A5069151362- Microbial Natural Products and Biosynthesis
- Biochemical and Molecular Research
- Enzyme Structure and Function
- Carbohydrate Chemistry and Synthesis
- Plant biochemistry and biosynthesis
- Photosynthetic Processes and Mechanisms
- Cancer Research and Treatments
- Biochemical Acid Research Studies
- Enzyme Production and Characterization
- RNA and protein synthesis mechanisms
- 14-3-3 protein interactions
- Chemical Synthesis and Analysis
- Parasitic Infections and Diagnostics
- Bioactive Compounds and Antitumor Agents
- Cancer therapeutics and mechanisms
- CRISPR and Genetic Engineering
- Fungal Biology and Applications
- Microbial Metabolic Engineering and Bioproduction
- Genomics and Phylogenetic Studies
- Pharmacological Effects of Natural Compounds
- Natural product bioactivities and synthesis
- Steroid Chemistry and Biochemistry
- RNA modifications and cancer
- Genomics, phytochemicals, and oxidative stress
- Lipid metabolism and biosynthesis
Stanford University
2020-2024
University of Southern California
2024
Southern California University for Professional Studies
2024
University of Illinois Urbana-Champaign
2015-2022
Division of Chemistry
2015
Michigan State University
2013
Assembly-line polyketide synthases, such as the 6-deoxyerythronolide B synthase (DEBS), are large enzyme factories prized for their ability to produce specific and complex products. By channeling protein-tethered substrates across multiple active sites in a defined linear sequence, these enzymes facilitate programmed small-molecule syntheses that could theoretically be harnessed access countless product structures. Using cryogenic electron microscopy study DEBS module 1, we present...
Significance Synthetic [4+2] cycloaddition reactions are prevalent and useful transformations employed in syntheses of valuable products. Coincidentally, nature also takes advantage this transformation, several cases devoted enzymes have been found to facilitate reaction the production small-molecule natural Prior examples involved either carbocyclic or oxygen heterocycle Recently, an enzymatic, formal aza -cycloaddition has confirmed, featuring a nitrogen atom final pyridine structure...
Lantibiotics are ribosomally synthesized and post-translationally modified antimicrobial peptides containing thioether rings. In addition to these cross-links, the clinical candidate lantibiotic NAI-107 also possesses a C-terminal S-[(Z)-2-aminovinyl]-d-cysteine (AviCys) unique 5-chloro-l-tryptophan (ClTrp) moiety linked its potent bioactivity. Bioinformatic genetic analyses on biosynthetic gene cluster identified mibH mibD as genes encoding flavoenzymes responsible for formation of ClTrp...
The peptide natural product nisin has been used as a food preservative for 6 decades with minimal development of resistance. Nisin contains the unusual amino acids dehydroalanine and dehydrobutyrine, which are posttranslationally installed by class I lanthipeptide dehydratases (LanBs) on linear substrate through an glutamyl-tRNA–dependent dehydration Ser Thr. To date, little is known about how LanBs catalyze transfer glutamate from charged tRNA Glu to substrate, or they carry out subsequent...
Accidental injury to the cardiac conduction system (CCS), a network of specialized cells embedded within heart and indistinguishable from surrounding muscle tissue, is major complication in surgeries. Here, we addressed this unmet need by engineering targeted antibody-dye conjugates directed against CCS, allowing for visualization CCS vivo following single intravenous injection mice. These optical imaging tools showed high sensitivity, specificity, resolution, with no adverse effects on...
Research studies in recent years have illuminated data on the mechanisms and targets of phosphonic acid antibiotics herbicides, including fosfomycin, glyphosate, fosmidomycin FR900098.
The proteasome has emerged as the primary target for treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type inhibitors such bortezomib. Herein, we describe optimization noncompetitive yield derivatives that exhibit nanomolar potency (compound 49, IC50 130 nM) toward inhibition and overcome bortezomib resistance. These studies illustrate feasibility development additives and/or alternatives competitive inhibitors.
Fragment antigen-binding domains of antibodies (Fabs) are powerful probes structure–function relationships assembly line polyketide synthases (PKSs). We report the discovery and characterization Fabs interrogating structure function ketosynthase-acyltransferase (KS-AT) core Module 2 6-deoxyerythronolide B synthase (DEBS). Two (AC2 BB1) were identified to potently inhibit catalytic activity 2. Both AC2 BB1 found modulate ACP-mediated reactions catalyzed by this module, albeit distinct...
While several bioactive natural products that contain tetramate or pyridone heterocycles have been described, information on the enzymology underpinning these functionalities has limited. Here we biochemically characterize an off-loading Dieckmann cyclase, NcmC, installs headgroup in nocamycin, a hybrid polyketide/nonribosomal peptide product. Crystal structures of enzyme (1.6 Å) and its covalent complex with epoxide cerulenin guide additional structure-based mutagenesis product-profile...
The 6-deoxyerythronolide B synthase (DEBS) is a prototypical assembly line polyketide (PKS) that synthesizes the macrocyclic core of antibiotic erythromycin. Each its six multidomain modules presumably sample distinct conformations, as biosynthetic intermediates tethered to their acyl carrier proteins interact with multiple active sites during courses catalytic cycles. spatiotemporal details underlying these protein dynamics remain elusive. Here, we investigate one aspect this conformational...
SignificanceThe channel-forming proteusins are bacterial helical peptides that allow permeation of positively charged ions to influence membrane potential and cellular physiology. We biochemically characterize the effect two critical posttranslational modifications on secondary structure peptide substrate. determine how a methyl group can be added side chains D-Asn residues in substrate show flanking selectivity. These studies should foster development small-molecule ion channels as therapeutics.
ABSTRACT Assembly-line polyketide synthases are large multienzyme systems with considerable potential for genetic reprogramming. To investigate the mechanisms by which reactive biosynthetic intermediates directionally channeled across a defined sequence of active sites in naturally occurring assembly line, we employed bifunctional reagent to crosslink transient domain-domain interfaces 6-deoxyerythronolide B synthase. Structural resolution these crosslinked states single-particle cryogenic...