A5003353735- Microbial Natural Products and Biosynthesis
- Biochemical and Molecular Research
- Carbohydrate Chemistry and Synthesis
- Chemical Synthesis and Analysis
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- RNA modifications and cancer
- Phytochemical compounds biological activities
- Fungal Biology and Applications
- Natural product bioactivities and synthesis
- Metal-Catalyzed Oxygenation Mechanisms
- Cyclization and Aryne Chemistry
- Chemical synthesis and alkaloids
- Antibiotic Resistance in Bacteria
- Enzyme Catalysis and Immobilization
- 14-3-3 protein interactions
- Genomics and Phylogenetic Studies
- Synthetic Organic Chemistry Methods
- Pneumocystis jirovecii pneumonia detection and treatment
- Glycosylation and Glycoproteins Research
- Microbial Metabolic Engineering and Bioproduction
- Plant tissue culture and regeneration
- Cancer-related gene regulation
- Marine Sponges and Natural Products
- Cancer therapeutics and mechanisms
University of Kentucky
2014-2024
Rice University
2021
University of Wisconsin–Madison
2005-2009
Pharmaceutical Biotechnology (Czechia)
2008-2009
Portland State University
2000-2007
Boston College
2007
University of Illinois Urbana-Champaign
2005-2006
Scripps Research Institute
2005
Abstract A chemoenzymatic platform for the synthesis of S ‐adenosyl‐ L ‐methionine (SAM) analogues compatible with downstream SAM‐utilizing enzymes is reported. Forty‐four non‐native S/Se‐alkylated Met were synthesized and applied to probing substrate specificity five diverse methionine adenosyltransferases (MATs). Human MAT II was among most permissive MATs analyzed enabled 29 SAM analogues. As a proof concept feasibility natural product “alkylrandomization”, small set...
The biosynthetic gene cluster for the enediyne antitumor antibiotic maduropeptin (MDP) from Actinomadura madurae ATCC 39144 was cloned and sequenced. Cloning of mdp confirmed by heterologous complementation polyketide synthase (PKS) mutants C-1027 producer Streptomyces globisporus neocarzinostatin carzinostaticus using MDP PKS associated genes. Furthermore, produced, its apoprotein isolated N-terminal sequenced; encoding gene, mdpA, found to reside within cluster. biosynthesis is highlighted...
Pathogenic bacteria scavenge ferric iron from the host for survival and proliferation using small-molecular chelators, siderophores. Here, we introduce assess gallium(III) complex of ciprofloxacin-functionalized desferrichrome (D2) as a potential therapeutic bacterial infection an in vitro assay radiochemical, tracer-based approach. Ga-D2 exhibits minimum inhibitory concentration 0.23 μM Escherichia coli, line with parent fluoroquinolone antibiotic. Competitive mutant strain assays show that...
The enzyme YkvM from Bacillus subtilis was identified previously along with three other enzymes (YkvJKL) in a bioinformatics search for involved the biosynthesis of queuosine, 7-deazaguanine modified nucleoside found tRNA GUN Bacteria and Eukarya. Genetic analysis ykvJKLM mutants Acinetobacter confirmed that each essential queuosine biosynthesis, genes were renamed queCDEF . QueF exhibits significant homology to type I GTP cyclohydrolases characterized by FolE. Given is precursor...
Acyl carrier protein (ACP) plays an essential role in fatty acid and polyketide biosynthesis, most of the synthases (FASs) (PKSs) known to date are characterized with a single ACP for each cycle chain elongation. Polyunsaturated (PUFA) biosynthesis is catalyzed by PUFA synthase, all contain tandem ACPs (ranging from 5 9). Using Pfa synthase Shewanella japonica as model system, we report here that these functionally equivalent regardless their physical location within subunit, but total...
The enediynes, unified by their unique molecular architecture and mode of action, represent some the most potent anticancer drugs ever discovered. biosynthesis enediyne core has been predicted to be initiated a polyketide synthase (PKS) that is distinct from all known PKSs. Characterization PKS involved in C-1027 (SgcE) neocarzinostatin (NcsE) now revealed ( i ) PKSs contain central acyl carrier protein domain C-terminal phosphopantetheinyl transferase domain; ii are functional heterologous...
C-1027 is a potent antitumor antibiotic composed of an apo-protein and reactive enediyne chromophore. The chromophore consists four different chemical subunits including (S)-3-chloro-4,5-dihydroxy-β-phenylalanine moiety, the biosynthesis which from l-α-tyrosine catalyzed by six proteins, SgcC, SgcC1, SgcC2, SgcC3, SgcC4, SgcC5. Biochemical characterization SgcC3 unveiled following: (i) flavin adenine dinucleotide (FAD)-dependent halogenase; (ii) acts only on SgcC2 peptidyl carrier...
Nonribosomal peptide synthetases (NRPSs) catalyze the biosynthesis of many biologically active peptides and typically are modular, with each extension module minimally consisting a condensation, an adenylation, peptidyl carrier protein domain responsible for incorporation amino acid into growing chain. C-1027 is chromoprotein antitumor antibiotic whose enediyne chromophore consists core, deoxy aminosugar, benzoxazolinate, β-amino moiety. Bioinformatics analysis suggested that activation...
The lipopeptidyl nucleoside antibiotics represented by A-90289, caprazamycin, and muraymycin are structurally highlighted a core that contains nonproteinogenic β-hydroxy-α-amino acid named 5′-C-glycyluridine (GlyU). Bioinformatic analysis of the biosynthetic gene clusters revealed shared open reading frame encoding protein with sequence similarity to serine hydroxymethyltransferases, resulting in proposal this enzyme catalyzes an aldol-type condensation glycine uridine-5′-aldehyde furnish...
Teamwork: Defucogilvocarcin M (1, see scheme) was synthesized in a one-pot, enzymatic reaction from acetyl-CoA and malonyl-CoA by combination of 15 enzymes obtained E. coli as well the gilvocarcin, jadomycin, ravidomycin biosynthetic pathways. The mixture systematically reduced varied to further delineate sequence reactions complex, post-polyketide steps gilvocarcin biosynthesis. Detailed facts importance specialist readers are published "Supporting Information". Such documents...
Abstract A chemoenzymatic platform for the synthesis of S ‐adenosyl‐ L ‐methionine (SAM) analogues compatible with downstream SAM‐utilizing enzymes is reported. Forty‐four non‐native S/Se‐alkylated Met were synthesized and applied to probing substrate specificity five diverse methionine adenosyltransferases (MATs). Human MAT II was among most permissive MATs analyzed enabled 29 SAM analogues. As a proof concept feasibility natural product “alkylrandomization”, small set...
The enediynes are structurally characterized by a 1,5-diyne-3-ene motif within 9- or 10-membered enediyne core. anthraquinone-fused (AFEs) subclass of that contain an anthraquinone moiety fused to the core as exemplified dynemicins and tiancimycins. A conserved iterative type I polyketide synthase (PKSE) is known initiate biosynthesis all cores, evidence has recently been reported suggest also originates from PKSE product. However, identity product converted not established. Here, we report...
The SgcC4 l-tyrosine 2,3-aminomutase (SgTAM) catalyzes the formation of (S)-β-tyrosine in biosynthetic pathway enediyne antitumor antibiotic C-1027. SgTAM is homologous to histidine ammonia lyase family enzymes whose activity dependent on methylideneimidazole-5-one (MIO) cofactor. Unlike enzymes, additional chemical transformations resulting an overall stereospecific 1,2-amino shift substrate generate (S)-β-tyrosine. Previously, we provided kinetic, spectroscopic, and mutagenesis data...
Lip reading: The biosynthetic gene cluster for A-90289, a fatty acid nucleoside antibiotic, was cloned and sequenced. sulfotransferase LipB is demonstrated to be essential A-90289 biosynthesis, in vitro characterization revealed utilizes p-nitrophenylsulfate as an aryl sulfate donor variety of nonaryl acceptors including caprazamycin A give the 2′-O-sulfated product, A-90289A. Enzymes involved peptidoglycan cell wall biosynthesis are proven targets antibacterial drugs that have...
Fe(II)- and α-ketoglutarate (α-KG)-dependent dioxygenases are a large diverse superfamily of mononuclear, non-heme enzymes that perform variety oxidative transformations typically coupling decarboxylation α-KG with hydroxylation prime substrate. The biosynthetic gene clusters for several nucleoside antibiotics contain modified uridine component, including the lipopeptidyl A-90289 from Streptomyces sp. SANK 60405, have recently been reported, revealing shared open reading frame sequence...
S-adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with expanding range of biocatalytic and therapeutic applications. We report the design, synthesis, evaluation stable, functional AdoMet isosteres that are resistant to primary contributors degradation (depurination, intramolecular cyclization, sulfonium epimerization). Corresponding biochemical structural studies demonstrate surrogates serve as competent cosubstrates bind a prototypical class I model...
Muraymycins are antibacterial natural products from Streptomyces spp. that inhibit translocase I (MraY), which is involved in cell wall biosynthesis. Structurally, muraymycins consist of a 5'-C-glycyluridine (GlyU) appended to 5″-amino-5″-deoxyribose (ADR), forming disaccharide core found several peptidyl nucleoside inhibitors MraY. For muraymycins, the GlyU-ADR further modified with an aminopropyl-linked peptide generate simplest structures, annotated as muraymycin D series. Two enzymes...
Terfestatins B (1) and C (2), new p-terphenyls bearing a novel unsaturated hexuronic acid (4-deoxy-α-l-threo-hex-4-enopyranuronate), unique β-d-glycosyl ester of 5-isoprenylindole-3-carboxylate (3) the same rare sugar, two hygromycin precursors, were characterized as metabolites coal mine fire isolate Streptomyces sp. RM-5–8. EtOH damage neuroprotection assays using rat hippocampal-derived primary cell cultures with 1, 2, 3 echoside (a terfestatin C-3′-β-d-glucuronide from RM-5–8) revealed 1...