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Biomolecular Engineering ------Exploitation of Enzymes toward Synthesis of Pharmaceuticals and Biofuels College of Chemistry Advisory Board Meeting Presentation,

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Presentation on theme: "Biomolecular Engineering ------Exploitation of Enzymes toward Synthesis of Pharmaceuticals and Biofuels College of Chemistry Advisory Board Meeting Presentation,"— Presentation transcript:

1 Biomolecular Engineering ------Exploitation of Enzymes toward Synthesis of Pharmaceuticals and Biofuels College of Chemistry Advisory Board Meeting Presentation, 10/24/2011 Wenjun Zhang Department of Chemical and Biomolecular Engineering University of California, Berkeley

2 Natural Products doxorubicin erythromycin vancomycin penicillin artemisinin lovastatin paclitaxel Pharmaceuticals Biofuels physostigmine

3 Enzyme and Pathway Engineering Genome Mining PredictNew Candidate Discovery Combinatorial Biosynthesis Prerequisite Biotransformation Research Themes Natural Products Pharmaceuticals and Biofuels Enzyme and Pathway Characterization

4 genome analysis Research Approach

5 Example 1: Engineered Biosynthesis of Bacterial Aromatic Polyketides ? Streptomyces rimosus

6 oxyAoxyC oxyEoxyG oxyI oxyKoxyMoxyO oxyQ oxyS otrBoxyBoxyDoxyFoxyHoxyJoxyLoxyNoxyPotrAoxyRoxyT ResistanceMinimal PKSInitiation ModuleCyclaseTailoringUnknown 024681012141618202224 kB KR Oxytetracycline Biosynthetic Pathway Zhang et al, AEM 2006; Zhang et al, JNP 2006; Zhang et al, JBC 2007; Zhang et al, JACS 2008

7 Combinatorial Biosynthesis : modification of natural product biosynthetic pathways toward the production of “unnatural” natural products.

8 Engineered Biosynthesis 1 (yield: ~10 mg/L) Zhang et al, JACS 2008

9 Engineered Biosynthesis 2

10 pannorin A C9-C14 and C7-C16 cyclase from the tetracenomycin pathway pannorin analog (yield: ~50 mg/L) Zhang et al, JACS 2007

11 E. coli as a Host for Bacterial Aromatic Polyketide Production Bacterial Aromatic Polyketides E. coli Actinomycetes Macrolides Cyclic Peptides TerpenoidsAlkaloids

12 Fungal type I PKS Malonyl-CoA (SAT)KSMATPTACPTE/CYC(SAT)KSMATPTACPTE/CYC Backbone Assembly Tailoring No crosstalk Bacterial type II PKS Malonyl-CoA Bacterial and Fungal Aromatic Polyketides Biosynthesis Bacterial Aromatic PolyketidesFungal Aromatic Polyketides

13 Bacterial type II PKSFungal type I PKS Malonyl-CoA Bacterial Aromatic Polyketides Fungal Aromatic Polyketides Biosynthesis of Bacterial Aromatic Polyketides in Escherichia coli KSMATACP Zhang et al, PNAS 2008

14 pacidamycins mureidomycins napsamycins sansanmycins UDP-MurNAc -pentapeptide substrate inhibitors liposidomycins caprazamycins capuramycin tunicamycins streptoviridins corynetoxins muraymycins Example 2: Biosynthesis of Uridyl Peptide Antibiotics

15 Pacidamycin Biosynthesis ? Streptomyces coeruleorubidus pacidamycins

16 Pacidamycin Scaffold Assembly Summary BCDEFGIJKLMNOPQRSTUVA H 2 kb Streptomyces coeruleorubidus NRRL 18370 W X Zhang et al, PNAS 2010; Zhang et al, Biochemistry 2010; Zhang et al, JACS 2011; Zhang et al, Biochemistry 2011; Zhang et al, PNAS 2011

17 NRPS Assembly Line

18 AA 1 = alanyl or H AA 2 = m-Tyr or Ala AA 5 = Phe or Trp or m-Tyr R = CH 3 or H In vitro Total Synthesis of >50 Pacidamycin Analogs

19 Ongoing Projects paclitaxel physostigmine undecene uridyl peptide antibiotics sparsomycin antimycin 4-methylquinazoline asukamycin

20 Acknowledgements HMS Walsh Lab Christopher T. Walsh Heidi Imker Steven Malcolmson Brian Ames Yi Tang Jixun Zhan Suzanne M. Ma Yanran Li UCLA Tang Lab Berkeley Zhang Lab Zhe Rui Moriah M. Sandy Funding: Berkeley Startup, EBI


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