Scott A Strobel PhD

Henry Ford II Prof MB&B,Vice Pres for West Campus; Prof HHMI; Prof Chemistry; Howard Hughes Medical Institute Professor; Henry Ford II Professor

Research Interests

Antibiotics; Nucleic Acid Bioorganic Chemistry; Ribosome; Ribozyme; RNA Catalysis; RNA-Protein Interaction; Translation; Riboswitches, Biofuels; Endophytes; Natural Product Discovery

Research Summary

Our research explores 1) hydrocarbon production by novel fungi as alternative fuel source and 2) RNA biochemistry. The first area focuses on endophytic fungus isolated from Northern Patagonia that produces and excretes a broad spectrum of fuel related hydrocarbons. The second area employs biochemistry and structural biology to study the ribosome reaction mechanism, RNA catalysis, and RNA small molecule interactions that regulate riboswitches.

Extensive Research Description

Research in the Strobel laboratory focuses on RNA catalysis and biofuel production.

Direct Conversion of Cellulose to Biofuel by a novel fungus.

This is the newest project in the lab and a new research direction for our group closely related to the undergraduate Rainforest Expedition program supported by HHMI. This project involves an emerging biotechnology for the production of hydrocarbons from cellulose-based waste feedstock with a low-carbon footprint that is chemically equivalent to jet fuel. Gliocladium roseum (NRRL 50072) is an endophytic fungus recently isolated from Northern Patagonia that produces and excretes a broad spectrum of straight and branched medium chain-length hydrocarbons, including heptane, octane, undecane, dodecane and hexadecane, when grown in an sealed vessel. G. roseum can also generate and release these products when grown on cellulose, the world's most abundant natural organic compound. This organism has the potential to produce desirable biofuels via a fermentation process that is nearly carbon neutral. It is a basic science observation with clear implications for energy production and utilization.
The goals of this project are to characterize the biosynthetic basis of hydrocarbon production and release by G. roseum, to isolate the enzymes responsible for hydrocarbon synthesis and transport, and to use this information to optimize the yields of biofuel output. Overproduction will be achieved either by biological engineering of keys genes in the pathway, or transfer of the biosynthetic pathway to organisms used in standard fermentation processes. The hydrocarbon products and their derivatives will be subjected to chemical analysis and combustion studies. Realization of these goals will transform this basic science observation into real world applications that could transform the source and long-term availability of petroleum fuels.
We also have several ongoing projects in the area of RNA biochemistry.
Protein Synthesis.

Crystallographic studies reveal that the ribosomal peptidyl transferase center is composed exclusively of rRNA, i.e., that the ribosome is a ribozyme. We aim to determine how this biologically fundamental reaction is catalyzed. We are taking several approaches to understand this enzyme, including: (i) synthesis and characterization of transition state inhibitors; (ii) preparation of modified A-site and P-site tRNA substrates to test for substrate assisted catalysis of peptide bond formation by enzyme kinetic analysis; (iii) purification of mutant ribosomes to assess the role of rRNA functional groups; (iv) investigating the reaction transition state by kinetic isotope effect analysis and by determining the Brønsted coefficient for the ester aminolysis reaction.
Intron Splicing.

The discovery of the RNA self-splicing group I intron provided the first demonstration that not all enzymes are proteins. We recently reported the X-ray crystal structure of a catalytically active group I intron splicing intermediate. This is the first splicing complex of any kind to include a complete intron, both exons and an organized active site occupied with metal ions. The exon ligation is chemically equivalent for pre-mRNA splicing by the spliceosome. As a result, the chemical themes of splice site selection, exon alignment, and catalytic metal ion positioning, which are manifest in this splicing intermediate complex, are likely to find parallels in pre-mRNA splicing. We are now undertaking several additional structural and biochemical studies to characterize the entire RNA splicing pathway. The overriding goals of these studies are to: (i) understand the mechanism of RNA splicing, (ii) explain how RNA tertiary structure is formed and active sites created in the absence of proteins, (iii) reveal how metal ions contribute to RNA catalysis, and (iv) visualize the nature of the transition state of the phosphoryl transfer reaction promoted during exon ligation.

Selected Publications

  • K. D. Smith, S. V. Lipchock, T. D. Ames, R. R. Breaker and S. A. Strobel, Structural basis of ligand binding by a c-di-GMP riboswitch Nature Struc. Molec. Biol. (in press).
  • J. C. Cochrane, S. V. Lipchock, K. D. Smith and S. A. Strobel Structural and chemical basis for glucosamine 6-phosphate binding and activating the glmS ribozyme, Biochemistry 48, 3239–3246 (2009).
  • D. A. Kingery, E. Pfund, R. M. Voorhees, K. Okuda, I. Wohlgemuth, D. E. Kitchen, M. V. Rodnina, and S. A. Strobel. An uncharged amine in the transition state of the ribosomal peptidyl transfer reaction. Chem. & Biol. 15, 493-500 (2008).
  • S. V. Lipchock and S. A. Strobel. A relaxed active site after exon ligation by the group I intron. Proc. Natl. Acad. Sci. U.S.A. 105, 5699-5704 (2008).
  • Cochrane, J.C., Lipchock, S.V., and Strobel, S.A. (2007). Structural investigation of the GlmS ribozyme bound to its catalytic cofactor. Chem. & Biol. 14:97-105.
  • Huang, K.S., Weinger, J.S., Butler, E.B., and Strobel, S.A. (2006). Regiospecificity of the peptidyl tRNA ester within the ribosomal P site. J. Amer. Chem. Soc. 128:3108-3109.

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