Abstract:Bioactive natural products containing a C-P bond act as mimics of phosphate esters and carboxylic acids, thereby competing with these compounds for active sites of enzymes. Dehydrophos (DHP), a broad-spectrum antibiotic, is a phosphonotripeptide produced by
Streptomyces luridus
, in which glycine and leucine are linked to an aminophosphonate analog of dehydroalanine, ΔAla(P). This unique feature, in combination with the monomethylation of the phosphonic acid, renders DHP a Trojan horse … Show more
“…The GNAT fold was recently identified in many more tRNA-dependent transferases in Streptomyces species, which utilize specific aa-tRNAs for synthesis of broad-spectrum antibiotics. For instance, the protein VlmA utilizes Ser-tRNA Ser for synthesis of the antibiotic valanimycin 45 ; DhpH and DhpK utilize Gly-tRNA Gly and Leu-tRNA Leu for biosynthesis of tripeptide phosphonate 46 ; the protein PacB utilizes Ala-tRNA Ala in the biosynthetic pathway for pacidamycin 47 ; FzmI uses Val-tRNA Val for synthesis of fosfazinomycin 48 ; Orf11 uses Gly-tRNA Gly for the synthesis of a streptothricin-related antibiotic. 49
10.1080/15476286.2017.1356980-f0003Figure 3.Role of aa-tRNA transferases exhibiting a GNAT fold.…”
Section: The Cytosolic Domain Of Aapgs Exhibits a Gcn5-like Acetyltramentioning
ABSTRACTtRNA-dependent addition of amino acids to lipids on the outer surface of the bacterial membrane results in decreased effectiveness of antimicrobials such as cationic antimicrobial peptides (CAMPs) that target the membrane, and increased virulence of several pathogenic species. After a brief introduction to CAMPs and the various bacterial resistance mechanisms used to counteract these compounds, this review focuses on recent advances in tRNA-dependent pathways for lipid modification in bacteria. Phenotypes associated with amino acid lipid modifications and regulation of their expression will also be discussed.
“…The GNAT fold was recently identified in many more tRNA-dependent transferases in Streptomyces species, which utilize specific aa-tRNAs for synthesis of broad-spectrum antibiotics. For instance, the protein VlmA utilizes Ser-tRNA Ser for synthesis of the antibiotic valanimycin 45 ; DhpH and DhpK utilize Gly-tRNA Gly and Leu-tRNA Leu for biosynthesis of tripeptide phosphonate 46 ; the protein PacB utilizes Ala-tRNA Ala in the biosynthetic pathway for pacidamycin 47 ; FzmI uses Val-tRNA Val for synthesis of fosfazinomycin 48 ; Orf11 uses Gly-tRNA Gly for the synthesis of a streptothricin-related antibiotic. 49
10.1080/15476286.2017.1356980-f0003Figure 3.Role of aa-tRNA transferases exhibiting a GNAT fold.…”
Section: The Cytosolic Domain Of Aapgs Exhibits a Gcn5-like Acetyltramentioning
ABSTRACTtRNA-dependent addition of amino acids to lipids on the outer surface of the bacterial membrane results in decreased effectiveness of antimicrobials such as cationic antimicrobial peptides (CAMPs) that target the membrane, and increased virulence of several pathogenic species. After a brief introduction to CAMPs and the various bacterial resistance mechanisms used to counteract these compounds, this review focuses on recent advances in tRNA-dependent pathways for lipid modification in bacteria. Phenotypes associated with amino acid lipid modifications and regulation of their expression will also be discussed.
“…phosphonates or phosphinates) are rarely encountered in living organisms and they still represent an underused functional group for the development of bioactive compounds [3,4]. The last few years have seen the revival of the work, originally started early in the 1970s, relating to the growing information on the genomic and metabolic pathways of bacteria [5,6]. Interestingly, the few synthetic or naturally occurring molecules which contain a phosphinate function play key roles in many different areas of life science.…”
This review first outlines general considerations on phosphinic acids and derivatives as bioisosteric groups. The next sections present key aspects of phosphinic acid-based molecules and include a brief description of the biological pathways involved for their activities. The synthetic aspects and the biological activities of such compounds reported in the literature between 2008 and 2013 are also described.
“…Instead, VlpB, a putative short-chain dehydrogenase, may reduce PnPy to 2-hydroxy-3-phosphonopropanoic acid (phosphonolactate) in a reaction analogous to the highly favorable reduction of pyruvate to lactate by NADH-dependent lactate dehydrogenases (equilibrium constant, K eq = 1 × 10 5 ) (42). Analogous to the proposed formation of 1-oxo-2-phosphorylethylphosphonic acid by the phosphoglycerate kinase DhpB in dehydrophos biosynthesis (37), phosphorylation of phosphonolactate by VlpD would yield 2-hydroxy-3-oxo-3-phosphoxypropylphosphonic acid. Reduction by VlpC, homologous to N-acetyl γ-glutamyl phosphate (AGP) reductase, results in 2-hydroxy-3-oxopropylphosphonic acid that could be converted to DHPPA via another reduction by VlpE (alcohol dehydrogenase).…”
Section: Valinophos a Phosphonopeptide Produced By A New Archetypicalmentioning
Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed "genome mining" as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N 5 -hydroxyarginine; valinophos, an N-acetyl L-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products.natural products | genome mining | phosphonic acid | antibiotic
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