Speakers

We are currently in the process of inviting speakers and fundraising. The symposium schedule will be updated as more information becomes available in the coming months.

If you would like more information as to how you can contribute to the ACS GSSPC, please contact us at gsspc@nd.edu.

Confirmed Speakers

Dr. Christopher Boddy

Dr. Gjalt Huisman

Dr. Amnon Kohen

Dr. Connie Lu

Dr. Yi Lu

Dr. Shelley Minteer

Dr. Yi Tang


Dr. Christopher Boddy

Dr

Harnessing Polyketide Thioesterases to Produce Complex Molecules

Brief Biography

Abstract: Biocatalysts have proven to be a powerful tool in organic chemistry. Their high selectivity is a blessing, enabling stereo-, regio-, and chemo-selective reactions to be performed efficiently, and a curse, severely limiting the substrates that can be effectively processed by the enzymes. This latter drawback has limited many biocatalysts to synthetic applications that occur early in syntheses, where substrates have reduced complexity. Unlike enzymes from primary metabolism, which have evolved to be exquisitely substrate selective, enzymes from secondary metabolite pathways, such as polyketide biosynthetic pathways, typically have relaxed substrate specificity. In this talk, we will discuss the development of macrocyclizing biocatalysts from the thioesterase domains embedded in polyketide biosynthetic pathways. Macrocyclization is a synthetically challenging reaction requiring high selectivity and greatly increasing the complexity of the substrate that is processed. It is typically the most decisive step of a synthesis and the step that defines the efficiency of a synthesis. As such it is ideal test case for development of a broadly substrate tolerant set of enzymes able to generate 12-18 member macrocycles. This would be of great value to the synthetic community as a late stage ring-forming catalyst. Thioesterase from polyketide biosynthesis selectively generate macrocycles from linear activated esters. To take advantage of this enzymatic activity, we have kinetically characterized recombinant purified thioesterases from the erythromycin, pimaricin, epothilone, zearalenone, radiciol, and bacillaene biosynthetic pathways with synthetic substrates. The selectivity of these thioesterase domains will be interpreted in light of the evolutionary pressures on the different pathways to identify ideal thioesterases for development as biocatalysts.

 

Dr. Gjalt Huisman

Dr

Innovations in Biocatalysis for Pharmaceutical Applications

Brief Biography

Abstract: In recent years, the use of biocatalytic approaches for chemical manufacture has seen an increasing interest from industry. In pharmaceutical manufacturing biocatalysis can provide many advantages, including reduction of manufacturing costs, increasing product quality, improving safety, and reducing hazardous waste and other harmful impacts on the environment. Advances in enzyme optimization technologies and new platform developments enable the various technical aspects required to dramatically improve enzymes for commercial use. However it is the collaboration between scientists with backgrounds in various life science disciplines that integrate such advances towards the common goal of solving the complex problem of enzyme optimization for commercial use.
This presentation will describe how CodeEvolver™ Directed Evolution Technologies were used to enable a new platform for synthesis of a broad range of chiral secondary and tertiary amines.

 

Dr. Amnon Kohen

Dr

Enzyme Mechanisms: From Physical Chemistry to Evolution and New Drug Targets

Brief Biography

Abstract: Enzymes are fascinating catalysts from both the point of view of a chemist and that of a biochemist. They can be studied on very different levels, ranging from the “circle meets triangular to produce a square” level, to examination of “arrows pushing” organic mechanisms to the physical chemistry level (dynamics and quantum mechanics). I will demonstrate this range via recent studies of dihydrofolate reductase and thymidylate synthase, which are enzymes catalyzing the de novo biosynthesis of the DNA base T (thymine). The role of such mechanistic understanding in identifying potential targets for antibiotic and chemotherapeutic drugs will be discussed. Aspects of molecular evolution from bacteria to human revealed by those methods will also be discussed.

 

Dr. Connie Lu

Dr

Design and Development of Metal-Metal Catalysts for Transforming Small Molecules

Brief Biography

Abstract: We seek to unravel how metalloenzymes convert small molecules using inorganic chemistry. Our approach is to develop, investigate, and exploit unusual structure-function motifs that are found in nature. For example, Fe-Fe hydrogenases may utilize metal-metal bonding for activating hydrogen. By preparing model coordination complexes featuring reactive metal-metal bonds, we can extract a detailed picture of their physical and electronic structures that may elucidate the underpinnings of their function. We can then apply this understanding towards new systems that improve on the natural counterparts in activity, selectivity, and substrate scope.

 

Dr. Yi Lu

Dr

Designing artificial metalloenzymes and their applications in biocatalysis for alternative energies

Brief Biography

Abstract: Metalloenzymes play critical roles in sustainable energy, such as in photosynthesis, biofuel cells and water oxidation. Designing metalloenzymes is an ultimate test of our knowledge about metalloenzymes and can result in new biocatalysts for practical applications.1 In this presentation, we provide three examples to demonstrate that, while reproducing the primary coordination sphere may be good enough to make structural models of metalloenzymes, careful design of the non-covalent secondary coordination sphere interactions is required to create functional metalloenzymes. In the first example, we demonstrate the fine-tuning of reduction potentials of azurin,2 a member of cupredoxin family that are involved in long-range electron transfers (ET) in many biological processes such as photosynthesis, to span ~1 V through carefully design of hydrophobicity and hydrogen bonding networks around the primary coordination sphere, and the use of these proteins to address fundamental questions in biological ET such as reorganization energy and Marcus inverted region.3 In the second example, we have shown the roles of two conserved glutamates in converting myoglobin into nitric oxide reductase (NOR), one through binding to a non-heme iron4 and the other through hydrogen bonding interactions.5 Such a model system allowed elucidation of reaction mechanism of NOR.6 Finally, we show that the presence of waters as part of new hydrogen-bonding network in myoglobin is necessary to confer oxidase activity in reducing O2 to water with minimum release of other reactive oxygen species and with > 1,000 turnovers.7 A combination of the above approach with rational tuning of redox potentials have recently resulted in a new oxygen reduction reaction (ORR) catalyst with a very low over-potential,8 and activity approaching to that of native enzymes. Recent results and their implications for designing novel biocatalysts for alternative energies will be discussed.

1. a) Y. Lu, et al., Nature 460, 855 (2009); b) I. D. Petrik, J. Liu, Y. Lu, Curr. Opin. Chem. Biol. 19, 67 (2014).
2. N. M. Marshall, et al., Nature 462, 113 (2009).
3. O. Farver, et al., Proc. Natl. Acad. Sci. 110, 10536 (2010).
4. N. Yeung, et al., Nature 462, 1079 (2009).
5. Y.-W. Lin, et al., Proc. Natl. Acad. Sci. 107, 8581 (2010).
6. S. Chakraborty, et al., Angew. Chem., Int. Ed. 53, 2417 (2014)
7. K. D. Miner, et al., Angew. Chem., Int. Ed. 51, 5589 (2012).
8. A. Bhagi et al., J. Am. Chem. Soc.136, 11882 (2014).

 

Dr. Shelley Minteer

Dr

Organelle Bioelectrocatalysis for Energy Conversion Applications

Brief Biography

Abstract: Over the last 5 decades, bioelectrocatalysis has been classified as either enzymatic bioelectrocatalysis or microbial bioelectrocatalysis, but there are biocatalysts that are neither proteins nor living cells. This talk will detail the use of organelles (specifically mitochondria and thylakoid membranes) for bioelectrocatalysis at carbon electrode surfaces. Both organelles are capable of direct electron transfer with carbon electrodes and can be used for both energy conversion applications (biofuel cells and biosolar cells) as well as self-powered sensors. This talk will detail the mechanistic investigation of organelle direct bioelectrocatalysis, as well as applications in energy conversion and pesticide and explosive sensing.

 

Dr. Yi Tang

Dr

A Lov Story in Biocatalysis: Natural Product Biosynthesis and Protein Engineering Coming Together

Brief Biography

Abstract: Many important drugs in the clinic today are natural products or semisynthetic versions of natural products. Investigations of the biosynthesis of these complex molecules have led to the discovery of new enzymes that catalyze interesting chemical reactions. For semisynthetic compounds, these enzymes can serve as candidates for biocatalytic reactions that improve the synthetic modifications steps. We have investigated the lovastatin (lov) biosynthetic pathway with an aim for finding enzymes that can improve the atom economy and cost effectiveness of the semisynthetic conversion of lovastatin to the blockbuster drug simvastatin. Although the difference between simvastatin and lovastatin is a single methyl substitution, the multistep chemical conversion process requires protection and deprotection steps and is costly overall. In this presentation, I will discuss our efforts in characterizing the lovastatin biosynthetic pathway during which we found an acyltransferase LovD; how we combined metabolic engineering, structural biology and protein engineering in transforming LovD into a powerful simvastatin synthase. The process we developed, in collaboration with Codexis Inc, is now used in the commercial production of simvastatin and replaced the multistep chemical processes. I hope the talk can illustrate how merging natural product enzymology and protein engineering can be a powerful marriage towards developing new biocatalysts.