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7.343 | Fall 2020 | Undergraduate

# Microbial Megaproducers: Discovery, Biosynthesis, Engineering and Applications of Natural Products

week # | topics | readings
--- | --- | ---

1 | Introduction to the Course See the Lecture Summary | No Readings

2 | RiPPs (ribosomally synthesized and post-translationally modified peptides): Discovery via Culture/Manipulation of the Native Producer See the Lecture Summary | Lynch D., O’Connor P.M., Cotter P.D., Hill C., Field D., Begley M. Identification and Characterisation of Capidermicin, a Novel Bacteriocin Produced by Staphylococcus capitis, PLoS ONE, 2019, 14, e0223541. Stein T., Borchert S., Conrad B., Feesch, J., Hofemeister B., Hofemeister J., Entian K.-D. Two Different Lantibiotic-Like Peptides Originate from the Ericin Gene Cluster of Bacillus subtilis A1/3, J. Bacteriol., 2002, 184, 1703–1711.

3 | RiPPs: Discovery via Genomics/Data-Driven Strategies See the Lecture Summary | Zhao X., van der Donk W.A. Structural Characterization and Bioactivity Analysis of the Two-Component Lantibiotic Flv System from a Ruminant Bacterium. Cell Chem. Biol. 2016, 23, 246–256. Schwalen C.J., Hudson G.A., Kille B., Mitchell D.A. Bioinformatic Expansion and Discovery of Thiopeptide Antibiotics. J. Am. Chem. Soc. 2018, 140, 9494–9501.

4 | RiPPs: Biosynthesis and Enzyme Function/Mechanism See the Lecture Summary | Ortega M.A., Hao Y., Walker, M.C., Donadio S., Sosio M., Nair S.K., van der Donk W.A. Structure and tRNA Specificity of MibB, a Lantibiotic Dehydratase from Actinobacteria Involved in NAI-107 Biosynthesis. Cell Chem. Biol. 2016, 23, 370–380. LaMattina J.W., Wang B., Badding E.D., Gadsby L.K., Grove T.L., Booker S.J. NosN, a Radical S-Adenosylmethionine Methylase, Catalyzes Both C1 Transfer and Formation of the Ester Linkage of the Side-Ring System During the Biosynthesis of Nosiheptide. J. Am. Chem. Soc. 2017, 139, 17438–17445.

5 | RiPPs: Engineering See the Lecture Summary | Ozaki T., Yamashita K., Goto Y., Shimomura M., Hayashi S., Asamizu S., Sugai Y., Ikeda H., Suga H., Onaka H. Dissection of Goadsporin Biosynthesis by in vitro Reconstitution Leading to Designer Analogues Expressed in vivo. Nat. Commun. 2017, 8, 14207. Sardar D., Lin Z., Schmidt E. Modularity of RiPP Enzymes Enables Designed Synthesis of Decorated Peptides. Chem. Biol. 2015, 22, 907–916.

6 | Panel Discussion with Natural Product Professionals See the Lecture Summary | No Readings

7 | NRPs (non-ribosomal peptide NPs): Discovery via Genomics/Data-Driven Strategies See the Lecture Summary | Yamanaka K., Reynolds K.A., Kerstena R.D., Ryana K.S., Gonzalez D.J., Nizete V., Dorrestein P.C., Moore B.S. Direct Cloning and Refactoring of a Silent Lipopeptide Biosynthetic Gene Cluster Yields the Antibiotic Taromycin A (PDF). Proc. Natl. Acad. Sci. U.S.A., 2014, 111, 1957–1962. Goering A.W., McClure R.A., Doroghazi J.R., Albright J.C., Haverland N.A., Zhang Y., Ju K.-S., Thomson R.J., Metcalf W.W., Kelleher N.L. Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer. ACS Cent. Sci. 2016, 2, 99–108.

8 | NRPs: Biosynthesis and Enzyme Function/Mechanism See the Lecture Summary | Kreitler D.F., Gemmell E.M., Schaffer J.E., Wencewicz T.A., Gulick A.M. The Structural Basis of N-acyl-alpha-amino-beta-lactone Formation Catalyzed by a Nonribosomal Peptide Synthetase. Nat. Commun. 2019, 10, 3432. Dunbar K.L., Dell M., Gude F., Hertweck C. Reconstitution of Polythioamide Antibiotic Backbone Formation Reveals Unusual Thiotemplated Assembly Strategy. Proc. Natl. Acad. Sci. U.S.A. 2020, 117, 8850–8858.

9 | NRPs: Engineering See the Lecture Summary | Niquille D.L., Hansen D.A., Mori T., Fercher D., Kries H., Hilvert D. Nonribosomal Biosynthesis of Backbone-Modified Peptides. Nat. Chem. 2018, 10, 282–287. Awakawa T., Fujioka T., Zhang L., Hoshino S., Hu Z., Hashimoto J., Kozone I., Ikeda H., Shin-Ya K., Liu W., Abe I. Reprogramming of the Antimycin NRPS-PKS Assembly Lines Inspired by Gene Evolution (PDF - 1.4MB). Nat. Commun. 2018, 9, 3534.

10 | Plant NPs See the Lecture Summary | Hodgson H., De La Peña R., Stephenson M.J., Thimmappa R., Vincent J.L., Sattely E.S., Osbourn A. Identification of Key Enzymes Responsible for Protolimonoid Biosynthesis in Plants: Opening the Door to Azadirachtin Production. Proc. Natl. Acad. Sci. U.S.A. 2019, 116, 17096–17104. Brown S., Clastre M., Courdavault V., O’Connor S.E. De Novo Production of the Plant-Derived Alkaloid Strictosidine in Yeast. Proc. Natl. Acad. Sci. U.S.A. 2015, 112, 3205–3210.

11 | Culture-Dependent and Metagenomic Methods of NP Discovery from Complex Environments See the Lecture Summary | Helfrich E.J.N., Vogel C.M., Ueoka R., Schäfer M., Ryffel F., Müller D.B., Probst S., Kreuzer M., Piel J., Vorholt J.A. Bipartite Interactions, Antibiotic Production and Biosynthetic Potential of the Arabidopsis Leaf Microbiome. Nat. Microbiol. 2018, 3, 909–919. Cohen L.J., Han S., Huang Y.-H., Brady S.F. Identification of the Colicin V Bacteriocin Gene Cluster by Functional Screening of a Human Microbiome Metagenomic Library. ACS Infect. Dis. 2018, 4, 27–32.

12 | Applications of NPs in Combating Diseases See the Lecture Summary | Anand P., Filipenko P., Huaman J., Lyudmer M., Hossain M., Santamaria C., Huang K., Ogunwobi O.O., Holford M. Selective Inhibition of Liver Cancer Cells Using Venom Peptide. Mar. Drugs 2019, 17, 587. Hartkoorn R.C., Sala C., Neres J., Pojer F., Magnet S., Mukherjee R., Uplekar S., Boy-Röttger S., Altmann K-H., Cole S.T. Towards a New Tuberculosis Drug: Pyridomycin - Nature’s Isoniazid. EMBO Mol. Med. 2012, 4, 1032–1042.

13 | Student Presentations and Evaluation See the Lecture Summary | No Readings

## Course Info

##### Instructors

- Dr. Emily C Ulrich
- Dr. Kenton Hetrick

##### Departments

- Biology

##### As Taught In

Fall 2020

##### Level

Undergraduate

##### Topics

- Engineering
  - Biological Engineering
    - Biomaterials
  - Chemical Engineering
    - Molecular Engineering
- Health and Medicine
  - Cellular and Molecular Medicine
- Science
  - Biology
    - Biochemistry
    - Molecular Biology
  - Chemistry
    - Organic Chemistry

##### Learning Resource Types

assignment Presentation Assignments
assignment Written Assignments

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