Abstract：
:Pyridoxal 5'-phosphate (PLP) is a versatile cofactor that catalyzes a plethora of chemical transformations within a cell. Although many human PLP-dependent enzymes (PLP-DEs) with crucial physiological and pathological roles are known, a global method enabling their cellular profiling is lacking. Here, we demonstrate the utility of a cofactor probe for the identification of human PLP-binding proteins in living cells. Striking selectivity of human pyridoxal kinase led to a customized labeling strategy covering a large fraction of known PLP-binding proteins across various cancer-derived cell lines. Labeling intensities of some PLP-DEs varied depending on the cell type while the overall protein expression levels of these proteins remained constant. In addition, we applied the methodology for in situ screening of PLP-antagonists and unraveled known binders as well as unknown off-targets. Taken together, our proteome-wide method to study PLP-DEs in human cancer-derived cells enables global understanding of the interactome of this important cofactor.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Fux A,Pfanzelt M,Kirsch VC,Hoegl A,Sieber SAdoi
10.1016/j.chembiol.2019.08.003subject
Has Abstractpub_date
2019-10-17 00:00:00pages
1461-1468.e7issue
10eissn
2451-9456issn
2451-9448pii
S2451-9456(19)30249-1journal_volume
26pub_type
杂志文章abstract：:Genetically encoded biosensors are useful tools for detecting the presence and levels of diverse biomolecules in living cells. However, low-abundance targets are difficult to detect because they are often unable to bind and activate enough biosensors to detect using standard microscopic imaging approaches. Here we des...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.01.005
更新日期：2019-04-18 00:00:00
abstract：:Disease sites in atherosclerosis and cancer feature cell masses (e.g., plaques/tumors), a low pH extracellular microenvironment, and various pro-inflammatory cytokines such as tumor necrosis factor α (TNFα). The ability to engineer a cell to seek TNFα sources allows for targeted therapeutic delivery. To accomplish thi...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.05.008
更新日期：2017-06-22 00:00:00
abstract：:Tumor suppressor genes represent a major class of oncogenic drivers. However, direct targeting of loss-of-function tumor suppressors remains challenging. To address this gap, we explored a variant-directed chemical biology approach to reverse the lost function of tumor suppressors using SMAD4 as an example. SMAD4, a c...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.11.010
更新日期：2020-12-04 00:00:00
abstract：:USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.03.002
更新日期：2017-04-20 00:00:00
abstract：:Reactivation of mutant p53 has emerged as a promising approach for cancer therapy. Recent studies have identified several mutant p53-reactivating compounds that target thiol groups in mutant p53. Here we have investigated the relationship between thiol reactivity, p53 thermostabilization, mutant p53 refolding, mutant ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.06.013
更新日期：2018-10-18 00:00:00
abstract：:Kinase inhibitors are effective cancer therapies. Unfortunately, drug resistance emerges in response to kinase inhibition leading to loss of drug efficacy. In this issue of Cell Chemical Biology, Peh et al. (2018) demonstrate that caspase activators effectively delay onset of resistance to kinase inhibitors and are ex...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2018.08.001
更新日期：2018-08-16 00:00:00
abstract：:Owing to their structural flexibility, most serpins inhibit the cognate proteases in a fast and specific manner and also are susceptible to pathogenic misfolding. In this issue of Cell Chemical Biology, Madsen et al. (2016) report on the selection and characterization of an RNA aptamer that stabilizes α1-antichymotryp...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2016.06.002
更新日期：2016-06-23 00:00:00
abstract：:While the wound healing property of the macrolide FK506 is well known, the underlying mechanism has been elusive. In this issue of Cell Chemical Biology, Peiffer et al. (2019) utilize FKBP12 ligand to demonstrate that wound healing effects of FK506 occur via activation of the BMP (bone morphogenic protein) signaling p...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2019.05.001
更新日期：2019-05-16 00:00:00
abstract：:The promise of phenotypic screening resides in its track record of novel biology and first-in-class therapies. However, challenges stemming from major differences between target-based and phenotypic screening do exist. These challenges prompted us to rethink the critical stage of hit triage and validation on the road ...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2020.08.009
更新日期：2020-11-19 00:00:00
abstract：:Antibiotic resistance is a rapidly evolving health concern that requires a sustained effort to understand mechanisms of resistance and to develop new agents that overcome those mechanisms. The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotic...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.11.007
更新日期：2016-12-22 00:00:00
abstract：:The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.08.009
更新日期：2017-10-19 00:00:00
abstract：:In this issue of Cell Chemical Biology, Radlinski et al. (2019) identify Pseudomonas-derived rhamnolipids that potentiate aminoglycoside antibiotics in the eradication of antibiotic-tolerant bacterial phenotypes. Microbial physiological and mechanistic studies indicate that rhamnolipids permeabilize S. aureus membrane...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2019.09.015
更新日期：2019-10-17 00:00:00
abstract：:H2S-producing enzymes in bacteria have been shown to be closely engaged in the process of microbial survival and antibiotic resistance. However, no inhibitors have been discovered for these enzymes, e.g., 3-mercaptopyruvate sulfurtransferase (MST). In the present study, we identified several classes of inhibitors for ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.10.012
更新日期：2020-12-17 00:00:00
abstract：:Mycobacterium tuberculosis synthesizes a wide variety of complex lipids that can serve as antigens in immune recognition of the bacterium. In this issue of Cell Chemical Biology, Gilleron et al. (2016) identify key enzymes essential for lipid antigen processing, which is required for CD1b-restricted T cell activation....
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2016.09.005
更新日期：2016-09-22 00:00:00
abstract：:The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.01.011
更新日期：2018-04-19 00:00:00
abstract：:The rise of antibiotic resistance threatens modern medicine; to combat it new diagnostic methods are required. Sequencing the whole genome of a pathogen offers the potential to accurately determine which antibiotics will be effective to treat a patient. A key limitation of this approach is that it cannot classify rare...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.12.009
更新日期：2018-03-15 00:00:00
abstract：:Alport syndrome is a hereditary glomerular disease caused by mutation in type IV collagen α3-α5 chains (α3-α5(IV)), which disrupts trimerization, leading to glomerular basement membrane degeneration. Correcting the trimerization of α3/α4/α5 chain is a feasible therapeutic approach, but is hindered by lack of informati...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.02.003
更新日期：2018-05-17 00:00:00
abstract：:Interfacial inhibitors exert their biological effects through co-association with two macromolecules. The pateamine A (PatA) class of molecules function by stabilizing eukaryotic initiation factor (eIF) 4A RNA helicase onto RNA, resulting in translation initiation inhibition. Here, we present the crystal structure of ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.12.006
更新日期：2021-01-05 00:00:00
abstract：:Lethal small molecules are useful probes to discover and characterize novel cell death pathways and biochemical mechanisms. Here we report that the synthetic oxime-containing small molecule caspase-independent lethal 56 (CIL56) induces an unconventional form of nonapoptotic cell death distinct from necroptosis, ferrop...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.09.014
更新日期：2019-12-19 00:00:00
abstract：:Increased telomerase activity is associated with malignancy and poor prognosis in human cancer, but the development of targeted agents has not yet provided clinical benefit. Here we report that, instead of targeting the telomerase enzyme directly, small molecules that bind to the G-hairpin of the hTERT G-quadruplex-fo...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.04.009
更新日期：2019-08-15 00:00:00
abstract：:Using light to control cellular processes is one of the attractive areas of research. Here, availability of different, light-responsive caged compounds has played a critical role. In this issue of Cell Chemical Biology, Hövelmann et al. (2016) give us an example of how to design and use caged lipids to guide chemotaxi...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2016.05.003
更新日期：2016-05-19 00:00:00
abstract：:In this issue of Cell Chemical Biology, Olson et al. (2019) develop the first selective CDK7 irreversible inhibitor. Elegant cell-based studies using a CDK7 mutant that is not covalently engaged by the probe helped decipher the effects of inhibiting the kinase on the cell cycle and gene transcription. ...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2019.05.012
更新日期：2019-06-20 00:00:00
abstract：:In a recent issue of Cell Systems, Forcina et al. (2017) developed a scalable time-lapse analysis of cell death kinetics (STACK) method and combined it with a "lag exponential death" model to quantitatively characterize the onset and rate of cell death. STACK provides a useful quantitative tool to determine how cell d...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2017.07.006
更新日期：2017-07-20 00:00:00
abstract：:The discovery of novel small molecules that induce stem cell reprogramming and give efficient access to pluripotent stem cells is of major importance for potential therapeutic applications and may reveal novel insights into the factors controlling pluripotency. Chemical reprogramming of mouse epiblast stem cells (EpiS...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.02.015
更新日期：2016-04-21 00:00:00
abstract：:Rifamycin monooxygenases (Rox) are present in a variety of environmental bacteria and are associated with decomposition of the clinically utilized antibiotic rifampin. Here we report the structure and function of a drug-inducible rox gene from Streptomyces venezuelae, which encodes a class A flavoprotein monooxygenase...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.01.009
更新日期：2018-04-19 00:00:00
abstract：:In this issue of Cell Chemical Biology, Ortega et al. (2016) determine the structure of another lantibiotic dehydratase with a tRNA(Glu)-dependent mechanism of modification. Moreover, they identify a common recognition motif involved in leader peptide binding in a number of different peptide-modification enzymes. Thes...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2016.03.001
更新日期：2016-03-17 00:00:00
abstract：:Recent advances in induced pluripotent stem cell technologies and phenotypic screening shape the future of bioactive small-molecule discovery. In this review we analyze the impact of small-molecule phenotypic screens on drug discovery as well as on the investigation of human development and disease biology. We further...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2019.05.007
更新日期：2019-08-15 00:00:00
abstract：:Polo-like kinase 1 has hundreds of substrates and multiple functions that operate within the ∼60 min of mitosis. Herein, we describe a chemical-genetic system that allows particular substrates to be "toggled" into or out of chemical control using engineered phosphoacceptor selectivity. Biochemical assays and phosphopr...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.01.007
更新日期：2020-03-19 00:00:00
abstract：:In this issue of Cell Chemical Biology, Diaz et al. (2017) report a strategy to achieve temporal, spatial, and stoichiometric control over the protein kinase cAbl in living cells. They achieve this by splitting cAbl into two inactive fragments that form an active kinase upon small molecule addition, potentially provid...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.10.004
更新日期：2017-10-19 00:00:00
abstract：:Identification and validation of the targets of bioactive small molecules identified in cell-based screening is challenging and often meets with failure, calling for the development of new methodology. We demonstrate that a combination of chemical proteomics with in silico target prediction employing the SPiDER method...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.05.016
更新日期：2018-09-20 00:00:00
