Biosynthetic Manipulation of Tryptophan in Bacteria: Pathways and Mechanisms

Abstract

Tryptophan, the most chemically complex and the least abundant of the 20 common proteinogenic amino acids, is a biosynthetic precursor to a large number of complex microbial natural products. Many of these molecules are promising scaffolds for drug discovery and development. The chemical features of tryptophan, including its ability to undergo enzymatic modifications at almost every atom in its structure and its propensity to undergo spontaneous, non-enzyme catalyzed chemistry, make it a unique biological precursor for the generation of chemical complexity. Here, we review the pathways that enable incorporation of tryptophan into complex metabolites in bacteria, with a focus on recently discovered, unusual metabolic transformations.

Targeted Metagenomics: Finding Rare Tryptophan Dimer Natural Products in the Environment

“…8 Despite differences in chemical structure and biological activity, biosynthetically characterized bacterial TDs share the two initial biosynthetic transformations: i ) the activation (oxidation) of tryptophan by an indole-3-pyruvic acid imine synthase and ii ) the dimerization of activated tryptophan by a chromopyrrolic acid ( 3 ) synthase (CPAS) (Figure 1A). 9–10 Following these conserved steps, TD biosynthesis diverges to give rise to a variety of distinct core structural classes (Figure 1) that are then often highly modified by pathway-specific collections of tailoring enzymes.…”

Kynurenine pathway metabolism and the microbiota-gut-brain axis

“…In addition to the examples mentioned above, bacteria can also use tryptophan to produce multiple other bioactive products with diverse properties (Alkhalaf and Ryan, 2015). The major direct microbial influence then on circulating availability of tryptophan, assuming an adequate dietary supply of this essential amino acid, likely arises as a result of bacterial tryptophan utilisation and metabolism and the impact of microbial metabolites on host serotonergic production.…”

Advances in Chromobacterium violaceum and properties of violacein-Its main secondary metabolite: A review

“…Commonly, the 1,2-shift of the indole nucleus on the left side of the violacein structure ( Fig. 8) is considered the most attractive biosynthetic mechanism in the entire proposed biosynthetic pathway because of the fact that no other pigment synthesis relies on this shift, nor does it occur in known natural product synthetic pathways (Alkhalaf and Ryan, 2015;Merlin et al, 2013).…”

“…2. This pathway requires the joint action of five enzymes, which enables the efficient biosynthesis of violacein (Alkhalaf and Ryan, 2015).…”