Engineered production of cancer targeting peptide (CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation.
Bioorganic & Medicinal Chemistry 24(17):3887 (2016)
Conjugation of cancer targeting peptides (CTPs) with small molecular therapeutics has emerged as a promising strategy to deliver potent (but typically nonspecific) cytotoxic agents selectively to cancer cells. Here we report the engineered production of a CTP (NGR)-containing C-1027 and evaluati...
Titer improvement and pilot-scale production of platensimycin from Streptomyces platensis SB12026.
Journal of Industrial Microbiology 43(7):1027 (2016)
Platensimycin (PTM) and platencin (PTN), isolated from several strains of Streptomyces platensis are potent antibiotics against multi-drug resistant bacteria. PTM was also shown to have antidiabetic and antisteatotic activities in mouse models. Through a novel genome-mining method, we have recen...
Synthetic biology to access and expand nature's chemical diversity.
Nature Reviews: Microbiology 14(3):135 (2016)
Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Accessing these natural products promises to reinvigorate drug discovery pipelines and provide novel routes to synthesi...
Overproduction of lactimidomycin by cross-overexpression of genes encoding Streptomyces antibiotic regulatory proteins.
Applied Microbiology and Biotechnology 100(5):2267 (2016)
The glutarimide-containing polyketides represent a fascinating class of natural products that exhibit a multitude of biological activities. We have recently cloned and sequenced the biosynthetic gene clusters for three members of the glutarimide-containing polyketides-iso-migrastatin (iso-MGS) f...
Genome neighborhood network reveals insights into enediyne biosynthesis and facilitates prediction and prioritization for discovery.
Journal of Industrial Microbiology 43(2-3):261 (2016)
The enediynes are one of the most fascinating families of bacterial natural products given their unprecedented molecular architecture and extraordinary cytotoxicity. Enediynes are rare with only 11 structurally characterized members and four additional members isolated in their cycloaromatized f...
A New Golden Age of Natural Products Drug Discovery.
Cell 163(6):1297 (2015)
The 2015 Nobel Prize in Physiology or Medicine has been awarded to William C. Campbell, Satoshi Omura, and Youyou Tu for the discovery of avermectins and artemisinin, respectively, therapies that revolutionized the treatment of devastating parasite diseases. With the recent technological advance...
Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892.
Biochemistry (Washington) 54(45):6842 (2015)
The bleomycins (BLMs), tallysomycins (TLMs), phleomycin, and zorbamycin (ZBM) are members of the BLM family of glycopeptide-derived antitumor antibiotics. The BLM-producing Streptomyces verticillus ATCC15003 and the TLM-producing Streptoalloteichus hindustanus E465-94 ATCC31158 both possess at l...
Synthesis and evaluation of 8,4'-dideshydroxy-leinamycin revealing new insights into the structure-activity relationship of the anticancer natural product leinamycin.
Bioorganic & Medicinal Chemistry Letters 25(21):4899 (2015)
Leinamycin (LNM, 1) is a novel antitumor antibiotic produced by Streptomyces atroolivaceus S-140 and features an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. The 1,3-dioxo-1,2-dithiolane moiety of LNM is essential for its antitumor...
Angucyclines and Angucyclinones from Streptomyces sp. CB01913 Featuring C-Ring Cleavage and Expansion.
Journal of Natural Products 78(10):2471 (2015)
Angucyclines and angucyclinones are aromatic polyketides with a tetracyclic benz[a]anthracene skeleton. The benz[a]anthracene scaffold is biosynthesized by type II polyketide synthases that catalyze the decarboxylative condensation of a short acyl-CoA starter and nine extender units. Angucycline...
Structural and evolutionary relationships of "AT-less" type I polyketide synthase ketosynthases.
PNAS 112(41):12693 (2015)
Acyltransferase (AT)-less type I polyketide synthases (PKSs) break the type I PKS paradigm. They lack the integrated AT domains within their modules and instead use a discrete AT that acts in trans, whereas a type I PKS module minimally contains AT, acyl carrier protein (ACP), and ketosynthase (...
A genetically amenable platensimycin- and platencin-overproducer as a platform for biosynthetic explorations: a showcase of PtmO4, a long-chain acyl-CoA dehydrogenase.
Molecular BioSystems 11(10):2717 (2015)
Platensimycin (PTM) and platencin (PTN) are members of a new class of promising drug leads that target bacterial and mammalian fatty acid synthases. We previously cloned and sequenced the PTM and PTN gene clusters, discovered six additional PTM-PTN dual producing strains, and demonstrated the dr...
Minimum Information about a Biosynthetic Gene cluster.
Nature Chemical Biology 11(9):625 (2015)
C-S bond cleavage by a polyketide synthase domain.
PNAS 112(33):10359 (2015)
Leinamycin (LNM) is a sulfur-containing antitumor antibiotic featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. The 1,3-dioxo-1,2-dithiolane moiety is essential for LNM's antitumor activity, by virtue of its ability to gener...
Adipostatins A-D from Streptomyces sp. 4875 inhibiting Brugia malayi asparaginyl-tRNA synthetase and killing adult Brugia malayi parasites.
Journal of Antibiotics 68(8):540 (2015)
Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species.
PNAS 112(27):8278 (2015)
Leinamycin (LNM) is a potent antitumor antibiotic produced by Streptomyces atroolivaceus S-140, featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. Upon reductive activation in the presence of cellular thiols, LNM exerts its ...
Deciphering poxvirus gene expression by RNA sequencing and ribosome profiling.
Journal of Virology 89(13):6874 (2015)
The more than 200 closely spaced annotated open reading frames, extensive transcriptional read-through, and numerous unpredicted RNA start sites have made the analysis of vaccinia virus gene expression challenging. Genome-wide ribosome profiling provided an unprecedented assessment of poxvirus g...
Quantitative profiling of initiating ribosomes in vivo.
Nature Methods 12(2):147 (2015)
Cells have evolved exquisite mechanisms to fine-tune the rate of protein synthesis in response to stress. Systemic mapping of start-codon positions and precise measurement of the corresponding initiation rate would transform our understanding of translational control. Here we present quantitativ...
Enediynes: Exploration of microbial genomics to discover new anticancer drug leads.
Bioorganic & Medicinal Chemistry Letters 25(1):9 (2015)
The enediyne natural products have been explored for their phenomenal cytotoxicity. The development of enediynes into anticancer drugs has been successfully achieved through the utilization of polymer- and antibody-drug conjugates (ADCs) as drug delivery systems. An increasing inventory of enedi...
Comparative characterization of the lactimidomycin and iso-migrastatin biosynthetic machineries revealing unusual features for acyltransferase-less type I polyketide synthases and providing an opportunity to engineer new analogues.
Biochemistry (Washington) 53(49):7854 (2014)
Lactimidomycin (LTM, 1) and iso-migrastatin (iso-MGS, 2) belong to the glutarimide-containing polyketide family of natural products. We previously cloned and characterized the mgs biosynthetic gene cluster from Streptomyces platensis NRRL 18993. The iso-MGS biosynthetic machinery featured an acy...
A proteogenomics approach integrating proteomics and ribosome profiling increases the efficiency of protein identification and enables the discovery of alternative translation start sites.
Proteomics 14(23-24):2688 (2014)
Next-generation transcriptome sequencing is increasingly integrated with MS to enhance MS-based protein and peptide identification. Recently, a breakthrough in transcriptome analysis was achieved with the development of ribosome profiling (ribo-seq). This technology is based on the deep sequenci...