Abstract：
:Pyrrole-imidazole alkaloids are natural products isolated from marine sponges, holobiont metazoans that are associated with symbiotic microbiomes. Pyrrole-imidazole alkaloids have attracted attention due to their chemical complexity and their favorable pharmacological properties. However, insights into how these molecules are biosynthesized within the sponge holobionts are scarce. Here, we provide a multiomic profiling of the microbiome and metabolomic architectures of three sponge genera that are prolific producers of pyrrole-imidazole alkaloids. Using a retrobiosynthetic scheme as a guide, we mine the metabolomes of these sponges to detect intermediates in pyrrole-imidazole alkaloid biosynthesis. Our findings reveal that the nonproteinogenic amino acid homoarginine is a critical branch point that connects primary metabolite lysine to the production of pyrrole-imidazole alkaloids. These insights are derived from the polar metabolomes of these sponges which additionally reveal the presence of zwitterionic betaines that may serve important ecological roles in marine habitats. We also establish that metabolomic richness does not correlate with microbial diversity of the sponge holobiont for neither the polar nor the nonpolar metabolomes. Our findings now provide the biochemical foundation for genomic interrogation of the sponge holobiont to establish biogenetic routes for pyrrole-imidazole alkaloid production.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Mohanty I,Moore SG,Yi D,Biggs JS,Gaul DA,Garg N,Agarwal Vdoi
10.1021/acschembio.0c00375subject
Has Abstractpub_date
2020-08-21 00:00:00pages
2185-2194issue
8eissn
1554-8929issn
1554-8937journal_volume
15pub_type
杂志文章abstract：:The 3D structure of a protein is determined by the unique sequence of amino acid residues comprising the polypeptide chain. Sequence changes can cause protein misfolding, a potentially toxic phenomenon implicated in various neurodegenerative disorders. In a recent paper, translational misincorporation is proposed to b...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb6004068
更新日期：2006-10-24 00:00:00
abstract：:Engineering gene circuits with novel functions holds promise for broad applications in biology, engineering, and medicine. Directed evolution complements rational design as an important strategy for optimizing gene circuits and circuit elements. ...
journal_title：ACS chemical biology
pub_type： 评论,杂志文章,评审
doi：10.1021/cb6004596
更新日期：2006-12-20 00:00:00
abstract：:A Natural Compound Library containing myxobacterial secondary metabolites was screened in murine macrophages for novel activators of IL-1β maturation and secretion. The most potent of three hits in total was a so far undescribed metabolite, which was identified from the myxobacterium Hyalangium minutum strain Hym3. Wh...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b00659
更新日期：2018-10-19 00:00:00
abstract：:Fusicoccin A is a diterpene glucoside phytotoxin generated by the fungal pathogen Phomopsis amygdali that causes the plant disease constriction canker, first discovered in New Jersey peach orchards in the 1930s. Fusicoccin A is also an emerging new lead in cancer chemotherapy. The hydrocarbon precursor of fusicoccin A...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.5b00960
更新日期：2016-04-15 00:00:00
abstract：:C-methylation of aromatic small molecules by C-methyltransferases (C-MTs) is an important biological transformation that involves C-C bond formation using S-adenosyl-l-methionine (SAM) as the methyl donor. Here, two advances in the mechanistic understanding of C-methylation of the 8-position of coumarin substrates cat...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.6b01053
更新日期：2017-02-17 00:00:00
abstract：:Hydrogen sulfide (H2S) is an important gasotransmitter and biomolecule, and many synthetic small-molecule H2S donors have been developed for H2S-related research. One important class of triggerable H2S donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly conver...
journal_title：ACS chemical biology
pub_type： 信件
doi：10.1021/acschembio.8b00981
更新日期：2019-02-15 00:00:00
abstract：:Establishing the relative configuration of a bioactive natural product represents the most challenging part in determining its structure. Residual dipolar couplings (RDCs) are sensitive probes of the relative spatial orientation of internuclear vectors. We adapted a force field structure calculation methodology to all...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00281
更新日期：2017-08-18 00:00:00
abstract：:Matrix metalloproteases (MMPs) are a large family of zinc-dependent endopeptidases involved in a diverse set of physiological and pathological processes, most notably in cancer. Current methods for imaging and quantifying MMP activity lack sufficient selectivity and spatiotemporal resolution to allow studies of specif...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b00562
更新日期：2018-09-21 00:00:00
abstract：:Aldehydes are key intermediates in many cellular processes, from endogenous metabolic pathways like glycolysis to undesired exogenously induced processes such as lipid peroxidation and DNA interstrand cross-linking. Alkyl aldehydes are well documented to be cytotoxic, affecting the functions of DNA and protein, and th...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.6b00269
更新日期：2016-08-19 00:00:00
abstract：:Apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii, the causative agents of severe malaria and toxoplasmosis, respectively, undergo several critical developmental transitions during their lifecycle. Most important for human pathogenesis is the asexual cycle, in which parasites undergo rounds...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb501004q
更新日期：2015-04-17 00:00:00
abstract：:The endoplasmic reticulum (ER) is the initial site of biogenesis of secretory pathway proteins, including proteins localized to the ER, Golgi, lysosomes, intracellular vesicles, plasma membrane, and extracellular compartments. Proteins within the secretory pathway contain a high abundance of disulfide bonds to protect...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.9b01014
更新日期：2020-02-21 00:00:00
abstract：:We have developed an improved tool for imaging acidic tumors by reporting the insertion of a transmembrane helix: the pHLIP-Fluorescence Insertion REporter (pHLIP-FIRE). In acidic tissues, such as tumors, peptides in the pHLIP family insert as α-helices across cell membranes. The cell-inserting end of the pHLIP-FIRE p...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb500388m
更新日期：2014-11-21 00:00:00
abstract：:Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies of the SMN1 gene, which produces an essential protein known as SMN. The severity of SMA is modified by variable copy number of a second gene,SMN2, which produces an mRNA that is incorrectly spliced with deletion of the last exon. We describ...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb800120t
更新日期：2008-11-21 00:00:00
abstract：:Chloropupukeananin and chloropestolides are novel metabolites of the plant endophyte Pestalotiopsis fici, showing antimicrobial, antitumor, and anti-HIV activities. Their highly complex and unique skeletons were generated from the coisolated pestheic acid (1) and iso-A82775C (10) based on our previous studies. Here, w...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b01059
更新日期：2018-03-16 00:00:00
abstract：:The limited clinical success of therapeutics targeting cellular signaling processes is due to multiple factors, including off-target effects and complex feedback regulation encoded within the signaling network. To understand these effects, chemical proteomics and chemical genetics tools have been developed to map the ...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb1002834
更新日期：2011-01-21 00:00:00
abstract：:The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-α isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, ...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb400088q
更新日期：2013-07-19 00:00:00
abstract：:Pentamycin is a polyene antibiotic, registered in Switzerland for the treatment of vaginal candidiasis, trichomoniasis, and mixed infections. Chemical instability has hindered its widespread application and development as a drug. Here, we report the identification of Streptomyces sp. S816, isolated from Philippine man...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.9b00270
更新日期：2019-06-21 00:00:00
abstract：:Novel strategies are needed to modulate β-cell differentiation and function as potential β-cell replacement or restorative therapies for diabetes. We previously demonstrated that small molecules based on the isoxazole scaffold drive neuroendocrine phenotypes. The nature of the effects of isoxazole compounds on β-cells...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.5b00993
更新日期：2016-04-15 00:00:00
abstract：:Photoinduced cross-linking (PIC) has become a powerful tool in chemical biology for the identification and mapping of stable or transient interactions between biomacromolecules and their (unknown) ligands. However, the value of PIC for in vitro and in vivo structural proteomics can be realized only if cross-linking re...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb400731s
更新日期：2014-03-21 00:00:00
abstract：:Hemolysis, a process by which the destruction of red blood cells leads to the release of hemoglobin, is a critical event observed during hemolytic disorders. Under oxidative stress conditions, hemoglobin can release its heme prosthetic group, which is highly cytotoxic and can catalyze the generation of reactive oxygen...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.8b00458
更新日期：2018-08-17 00:00:00
abstract：:Phenotypic screening of compound libraries is a significant trend in drug discovery, yet success can be hindered by difficulties in identifying the underlying cellular targets. Current approaches rely on tethering bioactive compounds to a capture tag or surface to allow selective enrichment of interacting proteins for...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.5b00351
更新日期：2015-10-16 00:00:00
abstract：:As part of the central core domain of the ribosome, helix 69 of 23S rRNA participates in an important intersubunit bridge and contacts several protein translation factors. Helix 69 is believed to play key roles in protein synthesis. Even though high-resolution crystal structures of the ribosome exist, the solution dyn...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb200497q
更新日期：2012-05-18 00:00:00
abstract：:Insights into the thermodynamic and kinetic signature of the transient opening of a protein-binding pocket resulting from accommodation of suitable substituents attached to a given parent ligand scaffold are presented. As a target, we selected human aldose reductase, an enzyme involved in the development of late-stage...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00062
更新日期：2017-05-19 00:00:00
abstract：:Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-molecule stabilizers of this mutant. One of these molecules, PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-in...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.6b00315
更新日期：2016-08-19 00:00:00
abstract：:A biophysical understanding of the mechanistic, chemical, and physical origins underlying antibiotic action and resistance is vital to the discovery of novel therapeutics and the development of strategies to combat the growing emergence of antibiotic resistance. The site-specific introduction of stable-isotope labels ...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.9b01054
更新日期：2020-05-15 00:00:00
abstract：:New technology for the derivatization of peptide natural products is required for drug development. Despite the recent advances in the genome sequencing technique enabling us to search for the biosynthetic genes for wide variety of natural products, the technical methods to get access to them are limited. A class of R...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.9b00330
更新日期：2019-06-21 00:00:00
abstract：:Lipopolysaccharide (LPS) is a crucial component in the outer membrane of Gram-negative bacteria that contributes to both pathogenicity as well as immunity against pathogenic bacteria. Typical LPS contains GlcN disaccharide as the core of lipid A. However, some bacteria such as Acidithiobacillus ferrooxidans and Leptos...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.0c00791
更新日期：2020-12-18 00:00:00
abstract：:In a process called quorum sensing, bacteria produce and secrete certain signaling compounds (called autoinducers) that bind to receptors on other bacteria and activate transcription of certain genes. A clever genetic selection yields a new quorum-sensing transcriptional regulator that marches to the beat of a differe...
journal_title：ACS chemical biology
pub_type： 杂志文章,评审
doi：10.1021/cb6003417
更新日期：2006-08-22 00:00:00
abstract：:The diterpene cyclase CotB2 catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to the tricyclic cyclooctat-9-en-7-ol, which is characterized by a 5-8-5-fused ring skeleton. We have previously proposed a cyclization cascade involving a unique carbon-carbon bond rearrangement combined with multiple hydride s...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/acschembio.7b00154
更新日期：2017-06-16 00:00:00
abstract：:The Morita-Baylis-Hillman reaction forms a carbon-carbon bond between the α-carbon of a conjugated carbonyl compound and a carbon electrophile. The reaction mechanism involves Michael addition of a nucleophile catalyst at the carbonyl β-carbon, followed by bond formation with the electrophile and catalyst disassociati...
journal_title：ACS chemical biology
pub_type： 杂志文章
doi：10.1021/cb3006227
更新日期：2013-04-19 00:00:00
