Accessing chemical diversity from the uncultivated symbionts of small marine animals

Smith, Thomas E.; Pond, Christopher D.; Pierce, Elizabeth; Harmer, Zachary P; Kwan, Jason C.; Zachariah, Malcolm M.; Harper, Mary Kay; Wyche, Thomas P.; Matainaho, Teatulohi; Bugni, Tim S.; Barrows, Louis R.; Ireland, Chris M.; Schmidt, Eric W.

doi:10.1038/nchembio.2537

Cited by 80 publications

(75 citation statements)

References 60 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the absence of SLFN11, this irreversible and lethal replication inhibition does not occur (67). SLFN11 expression is dynamic, owing to silencing by promoter methylation, which is responsible both for innate and acquired SLFN11-dependent resistance (69), although treatment with EZH2 and HDAC inhibitors may be capable of restoring SLFN11 expression, and therefore PARP inhibitor sensitivity (70,71).…”

Section: Predictive Biomarkers Beyond Hrdmentioning

confidence: 99%

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Pilié

Byers

O’Connor

et al. 2019

Clinical Cancer Research

263

195

View full text Add to dashboard Cite

A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. Although PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer. In this article, we highlight the key similarities and differences between individual PARP inhibitors and their implications for the clinic. We discuss data that currently support clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers, toward broader populations of patients through the use of novel biomarkers of homologous recombination repair deficiency (HRD), as well as predictive biomarkers rooted in mechanisms of sensitivity outside of HRD. We also explore the potential application of PARP inhibitors in earlier treatment settings, including neoadjuvant, adjuvant, and even chemoprevention approaches. Finally, we focus on promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness."

show abstract

Section: Predictive Biomarkers Beyond Hrdmentioning

confidence: 99%

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Pilié

Byers

O’Connor

et al. 2019

Clinical Cancer Research

263

195

View full text Add to dashboard Cite

show abstract

“…Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an expanding group of natural products [1]. Lanthipeptides are among the most studied RiPPs and have a diverse array of structures and biological activities, including antibiotic [2][3][4][5], anti-fungal [6], anti-HIV [7,8], and antinociceptive [9,10] activities. These peptidic natural products are characterized by the presence of macrocycles formed via thioether crosslinks between amino acid residue side chains, termed lanthionines or methyllanthionines [11].…”

mentioning

confidence: 99%

Precursor peptide-targeted mining of more than one hundred thousand genomes expands the lanthipeptide natural product family

Walker

Mitchell

Donk

2020

Preprint

View full text Add to dashboard Cite

BackgroundLanthipeptides belong to the ribosomally synthesized and post-translationally modified peptide group of natural products and have a variety of biological activities ranging from antibiotics to antinociceptives. These peptides are cyclized through thioether crosslinks and can bear other secondary post-translational modifications. While lanthipeptide biosynthetic gene clusters can be identified by the presence of characteristic enzymes involved in the post-translational modification of these peptides, locating the precursor peptides encoded within these clusters is challenging due to their short length and high sequence variability, which limits the high-throughput exploration of lanthipeptide precursor peptides. To address this challenge, we enhanced the predictive capabilities of Rapid ORF Description & Evaluation Online (RODEO) to identify all known classes of lanthipeptides. ResultsUsing RODEO, we mined over 100,000 bacterial and archaeal genomes in the RefSeq database. We identified nearly 8,500 lanthipeptide precursor peptides. These precursor peptides were identified in a broad range of bacterial phyla as well as the Euryarchaeota phylum of archaea. Bacteroidetes were found to encode a large number of these biosynthetic gene clusters, despite making up a relatively small portion of the genomes in this dataset. While a number of these precursor peptides are similar to those of previously characterized lanthipeptides, even more were not, including potential antibiotics. Additionally, examination of the biosynthetic gene clusters revealed enzymes that install secondary post-translational modifications are more widespread than initially thought. ConclusionLanthipeptide biosynthetic gene clusters are more widely distributed and the precursor peptides encoded within these clusters are more diverse than previously appreciated, demonstrating that the lanthipeptide sequence-function space remains largely underexplored.

show abstract

“…In this study, we provide the first in vitro demonstration that DurN catalyzes Lal formation, a step that had been recalcitrant in previous studies 6,15 . By comparing enzymatic and non-enzymatic Lal generation, our data suggest that DurN greatly facilitates the reaction and controls the stereoselectivity.…”

Section: Resultsmentioning

confidence: 78%

“…GC-MS analysis indicated that authentic duramycin isolated from the producer organism contained predominantly the natural LL-Lal isomer (Fig. 4a), with a small amount of epimer that is likely formed during acid hydrolysis 6,15 . However, deoxyduramycin formed in E. coli contained about equal amounts of two diastereomers.…”

Section: Stereochemistry Of Enzymatic and Non-enzymatic Lal Formationmentioning

confidence: 99%

See 1 more Smart Citation

Substrate-assisted Enzymatic Formation of Lysinoalanine in Duramycin

Cogan

Navo³

et al. 2018

Preprint

View full text Add to dashboard Cite

Duramycin is a heavily post-translationally modified peptide that binds phosphatidylethanolamine. It has been investigated as an antibiotic, inhibitor of viral entry, therapeutic for cystic fibrosis, and tumor and vasculature imaging agent. Duramycin contains a β-hydroxylated Asp (Hya) and four macrocycles, including an essential lysinoalanine (Lal) crosslink. The mechanism of Lal formation is not known. We here show that Lal is installed stereospecifically by DurN via addition of Lys19 to a dehydroalanine. The structure of DurN reveals an unusual dimer with a new fold. Surprisingly, in the structure of duramycin bound to DurN, no residues of the enzyme are near the Lal. Instead, Hya15 of the substrate makes interactions with Lal suggesting it acts as a base to deprotonate Lys19 during catalysis. Biochemical data suggest that DurN preorganizes the reactive conformation of the substrate, such that the Hya15 of the substrate can serve as the catalytic base for Lal formation. Duramycin and closely related compounds are ribosomally synthesized and post-translationally modified peptides (RiPPs) produced by various actinomycetes 1-5 and marine symbionts 6 . Duramycin binds phosphatidylethanolamine (PE), a major structural phospholipid in mammalian and microbial cell membranes 7, 8 . Duramycin contains 19 amino acids, and five final posttranslational modifications (PTMs), including one lanthionine (Lan), two methyllanthionines (MeLan), an erythro-3-hydroxy-L-aspartic acid (Hya) resulting from the hydroxylation of Asp15, and one (2S,9S)-Lal (Figure 1). The carboxylate and hydroxyl groups of Hya15 make key interactions with the ethanolamine head group of PE, providing

show abstract

Accessing chemical diversity from the uncultivated symbionts of small marine animals

Cited by 80 publications

References 60 publications

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Precursor peptide-targeted mining of more than one hundred thousand genomes expands the lanthipeptide natural product family

Substrate-assisted Enzymatic Formation of Lysinoalanine in Duramycin

Contact Info

Product

Resources

About