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Article ; Online: Assessment of phytoestrogen and mycoestrogen recognition by recombinant human estrogen receptor-α using ligand titration arrays.

Andres, Sarah A / Bumpus, Stefanie B / Wittliff, James L

2013 Volume 24, Issue 4, Page(s) 357–366

Abstract: Introduction: Exposure to phytoestrogens and mycoestrogens has emerged as a public health issue due to their potentially endocrine disruption activities resulting from direct interaction with sex-steroid hormone receptors. There is a significant ... ...

Abstract	Introduction: Exposure to phytoestrogens and mycoestrogens has emerged as a public health issue due to their potentially endocrine disruption activities resulting from direct interaction with sex-steroid hormone receptors. There is a significant requirement for comprehensive, reproducible methods to determine the extent of estrogen mimicry by compounds encountered in the environment to estimate risk:benefit ratios, particularly in humans. Objective: To develop a systematic approach for assessing recognition of chemically diverse compounds by human estrogen receptor proteins to aid in their assessment as endocrine disruptor compounds (EDCs). Methods: Recombinant human estrogen receptor-α protein (rhERα) was expressed in Saccharomyces cervisiae as an ubiquitin fusion under control of a CUP1 promoter and partially purified with heparin affinity chromatography in the unliganded state. A novel radio-ligand binding array was developed to evaluate structurally diverse compounds, both naturally occurring and synthetic, for estrogen binding activity and affinity. Results: Binding affinities of suspected estrogen mimics for rhERα were calculated over a range of [(3) H]estradiol-17β concentrations using Lundon OneSite® and Compete® software. Conclusion: β-zearalanol, a mycoestrogen similar to zearalenone used as an ICCVAM validation substance for the in vitro estrogen receptor binding assays (ICCAM report), was employed as a model estrogen mimic to illustrate the approach, methods and calculations using these techniques.
MeSH term(s)	Binding, Competitive ; Endocrine Disruptors ; Estradiol/metabolism ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Inhibitory Concentration 50 ; Ligands ; Models, Theoretical ; Molecular Mimicry ; Molecular Probe Techniques ; Phytoestrogens/analysis ; Phytoestrogens/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Titrimetry/methods ; Zearalenone/analysis ; Zearalenone/metabolism
Chemical Substances	ESR1 protein, human ; Endocrine Disruptors ; Estrogen Receptor alpha ; Ligands ; Phytoestrogens ; Recombinant Proteins ; Estradiol (4TI98Z838E) ; Zearalenone (5W827M159J) ; taleranol (HUN219N434)
Language	English
Publishing date	2013-02-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1073576-8
ISSN	1099-1565 ; 0958-0344
ISSN (online)	1099-1565
ISSN	0958-0344
DOI	10.1002/pca.2417
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Article: Accessing natural product biosynthetic processes by mass spectrometry.

Bumpus, Stefanie B / Kelleher, Neil L

Current opinion in chemical biology

2008 Volume 12, Issue 5, Page(s) 475–482

Abstract: Two important classes of natural products are made by nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). With most biosynthetic intermediates covalently tethered during biogenesis, protein mass spectrometry (MS) has proven ... ...

Abstract	Two important classes of natural products are made by nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). With most biosynthetic intermediates covalently tethered during biogenesis, protein mass spectrometry (MS) has proven invaluable for their interrogation. New mass spectrometric assay formats (such as selective cofactor ejection and proteomics style LC-MS) are showcased here in the context of functional insights into new breeds of NRPS/PKS enzymes, including the first characterization of an 'iterative' PKS, the biosynthesis of the enediyne antitumor antibiotics, the study of a new strategy for PKS initiation via a GNAT-like mechanism, and the analysis of branching strategies in the so-called 'AT-less' NRPS/PKS hybrid systems. The future of MS analysis of NRPS and PKS biosynthetic pathways lies in adoption and development of methods that continue bridging enzymology with proteomics as both fields continue their post-genomic acceleration.
MeSH term(s)	Biological Products/analysis ; Biological Products/biosynthesis ; Biological Products/chemistry ; Mass Spectrometry/methods ; Peptide Synthases/metabolism ; Polyketide Synthases/metabolism
Chemical Substances	Biological Products ; Polyketide Synthases (79956-01-7) ; Peptide Synthases (EC 6.3.2.-) ; non-ribosomal peptide synthase (EC 6.3.2.-)
Language	English
Publishing date	2008-07-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1439176-4
ISSN	1879-0402 ; 1367-5931
ISSN (online)	1879-0402
ISSN	1367-5931
DOI	10.1016/j.cbpa.2008.07.022
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Article ; Online: Interrogation of global active site occupancy of a fungal iterative polyketide synthase reveals strategies for maintaining biosynthetic fidelity.

Vagstad, Anna L / Bumpus, Stefanie B / Belecki, Katherine / Kelleher, Neil L / Townsend, Craig A

Journal of the American Chemical Society

2012 Volume 134, Issue 15, Page(s) 6865–6877

Abstract: Nonreducing iterative polyketide synthases (NR-PKSs) are responsible for assembling the core of fungal aromatic natural products with diverse biological properties. Despite recent advances in the field, many mechanistic details of polyketide assembly by ... ...

Abstract	Nonreducing iterative polyketide synthases (NR-PKSs) are responsible for assembling the core of fungal aromatic natural products with diverse biological properties. Despite recent advances in the field, many mechanistic details of polyketide assembly by these megasynthases remain unknown. To expand our understanding of substrate loading, polyketide elongation, cyclization, and product release, active site occupancy and product output were explored by Fourier transform mass spectrometry using the norsolorinic acid anthrone-producing polyketide synthase, PksA, from the aflatoxin biosynthetic pathway in Aspergillus parasiticus. Here we report the simultaneous observation of covalent intermediates from all catalytic domains of PksA from in vitro reconstitution reactions. The data provide snapshots of iterative catalysis and reveal an underappreciated editing function for the C-terminal thioesterase domain beyond its recently established synthetic role in Claisen/Dieckmann cyclization and product release. The specificity of thioesterase catalyzed hydrolysis was explored using biosynthetically relevant protein-bound and small molecule acyl substrates and demonstrated activity against hexanoyl and acetyl, but not malonyl. Processivity of polyketide extension was supported by the inability of a nonhydrolyzable malonyl analog to trap products of intermediate chain lengths and by the detection of only fully extended species observed covalently bound to, and as the predominant products released by, PksA. High occupancy of the malonyl transacylase domain and fast relative rate of malonyl transfer compared to starter unit transfer indicate that rapid loading of extension units onto the carrier domain facilitates efficient chain extension in a manner kinetically favorable to ultimate product formation.
MeSH term(s)	Biocatalysis ; Catalytic Domain ; Fungal Proteins ; Kinetics ; Polyketide Synthases/chemistry ; Polyketide Synthases/metabolism
Chemical Substances	Fungal Proteins ; Polyketide Synthases (79956-01-7)
Language	English
Publishing date	2012-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja3016389
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Article: The loading module of mycosubtilin: an adenylation domain with fatty acid selectivity.

Hansen, Darren B / Bumpus, Stefanie B / Aron, Zachary D / Kelleher, Neil L / Walsh, Christopher T

Journal of the American Chemical Society

2007 Volume 129, Issue 20, Page(s) 6366–6367

MeSH term(s)	Adenine/chemistry ; Bacillus subtilis/chemistry ; Bacillus subtilis/metabolism ; Fatty Acids/chemistry ; Lipoproteins/chemistry ; Mass Spectrometry ; Molecular Structure ; Substrate Specificity
Chemical Substances	Fatty Acids ; Lipoproteins ; mycosubtiline (1392-60-5) ; Adenine (JAC85A2161)
Language	English
Publishing date	2007-05-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja070890j
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Article: Interrogation of Global Active Site Occupancy of a Fungal Iterative Polyketide Synthase Reveals Strategies for Maintaining Biosynthetic Fidelity

Vagstad, Anna L / Belecki Katherine / Bumpus Stefanie B / Kelleher Neil L / Townsend Craig A

Journal of the American Chemical Society. 2012 Apr. 18, v. 134, no. 15

2012

Abstract	Nonreducing iterative polyketide synthases (NR-PKSs) are responsible for assembling the core of fungal aromatic natural products with diverse biological properties. Despite recent advances in the field, many mechanistic details of polyketide assembly by these megasynthases remain unknown. To expand our understanding of substrate loading, polyketide elongation, cyclization, and product release, active site occupancy and product output were explored by Fourier transform mass spectrometry using the norsolorinic acid anthrone-producing polyketide synthase, PksA, from the aflatoxin biosynthetic pathway in Aspergillus parasiticus. Here we report the simultaneous observation of covalent intermediates from all catalytic domains of PksA from in vitro reconstitution reactions. The data provide snapshots of iterative catalysis and reveal an underappreciated editing function for the C-terminal thioesterase domain beyond its recently established synthetic role in Claisen/Dieckmann cyclization and product release. The specificity of thioesterase catalyzed hydrolysis was explored using biosynthetically relevant protein-bound and small molecule acyl substrates and demonstrated activity against hexanoyl and acetyl, but not malonyl. Processivity of polyketide extension was supported by the inability of a nonhydrolyzable malonyl analog to trap products of intermediate chain lengths and by the detection of only fully extended species observed covalently bound to, and as the predominant products released by, PksA. High occupancy of the malonyl transacylase domain and fast relative rate of malonyl transfer compared to starter unit transfer indicate that rapid loading of extension units onto the carrier domain facilitates efficient chain extension in a manner kinetically favorable to ultimate product formation.
Keywords	active sites ; aflatoxins ; Aspergillus parasiticus ; biochemical pathways ; catalytic activity ; fungi ; hydrolysis ; mass spectrometry ; polyketide synthases
Language	English
Dates of publication	2012-0418
Size	p. 6865-6877.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021%2Fja3016389
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Article ; Online: A proteomics approach to discovering natural products and their biosynthetic pathways.

Bumpus, Stefanie B / Evans, Bradley S / Thomas, Paul M / Ntai, Ioanna / Kelleher, Neil L

Nature biotechnology

2009 Volume 27, Issue 10, Page(s) 951–956

Abstract: Many natural products with antibiotic, anticancer and antifungal properties are synthesized by nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). Although genome sequencing has revealed the diversity of these enzymes, identifying ... ...

Abstract	Many natural products with antibiotic, anticancer and antifungal properties are synthesized by nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). Although genome sequencing has revealed the diversity of these enzymes, identifying new products and their biosynthetic pathways remains challenging. By taking advantage of the size of these enzymes (often >2,000 amino acids) and unique marker ions derived from their common phosphopantetheinyl cofactor, we adapted mass spectrometry-based proteomics to selectively detect NRPS and PKS gene clusters in microbial proteomes without requiring genome sequence information. We detected known NRPS systems in members of the genera Bacillus and Streptomyces, and screened 22 environmental isolates to uncover production of unknown natural products from the hybrid NRPS-PKS zwittermicin A biosynthetic gene cluster. We also discovered an NRPS cluster that generates a seven-residue lipopeptide. This 'protein-first' strategy complements bioassay- and sequence-based approaches by finding expressed gene clusters that produce new natural products.
MeSH term(s)	Bacillus/genetics ; Bacillus/metabolism ; Biological Products/analysis ; Biological Products/biosynthesis ; Biological Products/metabolism ; Cluster Analysis ; Gene Regulatory Networks ; Lipopeptides/metabolism ; Mass Spectrometry/methods ; Metabolic Networks and Pathways ; Pantetheine/analogs & derivatives ; Pantetheine/metabolism ; Peptide Biosynthesis, Nucleic Acid-Independent ; Peptide Fragments/metabolism ; Peptide Synthases/metabolism ; Polyketide Synthases/metabolism ; Proteomics/methods ; Streptomyces/genetics ; Streptomyces/metabolism
Chemical Substances	Biological Products ; Lipopeptides ; Peptide Fragments ; Pantetheine (496-65-1) ; Polyketide Synthases (79956-01-7) ; Peptide Synthases (EC 6.3.2.-) ; 4'-phosphopantetheine (NM39WU8OFM)
Language	English
Publishing date	2009-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/nbt.1565
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Article ; Online: Polyunsaturated fatty-acid-like trans-enoyl reductases utilized in polyketide biosynthesis.

Bumpus, Stefanie B / Magarvey, Nathan A / Kelleher, Neil L / Walsh, Christopher T / Calderone, Christopher T

Journal of the American Chemical Society

2008 Volume 130, Issue 35, Page(s) 11614–11616

Abstract: Polyketide biosynthesis is typically directed by cis-acting catalytic domains. In the case of the Bacillus subtilis secondary metabolite dihydrobacillaene, the cis-acting domains are not sufficient to generate the saturated C14'-C15' bond. In this ... ...

Abstract	Polyketide biosynthesis is typically directed by cis-acting catalytic domains. In the case of the Bacillus subtilis secondary metabolite dihydrobacillaene, the cis-acting domains are not sufficient to generate the saturated C14'-C15' bond. In this communication, we identify PksE as a trans-acting enoyl reductase utilized in the biosynthesis of this portion of dihydrobacillaene. PksE is homologous to the enzymes predicted to serve as enoyl reductases in polyunsaturated fatty acid (PUFA) biosynthesis, and we confirmed this functional assignment in vitro. These results suggest a general enoyl reduction pathway in polyketide biosynthesis and a means by which PUFA-like biosynthetic machinery can modulate small-molecule function.
MeSH term(s)	Bacillus subtilis/enzymology ; Fatty Acids, Unsaturated/chemistry ; Fatty Acids, Unsaturated/metabolism ; Macrolides/chemistry ; Macrolides/metabolism ; Oxidoreductases/chemistry ; Oxidoreductases/metabolism ; Polyketide Synthases/chemistry ; Polyketide Synthases/metabolism
Chemical Substances	Fatty Acids, Unsaturated ; Macrolides ; Polyketide Synthases (79956-01-7) ; Oxidoreductases (EC 1.-)
Language	English
Publishing date	2008-08-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja8040042
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Article ; Online: A ketoreductase domain in the PksJ protein of the bacillaene assembly line carries out both alpha- and beta-ketone reduction during chain growth.

Calderone, Christopher T / Bumpus, Stefanie B / Kelleher, Neil L / Walsh, Christopher T / Magarvey, Nathan A

Proceedings of the National Academy of Sciences of the United States of America

2008 Volume 105, Issue 35, Page(s) 12809–12814

Abstract: The polyketide signaling metabolites bacillaene and dihydrobacillaene are biosynthesized in Bacillus subtilis on an enzymatic assembly line with both nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) modules acting along with catalytic ...

Abstract	The polyketide signaling metabolites bacillaene and dihydrobacillaene are biosynthesized in Bacillus subtilis on an enzymatic assembly line with both nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) modules acting along with catalytic domains servicing the assembly line in trans. These signaling metabolites possess the unusual starter unit alpha-hydroxyisocaproate (alpha-HIC). We show here that it arises from initial activation of alpha-ketoisocaproate (alpha-KIC) by the first adenylation domain of PksJ (a hybrid PKS/NRPS) and installation on the pantetheinyl arm of the adjacent thiolation (T) domain. The alpha-KIC unit is elongated to alpha-KIC-Gly by the second NRPS module in PksJ as demonstrated by mass spectrometric analysis. The third module of PksJ uses PKS logic and contains an embedded ketoreductase (KR) domain along with two adjacent T domains. We show that this KR domain reduces canonical 3-ketobutyryl chains but also the alpha-keto group of alpha-KIC-containing intermediates on the PksJ T-domain doublet. This KR activity accounts for the alpha-HIC moiety found in the dihydrobacillaene/bacillaene pair and represents an example of an assembly-line dual-function alpha- and beta-KR acting on disparate positions of a growing chain intermediate.
MeSH term(s)	Bacillus subtilis/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Chromatography, High Pressure Liquid ; Esters/metabolism ; Keto Acids/metabolism ; Ketones/metabolism ; Oxidation-Reduction ; Polyenes/chemistry ; Polyenes/metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship
Chemical Substances	Bacterial Proteins ; Esters ; Keto Acids ; Ketones ; Polyenes ; bacillaene ; alpha-ketoisocaproic acid (816-66-0)
Language	English
Publishing date	2008-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0806305105
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Article ; Online: Structure determination and interception of biosynthetic intermediates for the plantazolicin class of highly discriminating antibiotics.

Molohon, Katie J / Melby, Joel O / Lee, Jaeheon / Evans, Bradley S / Dunbar, Kyle L / Bumpus, Stefanie B / Kelleher, Neil L / Mitchell, Douglas A

ACS chemical biology

2011 Volume 6, Issue 12, Page(s) 1307–1313

Abstract: The soil-dwelling, plant growth-promoting bacterium Bacillus amyloliquefaciens FZB42 is a prolific producer of complex natural products. Recently, a new FZB42 metabolite, plantazolicin (PZN), has been described as a member of the growing thiazole/oxazole- ...

Abstract	The soil-dwelling, plant growth-promoting bacterium Bacillus amyloliquefaciens FZB42 is a prolific producer of complex natural products. Recently, a new FZB42 metabolite, plantazolicin (PZN), has been described as a member of the growing thiazole/oxazole-modified microcin (TOMM) family. TOMMs are biosynthesized from inactive, ribosomal peptides and undergo a series of cyclodehydrations, dehydrogenations, and other modifications to become bioactive natural products. Using high-resolution mass spectrometry, chemoselective modification, genetic interruptions, and other spectroscopic tools, we have determined the molecular structure of PZN. In addition to two conjugated polyazole moieties, the amino-terminus of PZN has been modified to N(α),N(α)-dimethylarginine. PZN exhibited a highly selective antibiotic activity toward Bacillus anthracis, but no other tested human pathogen. By altering oxygenation levels during fermentation, PZN analogues were produced that bear variability in their heterocycle content, which yielded insight into the order of biosynthetic events. Lastly, genome-mining has revealed the existence of four additional PZN-like biosynthetic gene clusters. Given their structural uniqueness and intriguing antimicrobial specificity, the PZN class of antibiotics may hold pharmacological value.
MeSH term(s)	Amino Acid Sequence ; Anti-Bacterial Agents/biosynthesis ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Bacillus/chemistry ; Bacillus anthracis/drug effects ; Bacteriocins/biosynthesis ; Bacteriocins/chemistry ; Bacteriocins/pharmacology ; Molecular Sequence Data ; Multigene Family ; Oligopeptides/biosynthesis ; Oligopeptides/chemistry ; Oligopeptides/pharmacology ; Oxazoles/chemistry ; Oxazoles/metabolism ; Oxazoles/pharmacology ; Thiazoles/chemistry ; Thiazoles/metabolism ; Thiazoles/pharmacology
Chemical Substances	Anti-Bacterial Agents ; Bacteriocins ; Oligopeptides ; Oxazoles ; Thiazoles
Language	English
Publishing date	2011-10-06
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/cb200339d
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Article ; Online: The nonribosomal peptide synthetase enzyme DdaD tethers N(β)-fumaramoyl-l-2,3-diaminopropionate for Fe(II)/α-ketoglutarate-dependent epoxidation by DdaC during dapdiamide antibiotic biosynthesis.

Hollenhorst, Marie A / Bumpus, Stefanie B / Matthews, Megan L / Bollinger, J Martin / Kelleher, Neil L / Walsh, Christopher T

Journal of the American Chemical Society

2010 Volume 132, Issue 44, Page(s) 15773–15781

Abstract: The gene cluster from Pantoea agglomerans responsible for biosynthesis of the dapdiamide antibiotics encodes an adenylation-thiolation didomain protein, DdaD, and an Fe(II)/α-ketoglutarate-dependent dioxygenase homologue, DdaC. Here we show that DdaD, a ... ...

Abstract	The gene cluster from Pantoea agglomerans responsible for biosynthesis of the dapdiamide antibiotics encodes an adenylation-thiolation didomain protein, DdaD, and an Fe(II)/α-ketoglutarate-dependent dioxygenase homologue, DdaC. Here we show that DdaD, a nonribosomal peptide synthetase module, activates and sequesters N(β)-fumaramoyl-l-2,3-diaminopropionate as a covalently tethered thioester for subsequent oxidative modification of the fumaramoyl group. DdaC catalyzes Fe(II)- and α-ketoglutarate-dependent epoxidation of the covalently bound N(β)-fumaramoyl-l-2,3-diaminopropionyl-S-DdaD species to generate N(β)-epoxysuccinamoyl-DAP (DAP = 2,3-diaminopropionate) in thioester linkage to DdaD. After hydrolytic release, N(β)-epoxysuccinamoyl-DAP can be ligated to l-valine by the ATP-dependent ligase DdaF to form the natural antibiotic N(β)-epoxysuccinamoyl-DAP-Val.
MeSH term(s)	Anti-Bacterial Agents/biosynthesis ; Epoxy Compounds/chemistry ; Iron/chemistry ; Ketoglutaric Acids/chemistry ; Molecular Structure ; Multigene Family ; Pantoea/enzymology ; Pantoea/genetics ; Pantoea/metabolism ; Peptide Synthases/antagonists & inhibitors ; Peptide Synthases/chemistry ; Peptide Synthases/genetics
Chemical Substances	Anti-Bacterial Agents ; Epoxy Compounds ; Ketoglutaric Acids ; Iron (E1UOL152H7) ; Peptide Synthases (EC 6.3.2.-)
Language	English
Publishing date	2010-11-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja1072367
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