The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases

Stachelhaus, Torsten; Mootz, Henning D.; Marahiel, Mohamed A.

doi:10.1016/s1074-5521(99)80082-9

Cited by 1,158 publications

(1,389 citation statements)

References 39 publications

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“…The amino acid binding pocket codes 23,24 in the NRPS enzymes were determined as described 25 using NRPS predictor (http://www-ab.informatik. uni-tuebingen.de/software), and were compared with those used by the daptomycin NRPS enzymes.…”

Section: Assignment Of Amino Acid Binding Pocket Specifitiesmentioning

confidence: 99%

Genomics and the ancient origins of the daptomycin biosynthetic gene cluster

Baltz¹

2010

J Antibiot

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Daptomycin is a clinically useful lipopeptide antibiotic produced by Streptomyces roseosporus. The antibiotic is assembled by a nonribosomal peptide synthetase (NRPS) mechanism, and the cyclized tridecapeptide contains three non-proteinogenic L-amino acids: ornithine (Orn), 3-methyl-glutamic acid (3mGlu) and kynurinine (Kyn). Daptomycin also has three D-amino acids. The two genes that encode proteins involved in the formation of 3mGlu and Kyn have no known orthologs, and hence they are good probes to search for daptomycin-like gene clusters among newly sequenced actinomycete genomes. A recent search with these genes revealed a daptomycin-like gene cluster in Saccharomonospora viridis, a causative agent for farmer's lung disease. S. viridis has a genome of 4.3 Mb, which is about one half the size of Streptomyces genomes. Searches for other NRPS and polyketide synthase (PKS) genes revealed only one other NRPS gene and no PKS genes in S. viridis. The orthologous lipopeptide biosynthetic genes and gene products in S. viridis and S. roseosporus have diverged extensively from a last common ancestor dating back to a pathway that had evolved over 1 billion years ago.

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Section: Assignment Of Amino Acid Binding Pocket Specifitiesmentioning

confidence: 99%

Genomics and the ancient origins of the daptomycin biosynthetic gene cluster

Baltz¹

2010

J Antibiot

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“…2, where the discrepancy in molecular weights is potentially due to difficulties in resolving the very high molecular weight bands and estimating their masses from standards. The domain structures of Pmen1902 and Pmen1901 are characteristic of NRPSs (Stachelhaus et al 1999) (Fig. 7).…”

Section: Discussionmentioning

confidence: 99%

Identification, isolation, and analysis of a gene cluster involved in iron acquisition by Pseudomonas mendocina ymp

Awaya

DuBois

2007

Biometals

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Microbial acquisition of iron from natural sources in aerobic environments is a little-studied process that may lead to mineral instability and trace metal mobilization. Pseudomonas mendocina ymp was isolated from the Yucca Mountain Site for long-term nuclear waste storage. Its ability to solubilize a variety of Fe-containing minerals under aerobic conditions has been previously investigated but its molecular and genetic potential remained uncharacterized. Here, we have shown that the organism produces a hydroxamate and not a catecholate-based siderophore that is synthesized via non-ribosomal peptide synthetases. Gene clustering patterns observed in other Pseudomonads suggested that hybridizing multiple probes to the same library could allow for the identification of one or more clusters of syntenic siderophore-associated genes. Using this approach, two independent clusters were identified. An unfinished draft genome sequence of P. mendocina ymp indicated that these mapped to two independent contigs. The sequenced clusters were investigated informatically and shown to contain respectively a potentially complete set of genes responsible for siderophore biosynthesis, uptake, and regulation, and an incomplete set of genes with low individual homology to siderophore-associated genes. A mutation in the cluster's pvdA homolog (pmhA) resulted in a siderophore-null phenotype, which could be reversed by complementation. The organism likely produces one siderophore with possibly different isoforms and a peptide backbone structure containing seven residues (predicted sequence: Acyl-Asp-DabSer-fOHOrn-Ser-fOHorn). A similar approach could be applied for discovery of Fe− and siderophore-associated genes in unsequenced or poorly annotated organisms.

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“…This surface charge modulation by D-alanylation appears to have profound effects on the antigenicity of the bacteria and immune response of host cells 2 . The D-alanyl carrier protein ligase DltA (~500 amino acid residues) 18 is an enzyme resembling the adenylation domains (also called AMP-forming domains) found in modular nonribosomal peptide synthetases 19 . Its remote homologues include the acyl-coenzyme A synthetases and firefly luciferases 20 .…”

Section: Introductionmentioning

confidence: 99%

Profiling and tandem mass spectrometry analysis of aminoacylated phospholipids in Bacillus subtilis

Atila

Luo

2016

F1000Res

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Cationic modulation of the dominantly negative electrostatic structure of phospholipids plays an important role in bacterial response to changes in the environment. In addition to zwitterionic phosphatidylethanolamine, Gram-positive bacteria are also abundant in positively charged lysyl-phosphatidylglycerol. Increased amounts of both types of lipids render Gram-positive bacterial cells more resistant to cationic antibiotic peptides such as defensins. Lysyl and alanyl-phosphatidylglycerol as well as alanyl-cardiolipin have also been studied by mass spectroscopy. Phospholipids modified by other amino acids have been discovered by chemical analysis of the lipid lysate but have yet to be studied by mass spectroscopy. We exploited the high sensitivity of modern mass spectroscopy in searching for substructures in complex mixtures to establish a sensitive and thorough screen for aminoacylated phospholipids. The search for deprotonated aminoacyl anions in lipid extracted from Bacillus subtilis strain 168 yielded strong evidence as well as relative abundance of aminoacyl-phosphatidylglycerols, which serves as a crude measure of the specificity of aminoacyl-phosphatidylglycerol synthase MprF. No aminoacyl-cardiolipin was found. More importantly, the second most abundant species in this category is D-alanyl-phosphatidylglycerol, suggesting a possible role in the D-alanylation pathway of wall- and lipo-teichoic acids.

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The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases

Cited by 1,158 publications

References 39 publications

Genomics and the ancient origins of the daptomycin biosynthetic gene cluster

Genomics and the ancient origins of the daptomycin biosynthetic gene cluster

Identification, isolation, and analysis of a gene cluster involved in iron acquisition by Pseudomonas mendocina ymp

Profiling and tandem mass spectrometry analysis of aminoacylated phospholipids in Bacillus subtilis

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