferase) is necessary and sufficient for PRA formation in the absence of YjgF [23]. (v) The contribution of R5P from the OPP pathway allows weak non-enzymatic formation of PRA [15]. Abbreviations: AIR, aminoimidazole ribotide; Cys, cysteine; DXP, 1-deoxyxylulose-5-phosphate; Gln, glutamine; HMP-PP, 4-amino-5-hydroxymethyl-2-methylpyrimidine-pyrophosphate; OPP, oxidative pentose phosphate pathway; PRA, phosphoribosylamine; PRPP, phosphoribosylpyrophosphate; R5P, ribose-5-phosphate THZ-P, thiazole phosphate; TrpD, bifunctional glutamine amidotransferase/anthranilate phosphoribosyltransferase; Tyr, tyrosine.

Figure I. The pantothenate biosynthesis pathway

A schematic representation of the pantothenate biosynthetic pathway in S. enterica.