A5043409563- Microbial Natural Products and Biosynthesis
- Chemical Synthesis and Analysis
- Cyclization and Aryne Chemistry
- Phytochemical compounds biological activities
- Synthetic Organic Chemistry Methods
- Genomics and Phylogenetic Studies
- Click Chemistry and Applications
- X-ray Diffraction in Crystallography
- Synthesis and Catalytic Reactions
- Crystallization and Solubility Studies
- Microbial Metabolism and Applications
- Marine Sponges and Natural Products
- Microbial Community Ecology and Physiology
- Protist diversity and phylogeny
- Polar Research and Ecology
- Polyamine Metabolism and Applications
- Plant and fungal interactions
- Catalytic C–H Functionalization Methods
- Plant biochemistry and biosynthesis
- Bioactive Compounds and Antitumor Agents
- Sesquiterpenes and Asteraceae Studies
- Carbohydrate Chemistry and Synthesis
- Cancer Treatment and Pharmacology
- HER2/EGFR in Cancer Research
- Steroid Chemistry and Biochemistry
University of Montana
2022-2023
Scripps (United States)
2022-2023
University of Florida
2022-2023
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
2023
Scripps Research Institute
2017-2022
University of California, Berkeley
2015
A new anthraquinone-fused enediyne, yangpumicin (YPM A, 1), along with four Bergman cyclization congeners B–E, 2–5), was isolated from Micromonospora yangpuensis DSM 45577 after mining enediyne biosynthetic gene clusters public actinobacterial genome databases and prioritizing the hits by an neighborhood network analysis for discovery. YPM is potent against a broad spectrum of human cancer cell lines. The discovery 1 provides opportunities functionalization enediynes to develop conjugation...
Abstract Calicheamicin, the payload of antibody-drug-conjugates (ADCs) gemtuzumab ozogamicin (Mylotarg®) and inotuzumab (Besponsa®), belongs to class enediyne natural products. Since isolation structural determination neocarzinostatin chromophore in 1985, enediynes have attracted considerable attention for their value as DNA damaging agents cancer chemotherapy. Due non-discriminatory cytotoxicity towards both healthy cells, clinical utilization products relies on conjugation an appropriate...
Comparative analyses of the four known anthraquinone-fused enediynes biosynthetic gene clusters identified genes, tnmE6, tnmH, tnmL, and tnmQ, unique to tnm cluster. Larger scale fermentation both S. sp. CB03234 wild-type ΔtnmH ΔtnmL mutant strains resulted in characterization 20 new tiancimycin (TNM) congeners, including five enediynes. These findings enabled a proposal for late stage TNM biosynthesis featuring an intermediate possibly common all
The enediynes are among the most cytotoxic molecules known, and their use as anticancer drugs has been successfully demonstrated by targeted delivery. Clinical advancement of anthraquinone-fused hindered low titers lack functional groups to enable preparation antibody–drug conjugates (ADCs). Here we report biochemical structural characterization TnmH from tiancimycin (TNM) biosynthetic pathway, revealing that (i) catalyzes regiospecific methylation at C-7 hydroxyl group, (ii) exhibits broad...
Abstract Sulfur incorporation into natural products is a critical area of biosynthetic studies. Recently, subset sulfur‐containing angucyclines has been discovered, and yet, the sulfur step poorly understood. In this work, series thioether‐bridged were cryptic epoxide Michael acceptor intermediate was revealed en route to thioangucyclines (TACs) A B. However, systematic gene deletion cluster (BGC) by CRISPR/Cas9 could not identify any responsible for conversion TACs. Instead, in vitro vivo...
First discovered in 1989, the anthraquinone-fused enediynes are a class of DNA-cleaving bacterial natural products composed DNA-intercalating anthraquinone moiety and 10-membered enediyne warhead. However, until recently, there has been lack genetically amenable hosts sequenced biosynthetic gene clusters available for solving questions surrounding these molecules. Herein, we have identified biochemically structurally characterized TnmK1, member α/β-hydrolase fold superfamily responsible C–C...
Actinobacteria, the bacterial phylum most renowned for natural product discovery, has been established as a valuable source drug discovery and biotechnology but is underrepresented within accessible genome strain collections. Herein, we introduce Natural Products Discovery Center (NPDC), featuring 122,449 strains assembled over eight decades, genomes of first 8490 NPDC (7142 Actinobacteria), online Portal making both publicly available. A comparative survey RefSeq Actinobacteria highlights...
Neogrisemycin (1) was isolated from recombinant Streptomyces albus J1074 strain SB4061 expressing an engineered thioangucycline (TAC) biosynthetic gene cluster (BGC). The structure and absolute configuration of 1 were established by a combination mass spectrometry, nuclear magnetic resonance, single-crystal X-ray diffraction analyses. Like the TACs, also proposed to derive non-enzymatically common epoxide (8), nascent product encoded tac BGC, mediated endogenous hydrogen trisulfide.
Tiancimycin (TNM) A belongs to the anthraquinone-fused subfamily of enediyne natural products, and selected enediynes have been translated into clinical drugs. Previously, inactivation tnmL in Streptomyces sp. CB03234 resulted accumulation TNM B E, supporting functional assignment TnmL as a cytochrome P450 hydroxylase that catalyzes A-ring modification biosynthesis. Herein, we report vitro characterization TnmL, revealing (i) two successive hydroxylations resulting sequential production F C,...
Antibody–drug conjugates (ADCs) are cancer chemotherapeutics that utilize a monoclonal antibody (mAb)-based delivery system, cytotoxic payload, and chemical linker. ADC payloads must be strategically functionalized to allow linker attachment without perturbing the potency required for efficacy. We previously developed biocatalytic system precise functionalization of tiancimycin (TNM)-based payloads. The TNMs anthraquinone-fused enediynes (AFEs) have yet translated into clinic. Herein, we...
The ammosamides (AMMs) are a family of pyrroloquinoline alkaloids that exhibits wide variety bioactivities. A biosynthetic gene cluster (BGC) is highly homologous in both content and genetic organization to the amm BGC was identified by mining Streptomyces uncialis DCA2648 genome, leading discovery sub-family new AMM congeners, named ammosesters (AMEs). AMEs feature C-4a methyl ester, differing from amide functional group characteristic AMMs, exhibit modest cytotoxicity against broad...
ABSTRACT The study of microbial evolution is hindered by the fact that populations leave few fossils. We hypothesized bacterial cells preserved in ancient ice could be used as a molecular fossil record if their DNA extracted and sequenced. Channels formed along triple junctions crystals contain liquid “veins” which may intact. Since vertical motion through matrix impossible, microbes found cores are representative present at time was formed. detected chlorophyll fluorescence intact taken...
Uncialamycin (UCM) belongs to the anthraquinone-fused subfamily of 10-membered enediyne natural products that exhibits an extraordinary cytotoxicity against a wide spectrum human cancer cell lines. Antibody-drug conjugates, utilizing synthetic analogues UCM as payloads, are in preclinical development. is exclusively produced by Streptomyces uncialis DCA2648 on solid agar medium with low titers (∼0.019 mg/l), limiting its supply microbial fermentation and hampering biosynthetic engineering...
Comparative analyses of four anthraquinone-fused enediyne biosynthetic gene clusters (BGCs) identified YpmL as a cytochrome P450 enzyme unique to the yangpumicin (YPM) BGC. In vitro characterization established it hydroxylase, catalyzing C-6 hydroxylation in YPM A biosynthesis. vivo application enabled engineered production new tiancimycin analogues (14–17). Evaluation their cytotoxicity against selected human cancer cell lines shed insights into structure–activity relationship.
Abstract Sulfur incorporation into natural products is a critical area of biosynthetic studies. Recently, subset sulfur‐containing angucyclines has been discovered, and yet, the sulfur step poorly understood. In this work, series thioether‐bridged were cryptic epoxide Michael acceptor intermediate was revealed en route to thioangucyclines (TACs) A B. However, systematic gene deletion cluster (BGC) by CRISPR/Cas9 could not identify any responsible for conversion TACs. Instead, in vitro vivo...