Biosynthesis of natural products containing β-amino acids

Kudo, Fumitaka; Miyanaga, Akimasa; Eguchi, Tadashi

doi:10.1039/c4np00007b

Cited by 209 publications

(153 citation statements)

References 135 publications

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“…5). Although there is no evidence that glutamate is directly involved in thalassospiramide biosynthesis, glutamate metabolism is at the center of several amino acid metabolic pathways, and it affects the biosynthesis of a variety of bacterium-sourced natural products (16,17). Enhancement of the tyrosine biosynthetic pathway can increase the production of salidrosides in engineered Escherichia coli (18).…”

Section: Discussionmentioning

confidence: 99%

Family-wide Structural Characterization and Genomic Comparisons Decode the Diversity-oriented Biosynthesis of Thalassospiramides by Marine Proteobacteria

Zhang

Liang

Lai

et al. 2016

Journal of Biological Chemistry

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Edited by Gerald W. HartThe thalassospiramide lipopeptides have great potential for therapeutic applications; however, their structural and functional diversity and biosynthesis are poorly understood. Here, by cultivating 130 Rhodospirillaceae strains sampled from oceans worldwide, we discovered 21 new thalassospiramide analogues and demonstrated their neuroprotective effects. To investigate the diversity of biosynthetic gene cluster (BGC) architectures, we sequenced the draft genomes of 28 Rhodospirillaceae strains. Our family-wide genomic analysis revealed three types of dysfunctional BGCs and four functional BGCs whose architectures correspond to four production patterns. This correlation allowed us to reassess the "diversity-oriented biosynthesis" proposed for the microbial production of thalassospiramides, which involves iteration of several key modules. Preliminary evolutionary investigation suggested that the functional BGCs could have arisen through module/domain loss, whereas the dysfunctional BGCs arose through horizontal gene transfer. Further comparative genomics indicated that thalassospiramide production is likely to be attendant on particular genes/pathways for amino acid metabolism, signaling transduction, and compound efflux. Our findings provide a systematic understanding of thalassospiramide production and new insights into the underlying mechanism.

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Section: Discussionmentioning

confidence: 99%

Family-wide Structural Characterization and Genomic Comparisons Decode the Diversity-oriented Biosynthesis of Thalassospiramides by Marine Proteobacteria

Zhang

Liang

Lai

et al. 2016

Journal of Biological Chemistry

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“…1). These β-amino acid carrying enzymes are conserved in various macrolactam polyketide biosynthetic gene clusters, suggesting that β-amino acid starter units are loaded to PKS through the same mechanism in their biosynthesis (10).…”

Section: Significancementioning

confidence: 99%

“…Macrolactam antibiotics are an important class of macrocyclic polyketides, and most contain a unique β-amino acid starter unit in their polyketide skeletons (10). Vicenistatin, produced by Streptomyces halstedii HC34, possesses a 3-aminoisobutyrate unit at the starter position of the polyketide backbone (11).…”

Section: Significancementioning

confidence: 99%

Structure-based analysis of the molecular interactions between acyltransferase and acyl carrier protein in vicenistatin biosynthesis

Miyanaga

Iwasawa

Shinohara

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Acyltransferases (ATs) are key determinants of building block specificity in polyketide biosynthesis. Despite the importance of protein-protein interactions between AT and acyl carrier protein (ACP) during the acyltransfer reaction, the mechanism of ACP recognition by AT is not understood in detail. Herein, we report the crystal structure of AT VinK, which transfers a dipeptide group between two ACPs, VinL and VinP1LdACP, in vicenistatin biosynthesis. The isolated VinK structure showed a unique substrate-binding pocket for the dipeptide group linked to ACP. To gain greater insight into the mechanism of ACP recognition, we attempted to crystallize the VinK-ACP complexes. Because transient enzyme-ACP complexes are difficult to crystallize, we developed a covalent cross-linking strategy using a bifunctional maleimide reagent to trap the VinK-ACP complexes, allowing the determination of the crystal structure of the VinK-VinL complex. In the complex structure, Arg-153, Met-206, and Arg-299 of VinK interact with the negatively charged helix II region of VinL. The VinK-VinL complex structure allows, to our knowledge, the first visualization of the interaction between AT and ACP and provides detailed mechanistic insights into ACP recognition by AT.polyketide | acyltransferase | acyl carrier protein | protein-protein interaction | cross-linking P olyketide synthases (PKSs) are multifunctional enzymes responsible for the biosynthesis of various polyketide natural products (1). Bacterial modular PKSs comprise several catalytic modules that are each responsible for a single round of the polyketide chain elongation reaction. Each module minimally consists of a ketosynthase (KS) domain, an acyltransferase (AT) domain, and an acyl carrier protein (ACP) domain. The AT domain recognizes a specific acyl building block and catalyzes its transfer reaction onto the 4′-phosphopantetheine arm of the ACP. KS extends the polyketide chain by condensing the resulting ACP-bound building blocks with the elongated acylACPs. Although standard modular PKSs contain AT domains in their modules, some modular PKSs lack AT domains in each module and instead receive their acyl building blocks by standalone trans-acting ATs (2).The selection of the starter unit is generally governed by the substrate specificity of the AT domain in the loading module (1). In some modular PKS systems, a didomain-type loading module comprising a loading AT domain and an ACP domain selects an acyl starter building block such as an acetate unit to generate an acyl-ACP intermediate, which is transferred to the downstream extension module for polyketide chain elongation. Alternatively, in a KS Q -type loading module consisting of three domains, the AT domain selects an α-carboxyacyl substrate such as a malonyl group, and the KS Q domain subsequently catalyzes its decarboxylation to construct an acyl-ACP thioester. For polyketide chain elongation, the AT domain of the extension module generally recognizes a specific α-carboxyacyl-CoA as an extender building block (3). Malony...

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“…However, they have been found as components of nonribosomal peptides, bacterial antibiotics, anticancer drugs, and other natural products (Kudo et al, 2014). In particular, the b-tyrosine and b-phenylalanine have been investigated as building blocks for the biosynthesis of several medically relevant metabolites.…”

Section: Introductionmentioning

confidence: 99%

The Tyrosine Aminomutase TAM1 Is Required for β-Tyrosine Biosynthesis in Rice

et al. 2015

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ORCID IDs: 0000-0001-8597-9841 (J.Y.); 0000-0002-0121-0048 (S.R.S.); 0000-0002-9675-934X (G.J.)Non-protein amino acids, often isomers of the standard 20 protein amino acids, have defense-related functions in many plant species. A targeted search for jasmonate-induced metabolites in cultivated rice (Oryza sativa) identified (R)-b-tyrosine, an isomer of the common amino acid (S)-a-tyrosine in the seeds, leaves, roots, and root exudates of the Nipponbare cultivar. Assays with 119 diverse cultivars showed a distinct presence/absence polymorphism, with b-tyrosine being most prevalent in temperate japonica cultivars. Genetic mapping identified a candidate gene on chromosome 12, which was confirmed to encode a tyrosine aminomutase (TAM1) by transient expression in Nicotiana benthamiana and in vitro enzyme assays. A point mutation in TAM1 eliminated b-tyrosine production in Nipponbare. Rice cultivars that do not produce b-tyrosine have a chromosome 12 deletion that encompasses TAM1. Although b-tyrosine accumulation was induced by the plant defense signaling molecule jasmonic acid, bioassays with hemipteran and lepidopteran herbivores showed no negative effects at physiologically relevant b-tyrosine concentrations. In contrast, root growth of Arabidopsis thaliana and other tested dicot plants was inhibited by concentrations as low as 1 mM. As b-tyrosine is exuded into hydroponic medium at higher concentrations, it may contribute to the allelopathic potential of rice.

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Biosynthesis of natural products containing β-amino acids

Cited by 209 publications

References 135 publications

Family-wide Structural Characterization and Genomic Comparisons Decode the Diversity-oriented Biosynthesis of Thalassospiramides by Marine Proteobacteria

Family-wide Structural Characterization and Genomic Comparisons Decode the Diversity-oriented Biosynthesis of Thalassospiramides by Marine Proteobacteria

Structure-based analysis of the molecular interactions between acyltransferase and acyl carrier protein in vicenistatin biosynthesis

The Tyrosine Aminomutase TAM1 Is Required for β-Tyrosine Biosynthesis in Rice

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