Abstract：
:Subtilosin A is a 35-residue, ribosomally synthesized bacteriocin encoded by the sbo-alb operon of Bacillus subtilis. It is composed of a head-to-tail circular peptide backbone that is additionally restrained by three unusual thioether bonds between three cysteines and the α-carbon of one threonine and two phenylalanines, respectively. In this study, we demonstrate that these bonds are synthesized by the radical S-adenosylmethionine enzyme AlbA, which is encoded by the sbo-alb operon and comprises two [4Fe-4S] clusters. One [4Fe-4S] cluster is coordinated by the prototypical CXXXCXXC motif and is responsible for the observed S-adenosylmethionine cleavage reaction, whereas the second [4Fe-4S] cluster is required for the generation of all three thioether linkages. On the basis of the obtained results, we propose a new radical mechanism for thioether bond formation. In addition, we show that AlbA-directed substrate transformation is leader-peptide dependent, suggesting that thioether bond formation is the first step during subtilosin A maturation.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Flühe L,Knappe TA,Gattner MJ,Schäfer A,Burghaus O,Linne U,Marahiel MAdoi
10.1038/nchembio.798subject
Has Abstractpub_date
2012-02-26 00:00:00pages
350-7issue
4eissn
1552-4450issn
1552-4469pii
nchembio.798journal_volume
8pub_type
杂志文章abstract：:A required course in communication at the graduate school level may help cure the disorder of poor scientific writing. ...
journal_title：Nature chemical biology
pub_type： 社论
doi：10.1038/nchembio0906-443
更新日期：2006-09-01 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：:The chemical scaffolds from which screening libraries are built have strong influence on the libraries' utility for screening campaigns. Here we present analysis of the scaffold composition of several types of commercially available screening collections and compare those compositions to those of drugs and drug candid...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio0807-442
更新日期：2007-08-01 00:00:00
abstract：:Oxidation of methionine disrupts the structure and function of a range of proteins, but little is understood about the chemistry that underlies these perturbations. Using quantum mechanical calculations, we found that oxidation increased the strength of the methionine-aromatic interaction motif, a driving force for pr...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2159
更新日期：2016-10-01 00:00:00
abstract：:The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. I...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2168
更新日期：2016-11-01 00:00:00
abstract：:The active site of [NiFe] hydrogenases contains a strictly conserved arginine that suspends a guanidine nitrogen atom <4.5 Å above the nickel and iron atoms. The guanidine headgroup interacts with the side chains of two conserved aspartic acid residues to complete an outer-shell canopy that has thus far proved intract...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1976
更新日期：2016-01-01 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：: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：:RNA capping and decapping are thought to be distinctive features of eukaryotes. The redox cofactor NAD was recently discovered to be attached to small regulatory RNAs in bacteria in a cap-like manner, and Nudix hydrolase NudC was found to act as a NAD-decapping enzyme in vitro and in vivo. Here, crystal structures of ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2132
更新日期：2016-09-01 00:00:00
abstract：:CRISPR-Cas9 has emerged as a powerful technology that enables ready modification of the mammalian genome. The ability to modulate Cas9 activity can reduce off-target cleavage and facilitate precise genome engineering. Here we report the development of a Cas9 variant whose activity can be switched on and off in human c...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2179
更新日期：2016-11-01 00:00:00
abstract：:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have distinct clinical features but a common pathology--cytoplasmic inclusions rich in transactive response element DNA-binding protein of 43 kDa (TDP43). Rare TDP43 mutations cause ALS or FTD, but abnormal TDP43 levels and localization may cause di...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1563
更新日期：2014-08-01 00:00:00
abstract：:Occurrence of the BCR-ABL(T315I) gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors i...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1085
更新日期：2012-11-01 00:00:00
abstract：:Enzymes that use the cofactor thiamin diphosphate (ThDP, 1), the biologically active form of vitamin B(1), are involved in numerous metabolic pathways in all organisms. Although a theory of the cofactor's underlying reaction mechanism has been established over the last five decades, the three-dimensional structures of...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio788
更新日期：2006-06-01 00:00:00
abstract：:Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio814
更新日期：2006-10-01 00:00:00
abstract：:Protein serine-threonine kinase casein kinase II (CK2) is involved in a myriad of cellular processes including cell growth and proliferation through its phosphorylation of hundreds of substrates, yet how CK2 function is regulated is poorly understood. Here we report that the CK2 catalytic subunit CK2α is modified by O...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.771
更新日期：2012-01-22 00:00:00
abstract：:The discovery of functional RNAs that are critical for normal and disease physiology continues to expand at a breakneck pace. Many RNA functions are controlled by the formation of specific structures, and an understanding of each structural component is necessary to elucidate its function. Measuring solvent accessibil...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2548
更新日期：2018-03-01 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：:The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.313
更新日期：2010-03-01 00:00:00
abstract：:As a field, lipidomics is in its infancy, yet it has already begun to influence lipid biochemistry in myriad ways. As with other omic technologies, the field is driven by advances in analytical chemistry, particularly by mass spectrometry. At the heart of a renaissance in lipid biochemistry, systems biology is being u...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio0909-602
更新日期：2009-09-01 00:00:00
abstract：:Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we used LC/MS and functional assays to identify cholic acid as a new Lxr ligand. Moreover, 24(S),25-epoxycholesterol (...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1156
更新日期：2013-02-01 00:00:00
abstract：:To maximize a desired product, metabolic engineers typically express enzymes to high, constant levels. Yet, permanent pathway activation can have undesirable consequences including competition with essential pathways and accumulation of toxic intermediates. Faced with similar challenges, natural metabolic systems comp...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-019-0284-8
更新日期：2019-06-01 00:00:00
abstract：:Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.1986
更新日期：2016-02-01 00:00:00
abstract：:We report here that fat mass and obesity-associated protein (FTO) has efficient oxidative demethylation activity targeting the abundant N6-methyladenosine (m(6)A) residues in RNA in vitro. FTO knockdown with siRNA led to increased amounts of m(6)A in mRNA, whereas overexpression of FTO resulted in decreased amounts of...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.687
更新日期：2011-10-16 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：:Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer's disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-cou...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-019-0453-9
更新日期：2020-03-01 00:00:00
abstract：:Synthetic mRNA is an attractive vehicle for gene therapies because of its transient nature and improved safety profile over DNA. However, unlike DNA, broadly applicable methods to control expression from mRNA are lacking. Here we describe a platform for small-molecule-based regulation of expression from modified RNA (...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/s41589-018-0146-9
更新日期：2018-11-01 00:00:00
abstract：:Post-transcriptional RNA modifications can be dynamic and might have functions beyond fine-tuning the structure and function of RNA. Understanding these RNA modification pathways and their functions may allow researchers to identify new layers of gene regulation at the RNA level. ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.482
更新日期：2010-12-01 00:00:00
abstract：:In response to decreasing Ca2+ levels in the endoplasmic reticulum, STIM proteins couple with Orai channels in the plasma membrane, leading to Ca2+ influx into the cell. In addition to Ca2+-related endoplasmic reticulum stress, STIM proteins are emerging as general stress sensors that react to multiple stress signals ...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.619
更新日期：2011-07-18 00:00:00
abstract：:Small molecules stabilize specific protein conformations from a larger ensemble, enabling molecular switches that control diverse cellular functions. We show here that the converse also holds true: the conformational state of the estrogen receptor can direct distinct orientations of the bound ligand. 'Gain-of-alloster...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.451
更新日期：2010-11-01 00:00:00
abstract：:Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in c...
journal_title：Nature chemical biology
pub_type： 杂志文章
doi：10.1038/nchembio.2463
更新日期：2017-11-01 00:00:00
