Chemistry 171: Biological Synthesis

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1 Chemistry 171: Biological Synthesis Harvard University Spring, 2012 Tuesday and Thursday, 10 11:30 AM Location: Pfizer Lecture Hall, Mallinckrodt Lab 12 Oxford St., Cambridge Nature is a remarkable synthetic chemist. In order to survive, all living organisms must perform a wide range of chemical transformations with exquisite speed and selectivity. This feat is accomplished via the use of enzymes: protein-based, catalysts that have evolved to perform chemistry in a biological setting. Recently, there has been growing interest in harnessing biological tools for the construction of small molecules of medicinal and industrial importance. The use of isolated enzymes and engineered organisms for making molecules can have both economic and environmental benefits and has the potential to fundamentally change the field of synthetic chemistry. This course will examine chemical synthesis from a biological perspective, focusing on how organisms naturally construct and manipulate metabolites, as well as how biological catalysts and systems can be used for non-natural small molecule production. Topics to be covered include mechanistic enzymology, biosynthetic pathways and logic, biocatalysis, protein engineering, and synthetic biology. Recent discoveries and applications from both the scientific literature and industry will be prominently featured throughout the course. Instructors Professor: Teaching Fellows: Emily Balskus balskus@chemistry.harvard.edu Office: Mallinckrodt 303N; Phone: (617) Office Hours: Tues 6 7 PM, Mallinckrodt 303N Carolyn Brotherton cbrother@fas.harvard.edu Mingyu Xue xue@fas.harvard.edu Office hours by appointment Prerequisites A strong background in organic chemistry is required (completion of Chem 17/27 or Chem 20/30). A basic understanding of biochemistry and molecular biology is assumed, although a lack of experience in this area can be remedied during the semester by very diligently reviewing the relevant materials. Literature Journal articles from the primary literature will form the majority of the course material. Assigned articles for section meetings will be posted on the course website one week in advance. Additionally, each lecture will have an attached Reference List

2 containing articles relevant to the lecture material. These papers are provided as reference material and should be consulted as necessary. There will be no required textbook for this course. The following textbooks may prove useful as supplementary materials and will be placed on reserve at the Chemistry Library: Course Website McMurray, J and Bagley, T. The Organic Chemistry of Biological Pathways Dewick, P. M. Medicinal Natural Products, A Biosynthetic Approach Silverman, R. B. The Organic Chemistry of Enzyme-Catalyzed Reactions Berg, J. M., Tymoczko, J. L., and Stryer, L. Biochemistry 7 th Editions The course website can be found at: The following information will be available on the website: Sections 1. Lecture Slides: PDF versions of each lecture and reference list will be posted on the website shortly after each lecture. Black-and-white copies of the slides will be provided at the beginning of each lecture. 2. Lecture Videos: Lectures will be filmed and put on the website shortly after class. 3. Assigned Papers: Papers that are assigned for section meetings will be posted on the web at the beginning of the week prior to the week in which they will be discussed. In other words, you will have at least a week (depending on your section) to read the papers. Sections are mandatory and will be held once a week starting the week of Jan 30th. Sections will involve a detailed discussion of 1-2 previously assigned journal articles, with an emphasis on experimental and mechanistic concepts. All students are required to read both papers, regardless of whether or not they are leading discussion that week. Participation accounts for a substantial portion of the section grade. Each student will be required to submit one question about the section paper to a drop box on the course website by 12 pm the day before section is held. Most weeks, at least one student will lead a ~25-minute discussion of one of the assigned papers that addresses at least four of the submitted questions (this can include questions of your own). Presenters should be prepared to communicate the central points of the paper and describe the important techniques used in the paper, as well as discuss relevant background information (which can usually be found by examining articles that are referenced in the introduction). Each discussion leader will be allowed to prepare three PowerPoint slides to aid in discussing the background and important techniques of the paper. The ENTIRE section will be expected to engage in discussion of the merits of the paper, what further experiments or controls could be

3 conducted to verify the results, and what future research could be conducted to continue the work. The instructors will assign sections. Possible section times are: Mon 5-6 pm, Weds 9-10 am, am, 11 am-12 pm, 4:30-5:30 pm, Thurs 4-5 pm and 5-6 pm. Please send your top two preferences to us by by 5 pm on Friday Jan 27 th - (balskuschem171@gmail.com). You will know your section assignment by Sunday Jan 29th. If we do not receive your section preference on time you will be assigned to a section of our choice. Problem Sets Three problem sets consisting of exam-level questions will be administered during the semester. Problem sets will be handed out and will be due in class on dates specified in the syllabus. Late problem sets will not be graded. The problem sets are designed to be preparation for the in-class exams and should be completed without searching the literature for the specific research discussed in the problems. Any papers used in answering problem sets must be clearly and properly cited. Exams There will be two in-class exams during the semester, each lasting ~75 minutes. The exams will be held on Tuesday March 6th and Thursday April 19th. While the exams are necessarily cumulative, the second exam will highly stress topics covered in the second half of the course. Research Proposal A proposal topic must be submitted for approval to your teaching fellow in the form of a specific aims page (two aims max) no later than April 5th. Your topic and specific aims will be evaluated and comments/critiques will be sent back to you in the form of a review. The final draft of your written proposal will be due by noon on May 3rd the last day of reading period. Grading criteria will focus less on the idea and its innovativeness and feasibility and more on the effort put into the proposal, such as quality and clarity of writing and presentation, proper referencing of the scientific literature, and your ability to address reviewer comments. Grading Course grades will be determined as follows: Section 10% Problem Sets 10% Proposal 20% Exam 1 30% Exam 2 30%

4 Policies You are expected to attend all lectures and sections, participate in discussions, and refrain from distracting behavior in class or section. If you have any conflicts with lectures or sections (med school interviews, etc.) we will figure out a way to work around them, but you must let Professor Balskus know about any issues in advance. Lastly, you are allowed to work and study together, but remember exams will be taken individually so it is important that you master the material on your own.

5 Lecture Schedule Lecture Date Topic Notes 1 01/24/12 Part 1: How Does Nature Make Molecules? Biological Synthesis: How Do Organisms Make Molecules and Why Do We Care? 2 01/26/12 Investigating Enzymes: Nature s Toolkit for Synthesis 3 01/31/12 Chemist vs. Nature I: Methods for Making Molecules 4 02/02/12 Chemist vs. Nature II: Methods for Making Molecules PS1 Out 5 02/07/12 Polyketides and Fatty Acids 6 02/09/12 Ribosomal and Non-Ribosomal Peptides PS1 Due 7 02/14/12 Terpenes and Steroids 8 02/16/12 Alkaloids and Aromatics PS2 Out 9 02/21/12 Unusual Enzymes: Novel Chemistry from Secondary Metabolism 10 02/23/12 Discovering New Biosynthetic Pathways PS2 Due 11 02/28/12 Guest Lecture: Matthew LaMarche from Novartis 12 03/01/12 Breaking Molecules Apart: Catabolism and Bioremediation 03/06/12 Exam /08/12 Part 2: How Can We Use Biological Tools for Synthesis? Biocatalysis: Using Organisms and Enzymes for Chemistry 14 03/20/12 Protein Engineering I: Rational Design 15 03/22/12 Protein Engineering II: Directed Evolution 16 03/27/12 Guest Lecture: Greg Hughes from Merck Biocatalysis 17 03/29/12 Chemoenzymatic Synthesis and In Vitro Biosynthesis 18 04/03/ /05/ /10/ /12/ /17/12 Fermentation and Metabolic Engineering: Beer to Biofuels Unnatural Natural Products: Engineering Secondary Metabolite Biosynthesis Making Drugs with Bugs: Synthetic Biology for Pharmaceutical and Industrial Chemical Production Biosynthesis Nature Never Evolved: De Novo Pathway Design The Future of Synthetic Biology: Whole Genome Synthesis and Engineering No section this week PS3 Out PS3 Due Proposal Topic Due

6 23 4/19/12 Guest Lecture : Curt Fischer from Ginkgo Bioworks 4/24/12 Exam 2 No section this week The research proposal will be due by noon on May 3 rds

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