The main focus of Professor Cane's research has been to establish the mechanism of formation of a wide variety of naturally occurring substances of diverse biological origins. These metabolites include antibiotics, toxins, plant defense substances, essential oils, and vitamins. Over the last several years his research group has concentrated on the mechanistic enzymology and molecular genetics of two broad areas, terpenoid metabolism and polyketide antibiotic biosynthesis.

Biography

David E. Cane was born in New York in 1944. After undergraduate study at Harvard, he received his Ph. D. in 1971 from Harvard University for research in organic synthesis carried out under the direction of Prof. E. J. Corey. During this period he developed an interest in the origins of natural products that led him to pursue postdoctoral study in natural products biosynthesis and bioorganic chemistry with Prof. Duilio Arigoni at the Eidgenössiche Technische Hochschule in Zürich. In 1973, he joined the faculty of Brown University where he is now Vernon K. Krieble Professor of Chemistry and Professor of Biochemistry. His research interests include the chemistry, enzymology and molecular genetics of natural products biosynthesis. This research has led to the identification, purification, and characterization of a variety of new enzymes that catalyze the conversion of the universal acyclic precursor, farnesyl diphosphate, to cyclic sesquiterpenes. Studies on these enzymes have established many key details of this fascinating cyclization process. In addition, cloning, over-expression, and site-directed mutagenesis of terpenoid synthase genes has provided large quantities of protein for further mechanistic and structural studies, and resulted in the elucidation of several crystal structures of a terpene synthase, the latter work carried out in collaboration with Prof. David W. Christianson of the University of Pennsylvania. In work on macrolide antibiotics, carried out in close collaboration with Prof. Chaitan Khosla of Stanford University, a combination of synthetic, enzymological, and molecular genetic approaches is being used to clarify the intricate sequence of events that is required to convert the simple building blocks such as acetate and propionate to complex macrolides such as the broad spectrum antibiotic erythromycin A and picromycin. In other recent work, Prof. Cane and his collaborators have investigated the enzymology and mechanism of formation of vitamin B6 and have established the role of two key enzymes in the formation of the characteristic pyridoxine ring. Prof. Cane has been a Fellow of the Japan Society for the Promotion of Science (1983) and a John Simon Guggenheim Memorial Foundation Fellow (1990), and has twice held Senior International Fellowships (1990, 1999) from the Fogarty International Center of the National Institutes of Health. In addition, he has received a number of awards, including the Ernest Guenther Award (1985), the Cope Scholar Award (2000), and the Repligen Award (2005) of the American Chemical Society, the Simonsen Lecture of the Royal Society of Chemistry (1990-91), the Kitasato Medal in Microbial Chemistry (1995), the Prelog Medal of the Eidgenössische Technische Hochschule, Zürich, and a Ph. D. (honoris causa) from the University of Kalmar, Sweden. He is a Fellow of the American Association of the Advancement of Science. In addition to over 250 scientific publications, he has recently co-edited a book of his father's World War II Letters published by Fordham University Press.

Research Description

Prof. Cane's major research interests are the elucidation of the enzymology and genetics of biosynthetic pathways.
1) Studies of the genetics and enzymology of polyketide antibiotic biosynthesis are carried out in close collaboration with the group of Prof. Chaitan Khosla of Stanford University. This work includes the study of the antibiotics erythromycin, picromycin, methymycin and tylosin, as well as the polyether antibiotic nanchangmycin (dianemycin, in collaboration with Prof. Zixin Deng of Shanghai Jiaotong University). Major accomplishments in the last year include the development of a sensitive and robust method to determine the stereochemical specifity of the fundamental polyketide chain building reaction, based on the dissection of several modular synthases into their functional component domains and reconstitution of the activity of the complete modules.
2) Studies of terpenoid synthesizing enzymes have focused in recent years on determination of the structure of these proteins and in the use of various genetic and chemical tools to elucidate the mode of action of these enzymes. One of the great challenges in genomics and proteomics is the identification of the biochemical function of the thousands of uncharacterized gene products that are filling the emerging genome sequence databases. Using an approach that can be called "genome mining" the Cane lab has been expressing and characterizing the component genes of terpenoid biosynthetic gene clusters in Streptomyces species that play an important role in microbial genetics and serve as the sources of majority of known antibiotic natural products. In the course of this work they continue to discover previously unknown enzymes and to identify their mode of action. For example they have now defined the role of two-thirds of the 12 genes encoding biosynthesis of the antibiotic pentalenolactone and have discovered a completely unanticipated mechanism for the enzymatic formation of geosmin, the ubiquitous microbial metabolite responsible for the characteristic odor of soil and the source of the "off-taste" of water and various foods. Recently Prof. Cane and his coworkers have also uncovered an entirely new pathway for the biosynthesis of a second "off-taste" constituent, methyl isoborneol. In collaborative research with Prof. David Christianson of the University of Pennsylvania, they have also continued to determine new terpenoid synthase structures of both native and mutant enzymes, either free or with bound substrates or inhibitors.

Awards

      -National Science Foundation, Predoctoral Fellowship,1966 - 1971

      -National Institutes of Health, Postdoctoral Fellowship,1971 - 1972

      -Eli Lilly Grant Award,1976 - 1978

      -Alfred P. Sloan Research Fellow,1978 - 1982

      -National Institutes of Health, Research Career Development Award,1978 - 1983

      -Japan Society for the Promotion of Science Fellow,1983

      -Ernest Guenther Award of the American Chemical Society,1985

      -Fogarty International Center Senior International Fellow,1989

      -Distinguished Visiting Fellow, Christ's College, Cambridge,1989 - 1990

      -John Simon Guggenheim Memorial Foundation Fellow, 1990

      -Fulbright Scholar, 1990

      -Simonsen Lecturer, Royal Society of Chemistry, 1990 - 1991

      -National Institutes of Health, MERIT Award, 1994 - 2004

      -Microbial Chemistry Medal of the Kitasato Institute

          and Kitasato University, 1995

      -Fogarty International Center Senior International Fellow, 1999

      -Institut Universitaire de France, Fellow,1999

      -A. C. Cope Scholar Award of the American Chemical Society,2000

      -Prelog Lecture and Medal, ETH Zürich, 2002

      -Royce Faculty Fellow, 2002-2009

      -Fellow of the American Association for the Advancement of Science (AAAS), 2003

      -Derek Brewer Visiting Fellow, Emmanuel College, Cambridge, 2004

   -Repligen Award in Chemistry of Biological Processes, Division of Biological Chemistry

          of the American Chemical Society, 2005

-Ph. D. honoris causa University of Kalmar, Sweden 2007

-Philip J. Bray Award for Teaching Excellence in the Physical Sciences, Brown University, 2008

Affiliations

Memberships

-American Chemical Society

-Royal Society of Chemistry

-American Society of Microbiology

-American Society for Biochemistry and Molecular Biology

-American Society of Pharmacognosy

-American Association for the Advancement of Science

Editorial Boards

            -Editorial Board, Bioorganic Chemistry            1983 - 2003

            -Editorial Board, Journal of Antibiotics            1983 -

            -Editorial Advisory Board, Chemical Reviews1987-1990

            -Associate Editor, Journal of Organic Chemistry            1995 - 2003

            -Editorial Advisory Board, Topics in Stereochemistry          1996 - 2006

            -Editorial Board, Current Opinion in Chemical Biology 1997 -2005

            -Faculty of 1000, Contributor            2000-

-Section Editor, Journal of Antibiotics 2006 -
-Advisory Board, Wiley Encyclopedia of Chemical Biology 2006 -
Review Panels/Professional Committees

            -NIH Bioorganic and Natural Products Study Section            1980 - 1984

            -ACS Ad Hoc Committee to Review the Journal of Organic Chemistry            1992 - 1993

            -Visiting Committee, Department of Chemistry, Washington State University            1998

            -Alternate Counselor, Biological Chemistry Division, ACS            1993-1998

            Chair, NIH Scientific Review Group, Centers of Excellence in Chemical

         Methodologies and Library Development            2002

-NIH SBCB Study Section 2006

- Chair, External Review Committe, Brandeis University Department of Chemistry 2006

Consulting       

            -Consultant, Smith Kline & French Laboratories            1984 - 1985

            -Consultant, American Cyanamid            1986 -1988

            -Myco Pharmaceuticals Lead Discovery Forum   1993

            -Scientific Advisory Board, KOSAN Biosciences, Inc.            1995 - 2006

Funded Research

National Institutes of Health - General Medicine: "Stereochemical Studies of Isoprenoid Biosynthesis"; $1,809,734; 2/1/08 - 1/31/12

National Institutes of Health - General Medicine: "Biosynthesis of Microbial Polyketides"; $1,414,932; 7/1/06 - 6/30/10

Teaching Experience

Organic chemistry, biochemistry, enzyme mechanisms, chemical biology

Courses Taught

• Biochemistry - Mechanistic Enzymology (CH0124)
• Biochemistry - Mechanistic Enzymology (CH1240)
• Bioorganic Chemistry (CH0123)
• Organic Chemistry (CH0360)
• Undergraduate Organic Chemistry (CH0035)
• Undergraduate Organic Chemistry (CH0036)

View My Full Publication List in pdf format

Selected Publications

• Shiven Kapur, Andrew Worthington, Yinyan Tang, David E. Cane, Michael D. Burkart, and Chaitan Khosla, "Mechanism based protein cross-linking of domains from the 6-deoxyerythronolide B synthase," Bioorg. Med. Chem. Lett. EPub Jan 24, 2008.(2008)
• Thorben Nawrath, Jeroen S. Dickschat, Rolf Müller, Jiaoyang Jiang, David E. Cane, and Stefan Schulz, "Identification of (8S,9S,10S)-8,10-dimethyl-1-octalin, a key intermediate in the biosynthesis of geosmin in bacteria," J. Am. Chem. Soc. 130, 430-431 (2008).(2008)
• Ekaterina Y. Shishova, Fanglei Yu, David J. Miller, Juan A. Faraldos, Yuxin Zhao, Robert M. Coates, Rudolf K. Allemann, David E. Cane, and David W. Christianson, "X-ray Crystallographic Studies of Substrate Binding to Aristolochene Synthase Suggest a Metal Binding Sequence for Catalysis," J. Biol. Chem.. ePub, April 2, 2008.(2008)
• Bin Zhao, Xin Lin, Li Lei, David C. Lamb, Steven L. Kelly, Michael R. Waterman, and David E. Cane, "Biosynthesis of the Sesquiterpene Antibiotic Albaflavenone in Streptomyces Coelicolor A3(2)," J. Biol. Chem. 283, 8183-8189 (2008).(2008)
• L. Sangeetha Vedula, David E. Cane, and David W. Christianson, "Structural and Mechanistic Analysis of Trichodiene Synthase using Site-Directed Mutagenesis: Probing the Catalytic Function of Tyrosine-295 and the Asparagine-225/Serine-229/Glutamate-233–Mg2+ Motif," Arch. Biochem. Biophys, 469, 184-194 (2008).(2008)
• Jiaoyang Jiang and David E. Cane, "Geosmin Biosynthesis. Mechanism of the Fragmentation–Rearrangement in the Conversion of Germacradienol to Geosmin," J. Am. Chem. Soc. 130, 428-429 (2008).(2008)
• Zheng You, Satoshi Omura, Haruo Ikeda, David E. Cane, and Gerwald Jogl, "Crystal Structure of the Non-heme Iron Dioxygenase PtlH in Pentalenolactone Biosynthesis," J. Biol. Chem. 282, 36552-36560 (2007).(2007)
• Roselyne Castonguay, Weiguo He, Alice Y. Chen, Chaitan Khosla, and David E. Cane, "Stereospecificity of Ketoreductase Domains of the 6 Deoxyerythronolide B Synthase," J. Am. Chem. Soc. 129, 13758-13769 (2007).(2007)
• L. Sangeetha Vedula, Yuxin Zhao, Robert M. Coates, Tanetoshi Koyama, David E. Cane, and David W. Christianson, "Exploring Biosynthetic Diversity with Trichodiene Synthase," Arch. Biochem. Biophys. 466, 260-266 (2007).(2007)
• 245. Jiaoyang Jiang, Xiaofei He, and David E. Cane, "Biosynthesis of the earthy odorant geosmin by a bifunctional Streptomyces coelicolor enzyme," Nat. Chem. Biol. 11, 711-715 (2007).(2007)
• Alice Y. Chen, David E. Cane, and Chaitan Khosla, "Structure-Based Dissociation of a Type I Polyketide Synthase Module" Chem. Biol. 14, 784-792 (2007).(2007)
• Yinyan Tang, Chu-Young Kim, Alice Y. Chen, David E. Cane, and Chaitan Khosla, "Structural and Mechanistic Analysis of Protein Interactions in Module 3 of the 6-Deoxyerythronolide B Synthase," Chem. Biol.14, 931-943 (2007).(2007)
• Chaitan Khosla, Yinyan Tang, Alice Y. Chen, Nathan A. Schnarr, and David E. Cane, "Structure and Mechanism of the 6-Deoxyerythronolide B Synthase," Ann. Rev. Biochem. 76, 195-221 (2007).(2007)
• Zheng You, Satoshi Omura, Haruo Ikeda, and David E. Cane, "Pentalenolactone biosynthesis. Molecular cloning and assignment of biochemical function to PtlF, a short-chain dehydrogenase from Streptomyces avermitilis, and identification of a new biosynthetic intermediate," Arch. Biochem. Biophys. 459, 233-240 (2007).(2007)
• Viktor Y. Alekseyev, Corey W. Liu, David E. Cane, Joseph D. Puglisi, and Chaitan Khosla, "Solution Structure and Proposed Domain-domain Recognition Interface of an Acyl Carrier Protein Domain from a Modular Polyketide Synthase," Protein. Sci. 16, 2093-2107 (2007).(2007)