Abstract：
:Genetic screens in cultured human cells represent a powerful unbiased strategy to identify cellular pathways that determine drug efficacy, providing critical information for clinical development. We used insertional mutagenesis-based screens in haploid cells to identify genes required for the sensitivity to lasonolide A (LasA), a macrolide derived from a marine sponge that kills certain types of cancer cells at low nanomolar concentrations. Our screens converged on a single gene, LDAH, encoding a member of the metabolite serine hydrolase family that is localized on the surface of lipid droplets. Mechanistic studies revealed that LasA accumulates in lipid droplets, where it is cleaved into a toxic metabolite by LDAH. We suggest that selective partitioning of hydrophobic drugs into the oil phase of lipid droplets can influence their activation and eventual toxicity to cells.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Dubey R,Stivala CE,Nguyen HQ,Goo YH,Paul A,Carette JE,Trost BM,Rohatgi Rdoi
10.1038/s41589-019-0447-7subject
Has Abstractpub_date
2020-02-01 00:00:00pages
206-213issue
2eissn
1552-4450issn
1552-4469pii
10.1038/s41589-019-0447-7journal_volume
16pub_type
杂志文章abstract：:The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2148
更新日期：2016-10-01 00:00:00
abstract：:Serine hydrolases play diverse roles in regulating host-pathogen interactions in a number of organisms, yet few have been characterized in the human pathogen Staphylococcus aureus. Here we describe a chemical proteomic screen that identified ten previously uncharacterized S. aureus serine hydrolases that mostly lack h...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0060-1
更新日期：2018-06-01 00:00:00
abstract：:The eukaryotic replicative DNA polymerases (Pol α, δ and ɛ) and the major DNA mutagenesis enzyme Pol ζ contain two conserved cysteine-rich metal-binding motifs (CysA and CysB) in the C-terminal domain (CTD) of their catalytic subunits. Here we demonstrate by in vivo and in vitro approaches the presence of an essential...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.721
更新日期：2011-11-27 00:00:00
abstract：:Accumulation of unfolded proteins within the endoplasmic reticulum (ER) of eukaryotic cells leads to an unfolded protein response (UPR) that either restores homeostasis or commits the cells to apoptosis. Tools traditionally used to study the UPR are proapoptotic and thus confound analysis of long-term cellular respons...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1638
更新日期：2014-11-01 00:00:00
abstract：: ...
journal_title：Nature chemical biology
pub_type： 评论,杂志文章
doi：10.1038/s41589-019-0230-9
更新日期：2019-03-01 00:00:00
abstract：:Biotin is an essential vitamin in plants and mammals, functioning as the carbon dioxide carrier within central lipid metabolism. Bacterial pimeloyl-CoA synthetase (BioW) acts as a highly specific substrate-selection gate, ensuring the integrity of the carbon chain in biotin synthesis. BioW catalyzes the condensation o...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2361
更新日期：2017-06-01 00:00:00
abstract：:Hapalindole alkaloids are a structurally diverse class of cyanobacterial natural products defined by their varied polycyclic ring systems and diverse biological activities. These complex metabolites are generated from a common biosynthetic intermediate by the Stig cyclases in three mechanistic steps: a rare Cope rearr...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0003-x
更新日期：2018-04-01 00:00:00
abstract：:Nature is a diverse and rich source of bioactive pathways or novel building blocks for synthetic biology. In this Perspective, we describe the emerging research field in which metagenomes are functionally interrogated using synthetic biology. This approach substantially expands the set of identified biological activit...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/s41589-018-0100-x
更新日期：2018-08-01 00:00:00
abstract：:The resistance of Caenorhabditis elegans to pharmacological perturbation limits its use as a screening tool for novel small bioactive molecules. One strategy to improve the hit rate of small-molecule screens is to preselect molecules that have an increased likelihood of reaching their target in the worm. To learn whic...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.380
更新日期：2010-07-01 00:00:00
abstract：:Only 25% of bacterial membrane transporters have functional annotation owing to the difficulty of experimental study and of accurate prediction of their function. Here we report a sequence-independent method for high-throughput mining of novel transporters. The method is based on ligand-responsive biosensor systems th...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2189
更新日期：2016-12-01 00:00:00
abstract：:The N-end rule pathway senses the N-terminal destabilizing residues of degradation substrates for the ubiquitin-proteasome system, whose integrity shields against various human syndromes including cancer and cardiovascular diseases. GID4, a subunit of the ubiquitin ligase GID complex, has been recently identified as t...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0036-1
更新日期：2018-05-01 00:00:00
abstract：:We document a new dimension of surface recognition in which communication is controlled through the collective behavior of lipids. Membrane cholesterol induces a tilt in glycolipid receptor headgroup, resulting in loss of access for ligand binding. This property appears to organize erythrocyte blood group presentation...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.551
更新日期：2011-05-01 00:00:00
abstract：:Gentamicin B (GB), a valuable starting material for the preparation of the semisynthetic aminoglycoside antibiotic isepamicin, is produced in trace amounts by the wild-type Micromonospora echinospora. Though the biosynthetic pathway to GB has remained obscure for decades, we have now identified three hidden pathways t...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0203-4
更新日期：2019-03-01 00:00:00
abstract：:Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.694
更新日期：2011-10-30 00:00:00
abstract：:Molecular dynamics are essential for protein function. In some cases these dynamics involve the interconversion between ground state, highly populated conformers and less populated higher energy structures ('excited states') that play critical roles in biochemical processes. Here we describe recent advances in NMR spe...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.238
更新日期：2009-11-01 00:00:00
abstract：:Bioinorganic chemistry remains a vibrant discipline at the interface of chemistry and the biological sciences. Metal ions function in numerous metalloenzymes, are incorporated into pharmaceuticals and imaging agents, and inspire the synthesis of catalysts used to achieve many chemical transformations. ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio1006-504
更新日期：2006-10-01 00:00:00
abstract：:Here we present a natural product discovery approach, whereby structures are bioinformatically predicted from primary sequence and produced by chemical synthesis (synthetic-bioinformatic natural products, syn-BNPs), circumventing the need for bacterial culture and gene expression. When we applied the approach to nonri...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2207
更新日期：2016-12-01 00:00:00
abstract：:Nontranslational functions of vertebrate aminoacyl tRNA synthetases (aaRSs), which catalyze the production of aminoacyl-tRNAs for protein synthesis, have recently been discovered. Although these new functions were thought to be 'moonlighting activities', many are as critical for cellular homeostasis as their activity ...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.1158
更新日期：2013-03-01 00:00:00
abstract：:Chemistry drives many biological interactions between the microbiota and host animals, yet it is often challenging to identify the chemicals involved. This poses a problem, as such small molecules are excellent sources of potential pharmaceuticals, pretested by nature for animal compatibility. We discovered anti-HIV c...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2537
更新日期：2018-02-01 00:00:00
abstract：:The plant hormone auxin regulates virtually every aspect of plant growth and development. Auxin acts by binding the F-box protein transport inhibitor response 1 (TIR1) and promotes the degradation of the AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) transcriptional repressors. Here we show that efficient auxin binding requires...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.926
更新日期：2012-04-01 00:00:00
abstract：:Gut microbiota is found in virtually any metazoan, from invertebrates to vertebrates. It has long been believed that gut microbiota, more specifically, the activity of the microbiome and its metabolic products, directly influence a variety of aspects in metazoan physiology. However, the exact molecular relationship am...
journal_title：Nature chemical biology
pub_type： 杂志文章,评审
doi：10.1038/nchembio.1535
更新日期：2014-06-01 00:00:00
abstract：:Single-molecule observations reveal that lipid- and protein-based interactions jointly contribute to the interactions among glycosylphosphatidylinositol-anchored proteins in membranes. Understanding these interactions will help to refine long-evolving (and still debated) models of 'raft' domains in biological membrane...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1045
更新日期：2012-09-01 00:00:00
abstract：:Drug discovery resources in academia and industry are not used efficiently, to the detriment of industry and society. Duplication could be reduced, and productivity could be increased, by performing basic biology and clinical proofs of concept within open access industry-academia partnerships. Chemical biologists coul...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio0709-436
更新日期：2009-07-01 00:00:00
abstract：:N6-Methyladenosine (m6A) RNA modification is present in messenger RNAs (mRNA), ribosomal RNAs (rRNA), and spliceosomal RNAs (snRNA) in humans. Although mRNA m6A modifications have been extensively studied and shown to play critical roles in many cellular processes, the identity of m6A methyltransferases for rRNAs and ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0184-3
更新日期：2019-01-01 00:00:00
abstract：:Jasmonates are lipid-derived plant hormones that regulate plant defenses and numerous developmental processes. Although the biosynthesis and molecular function of the most active form of the hormone, (+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile), have been unraveled, it remains poorly understood how the diversity of bioac...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1591
更新日期：2014-10-01 00:00:00
abstract：:Although the protein synthesis inhibitor cycloheximide (CHX) has been known for decades, its precise mechanism of action remains incompletely understood. The glutarimide portion of CHX is seen in a family of structurally related natural products including migrastatin, isomigrastatin and lactimidomycin (LTM). We found ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.304
更新日期：2010-03-01 00:00:00
abstract：:The heat shock protein 90 (Hsp90) has a critical role in malignant transformation. Whereas its ability to maintain the functional conformations of mutant and aberrant oncoproteins is established, a transformation-specific regulation of the antiapoptotic phenotype by Hsp90 is poorly understood. By using selective compo...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2007.10
更新日期：2007-08-01 00:00:00
abstract：:Biosynthesis enables renewable production of manifold compounds, yet often biosynthetic performance must be improved for it to be economically feasible. Nongenetic, cell-to-cell variations in protein and metabolite concentrations are naturally inherent, suggesting the existence of both high- and low-performance varian...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2046
更新日期：2016-05-01 00:00:00
abstract：: ...
journal_title：Nature chemical biology
pub_type： 评论,杂志文章
doi：10.1038/s41589-018-0199-9
更新日期：2019-01-01 00:00:00
abstract：:Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-019-0393-4
更新日期：2020-01-01 00:00:00
