ArticleProceedings of the National Academy of Sciences of the United States of America2015
C-S bond cleavage by a polyketide synthase domain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Amplicon-based prediction of secondary metabolic potential of microbiomes facilitates natural product discovery.Synthetic and systems biotechnology · 2026Article
- Sulfur-Containing Microbial Natural Products and Their Role in Communal Interactions.Journal of natural products · 2025Review
- Discovery of acylsulfenic acid-featuring natural product sulfenicin and characterization of its biosynthesis.Nature chemistry · 2025Article
- How nature incorporates sulfur and selenium into bioactive natural products.Current opinion in chemical biology · 2023Review
- Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium.Nature chemistry · 2022Article
- Biosynthesis of DNA-Alkylating Antitumor Natural Products.Molecules (Basel, Switzerland) · 2022Review
- Cleavage Off-Loading and Post-assembly-Line Conversions Yield Products with Unusual Termini during Biosynthesis.ACS chemical biology · 2022Article
- Genome mining methods to discover bioactive natural products.Natural product reports · 2021Review
- Thiocysteine lyases as polyketide synthase domains installing hydropersulfide into natural products and a hydropersulfide methyltransferase.Nature communications · 2021Article
- Leveraging a large microbial strain collection for natural product discovery.The Journal of biological chemistry · 2019Review
- Automated structure prediction of trans-acyltransferase polyketide synthase products.Nature chemical biology · 2019Article
- The hidden enzymology of bacterial natural product biosynthesis.Nature reviews. Chemistry · 2019Article
- Challenges and opportunities for natural product discovery, production, and engineering in native producers versus heterologous hosts.Journal of industrial microbiology & biotechnology · 2019Review
- P450-Catalyzed Tailoring Steps in Leinamycin Biosynthesis Featuring Regio- and Stereoselective Hydroxylations and Substrate Promiscuities.Biochemistry · 2018Article
- The modules of trans-acyltransferase assembly lines redefined with a central acyl carrier protein.Proteins · 2018Article
- Discovery of the leinamycin family of natural products by mining actinobacterial genomes.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Heteroatom-Heteroatom Bond Formation in Natural Product Biosynthesis.Chemical reviews · 2017Review
- Characterization of LnmO as a pathway-specific Crp/Fnr-type positive regulator for leinamycin biosynthesis in Streptomyces atroolivaceus and its application for titer improvement.Applied microbiology and biotechnology · 2016Article
- Characterization of the Ketosynthase and Acyl Carrier Protein Domains at the LnmI Nonribosomal Peptide Synthetase-Polyketide Synthase Interface for Leinamycin Biosynthesis.Organic letters · 2016Article
- Harnessing natural product assembly lines: structure, promiscuity, and engineering.Journal of industrial microbiology & biotechnology · 2016Review
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4 authors.
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Abstract
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 generate an episulfonium ion intermediate capable of alkylating DNA. We have previously cloned and sequenced the lnm gene cluster from Streptomyces atroolivaceus S-140. In vivo and in vitro characterizations of the LNM biosynthetic machinery have since established that: (i) the 18-membered macrolactam backbone is synthesized by LnmP, LnmQ, LnmJ, LnmI, and LnmG, (ii) the alkyl branch at C-3 of LNM is installed by LnmK, LnmL, LnmM, and LnmF, and (iii) leinamycin E1 (LNM E1), bearing a thiol moiety at C-3, is the nascent product of the LNM hybrid nonribosomal peptide synthetase (NRPS)-acyltransferase (AT)-less type I polyketide synthase (PKS). Sulfur incorporation at C-3 of LNM E1, however, has not been addressed. Here we report that: (i) the bioinformatics analysis reveals a pyridoxal phosphate (PLP)-dependent domain, we termed cysteine lyase (SH) domain (LnmJ-SH), within PKS module-8 of LnmJ; (ii) the LnmJ-SH domain catalyzes C-S bond cleavage by using l-cysteine and l-cysteine S-modified analogs as substrates through a PLP-dependent β-elimination reaction, establishing l-cysteine as the origin of sulfur at C-3 of LNM; and (iii) the LnmJ-SH domain, sharing no sequence homology with any other enzymes catalyzing C-S bond cleavage, represents a new family of PKS domains that expands the chemistry and enzymology of PKSs and might be exploited to incorporate sulfur into polyketide natural products by PKS engineering.
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