Conversion of Anthranilate Synthase into Isochorismate Synthase: Implications for the Evolution of Chorismate‐Utilizing Enzymes

Plach, Maximilian G.; Löffler, Patrick; Merkl, Rainer; Sterner, Reinhard

doi:10.1002/anie.201505063

Cited by 14 publications

(40 citation statements)

References 14 publications

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“…6B). A protein alignment of the A. fumigatus IcsA and TrpE with characterized bacterial ASS-I and isochorismate synthases revealed that important residues that changed enzymatic activity of the Salmonella typhimorium ASS-I from producing anthranilate to isochorismate (Plach et al, 2015) are identical to the A. fumigatus IcsA, suggesting that it likely is responsible for isochorismate formation although we did not identify this metabolite in our study. Identification of the putative IcsA metabolic product will be a future task.…”

Section: Discussionmentioning

confidence: 65%

TrpE feedback mutants reveal roadblocks and conduits toward increasing secondary metabolism in Aspergillus fumigatus

Wang

Choera

Wiemann

et al. 2016

Fungal Genetics and Biology

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Small peptides formed from non-ribosomal peptide synthetases (NRPS) are bioactive molecules produced by many fungi including the genus Aspergillus. A subset of NRPS utilizes tryptophan and its precursor, the non-proteinogenic amino acid anthranilate, in synthesis of various metabolites such as A. fumigatus fumiquinazolines (Fqs) produced by the fmq gene cluster. The A. fumigatus genome contains two putative anthranilate synthases - a key enzyme in conversion of anthranilic acid to tryptophan - one beside the fmq cluster and one in a region of co-linearity with other Aspergillus spp. Only the gene found in the co-linear region, trpE, was involved in tryptophan biosynthesis. We found that site-specific mutations of the TrpE feedback domain resulted in significantly increased production of anthranilate, tryptophan, p-aminobenzoate and fumiquinazolines FqF and FqC. Supplementation with tryptophan restored metabolism to near wild type levels in the feedback mutants and suggested that synthesis of the tryptophan degradation product kynurenine could negatively impact Fq synthesis. The second putative anthranilate synthase gene next to the fmq cluster was termed icsA for its considerable identity to isochorismate synthases in bacteria. Although icsA had no impact on A. fumigatus Fq production, deletion and over-expression of icsA increased and decreased respectively aromatic amino acid levels suggesting that IcsA can draw from the cellular chorismate pool.

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Section: Discussionmentioning

confidence: 65%

TrpE feedback mutants reveal roadblocks and conduits toward increasing secondary metabolism in Aspergillus fumigatus

Wang

Choera

Wiemann

et al. 2016

Fungal Genetics and Biology

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“…Networks were visualized with the organic y-files layout in Cytoscape 3.2.0 [ 29 , 30 ]. Phylum-specific sequence sets were compiled from the SSN and used to compute sequence logos of the active site residues, essentially as described [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

Long-Term Persistence of Bi-functionality Contributes to the Robustness of Microbial Life through Exaptation

et al. 2016

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Modern enzymes are highly optimized biocatalysts that process their substrates with extreme efficiency. Many enzymes catalyze more than one reaction; however, the persistence of such ambiguities, their consequences and evolutionary causes are largely unknown. As a paradigmatic case, we study the history of bi-functionality for a time span of approximately two billion years for the sugar isomerase HisA from histidine biosynthesis. To look back in time, we computationally reconstructed and experimentally characterized three HisA predecessors. We show that these ancient enzymes catalyze not only the HisA reaction but also the isomerization of a similar substrate, which is commonly processed by the isomerase TrpF in tryptophan biosynthesis. Moreover, we found that three modern-day HisA enzymes from Proteobacteria and Thermotogae also possess low TrpF activity. We conclude that this bi-functionality was conserved for at least two billion years, most likely without any evolutionary pressure. Although not actively selected for, this trait can become advantageous in the case of a gene loss. Such exaptation is exemplified by the Actinobacteria that have lost the trpF gene but possess the bi-functional HisA homolog PriA, which adopts the roles of both HisA and TrpF. Our findings demonstrate that bi-functionality can perpetuate in the absence of selection for very long time-spans.

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“…Anthranilate synthase is considered to share evolutionary origins with other chorismate-metabolizing enzymes such as salicylate synthase (EC 4.2.99.21), aminodeoxychorismate synthase (ACDS) (EC 2.6.1.85) and isochorismate synthase (ICS) (EC 5.4.4.2), owing to similarities in reaction chemistry and polypeptide folding (Bulloch et al, 2004 ; He et al, 2004 ; He and Toney, 2006 ). It has been shown that S. typhimurium AS can accommodate water as a nucleophile (as in ICS) instead of ammonia, thereby displaying a bifunctional AS/ICS activity (Plach et al, 2015 ). Another study demonstrated that only a few mutations were sufficient to induce AS activity in an aminodeoxychorismate synthase, which in its native form does not eliminate pyruvate (Culbertson et al, 2015 ).…”

Section: The Biosynthesis Of Aaamentioning

confidence: 99%

A Three-Ring Circus: Metabolism of the Three Proteogenic Aromatic Amino Acids and Their Role in the Health of Plants and Animals

Parthasarathy

Cross

Dobson

et al. 2018

Front. Mol. Biosci.

237

169

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Tyrosine, phenylalanine and tryptophan are the three aromatic amino acids (AAA) involved in protein synthesis. These amino acids and their metabolism are linked to the synthesis of a variety of secondary metabolites, a subset of which are involved in numerous anabolic pathways responsible for the synthesis of pigment compounds, plant hormones and biological polymers, to name a few. In addition, these metabolites derived from the AAA pathways mediate the transmission of nervous signals, quench reactive oxygen species in the brain, and are involved in the vast palette of animal coloration among others pathways. The AAA and metabolites derived from them also have integral roles in the health of both plants and animals. This review delineates the de novo biosynthesis of the AAA by microbes and plants, and the branching out of AAA metabolism into major secondary metabolic pathways in plants such as the phenylpropanoid pathway. Organisms that do not possess the enzymatic machinery for the de novo synthesis of AAA must obtain these primary metabolites from their diet. Therefore, the metabolism of AAA by the host animal and the resident microflora are important for the health of all animals. In addition, the AAA metabolite-mediated host-pathogen interactions in general, as well as potential beneficial and harmful AAA-derived compounds produced by gut bacteria are discussed. Apart from the AAA biosynthetic pathways in plants and microbes such as the shikimate pathway and the tryptophan pathway, this review also deals with AAA catabolism in plants, AAA degradation via the monoamine and kynurenine pathways in animals, and AAA catabolism via the 3-aryllactate and kynurenine pathways in animal-associated microbes. Emphasis will be placed on structural and functional aspects of several key AAA-related enzymes, such as shikimate synthase, chorismate mutase, anthranilate synthase, tryptophan synthase, tyrosine aminotransferase, dopachrome tautomerase, radical dehydratase, and type III CoA-transferase. The past development and current potential for interventions including the development of herbicides and antibiotics that target key enzymes in AAA-related pathways, as well as AAA-linked secondary metabolism leading to antimicrobials are also discussed.

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Conversion of Anthranilate Synthase into Isochorismate Synthase: Implications for the Evolution of Chorismate‐Utilizing Enzymes

Cited by 14 publications

References 14 publications

TrpE feedback mutants reveal roadblocks and conduits toward increasing secondary metabolism in Aspergillus fumigatus

TrpE feedback mutants reveal roadblocks and conduits toward increasing secondary metabolism in Aspergillus fumigatus

Long-Term Persistence of Bi-functionality Contributes to the Robustness of Microbial Life through Exaptation

A Three-Ring Circus: Metabolism of the Three Proteogenic Aromatic Amino Acids and Their Role in the Health of Plants and Animals

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