Eli Lilly Award in Biological Chemistry

Professor Yi Tang, University of California, Los Angeles.

For outstanding research in biological chemistry of unusual merit and independence of thought and originality.

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Professor Yi Tang is the recipient of the 2014 Eli Lilly Award in Biological Chemistry, in recognition of his contributions to elucidation and characterization of natural product biosynthesis. His lab is particularly interested in identifying new enzymes from the biosynthetic pathways of polyketides, nonribosomal peptides, terpenoids, alkaloids and hybrid compounds. Tang and coworkers have studied the functions of multidomain megaenzymes such as those central to the biosynthesis of lovastatin, fumiquinazoline and aspyridone. In the lovastatin work, his team reconstituted the activities of the iterative polyketide synthase LovB that catalyzes the synthesis of dihydromonacolin L in more than 35 highly programmed steps. This work provides important insights into the iterative functions of fungal polyketide synthases, which is a large, but highly enigmatic group of enzymes widely found in sequenced fungal genomes. His group has mined numerous cryptic natural products from fungal species, including potential immunosuppressant polyketides from pathogenic fungi. Tang and coworkers are also interested in combining enzyme discovery and protein engineering towards the green synthesis of important pharmaceuticals. They demonstrated the potential of this approach by establishing a biocatalytic approach for making the blockbuster drug simvastatin.

Pfizer Award in Enzyme Chemistry

Professor Hening Lin, Cornell University.

For outstanding work in enzyme chemistry where the presence of enzyme action is unequivocally demonstrated.

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Prof. Hening Lin’s research is centered on nicotinamide adenine dinucleotide (NAD)-consuming enzymes and enzymes involved in diphthamide biosynthesis. Among the NAD-consuming enzymes, the focus is on sirtuins, which were known as NAD-dependent deacetylases. Sirtuins regulate aging, transcription, and metabolism, and are important targets for treating several human diseases. There are seven sirtuins in humans, Sirt1-7. Four of them (Sirt4-7) have very weak deacetylase activity, which have caused confusions and debates in the biological community. Lin and coworkers demonstrated that Sirt5 catalyzes the hydrolysis of malonyl and succinyl lysine efficiently. Furthermore, malonylated and succinylated proteins were identified from mammalian and bacterial cells, demonstrating that they are common protein posttranslational modifications. Similarly, Lin and coworkers demonstrated that mammalian Sirt6 can efficiently hydrolyze long chain fatty acyl groups from protein lysine residues. One of the substrate proteins is tumor necrosis factor α (TNFα). Sirt6 promotes the secretion of TNFα by removing long chain fatty acyl groups from TNFα. Utilizing the fact that different sirtuins have different acyl group preferences, Lin and coworker developed inhibitors that are specific for particular sirtuins. On the diphthamide biosynthesis project, Lin and coworkers discovered a novel radical SAM enzyme (PhDph2) that generates a 3-amino-3-carboxypropyl radical. Diphthamide is a modified histidine residue in translation elongation factor 2 and the target of diphtheria toxin. Its biosynthesis has been a puzzle for several decades. Lin and coworkers demonstrated that the biosynthetic enzyme PhDph2 uses a [4Fe-4S] cluster to cleave S-adenosylmethionine (SAM) to generate a 3-amino-3-carboxypropyl radical, which then reacts with the histidine residue in route to form diphthamide. Radical SAM enzymes are known to use [4Fe-4S] clusters to cleave SAM. However, classical radical SAM enzymes generate a 5’-deoxyadenosyl radical, in contrast to the 3-amino-3-carboxypropyl radical formed by PhDph2. Therefore, PhDph2 represents a novel [4Fe-4S] enzyme that uses unprecedented chemistry. This offers new opportunities to understand how different radical SAM enzymes control the reactivity of the bound [4Fe-4S] cluster to cleave SAM at different positions to carry out chemically challenging reactions. In addition, Lin and coworkers also identified the enzyme required for the last step of diphthamide biosynthesis, completing the last piece of the puzzle in the biosynthesis pathway.

The Repligen Award in Chemistry of Biological Processes

Professor John Lipscomb, University of Minnesota

For outstanding contributions to the understanding of biological processes with particular emphasis on structure, function and mechanism.

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Professor John D. Lipscomb is the recipient of the 2014 Repligen Award in the Chemistry of Biological Processes, in recognition of his contributions to our understanding of the mechanisms used in nature to activate molecular oxygen for insertion into biological molecules. The work has focused on non-heme iron containing oxygenases with a special emphasis on the development of methods to trap and characterize intermediates from their reaction cycles. Early studies of mononuclear iron-containing dioxygenases that cleave aromatic substrates led to the first crystal structure of a non-heme iron enzyme as well as a range of spectroscopic tools that revealed the ability of the iron to employ three adjacent coordination sites to effect catalysis. This allows the metal to simultaneously bind substrate and O2, thereby preparing them electronically and spatially for reaction. Similar mechanistic strategies have now been recognized throughout the superfamily of non-heme iron O2-activating enzymes. Recently, Lipscomb has shown that it is possible to characterize O2-activation mechanisms by conducting reactions in oxygenase single crystals. Remarkably, in some cases, the reactions were found to halt at discrete intermediates in the reaction cycle, thereby allowing the first structural characterizations of these species. Parallel studies of non-heme iron monooxygenases that contain dinuclear iron clusters have been similarly successful. Transient kinetic investigations of methane monooxygenase (MMO) allowed many intermediates to be trapped from the reaction cycle including compound Q, the first dinuclear Fe(IV) species found in a biological or chemical system. Building on the mechanistic insights from MMO, the Lipscomb lab has demonstrated the diversity of diiron cluster catalysis, which extends from biofuel production to antibiotic biosynthesis. Lipscomb will present a lecture as part of a symposium at the Fall 2014 ACS National Meeting.


Gordon Hammes ACS Biochemistry Lectureship

Professor Thomas L. Poulos, University of California, Irvine.

For outstanding contributions in scientific research at the interface of chemistry and biology, particularly in the realm of biochemistry, biological chemistry and molecular biology.

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Professor Thomas L. Poulos will present the 2014 Gordon Hammes ACS Biochemistry Lecture at the Fall 2014 National Meeting of the American Chemical Society in recognition of his research achievements on the structural biology of heme enzymes. Poulos’ research focuses on the structural biology of heme enzymes. He solved the first heme enzyme crystal structure, cytochrome c peroxidase, and the first cytochrome P450 crystal structure. Since then he and his coworkers have solved the structure of other metallo-enzymes and related electron transfer proteins including nitric oxide synthase (NOS). These structures coupled with protein engineering, enzymological, and spectroscopic approaches have sought to elucidate how these enzymes activate peroxide and molecular oxygen, a required step in many substrate oxidation reactions. A related area is the structure of redox protein complexes and how redox partner recognition is coupled to functionally important structural changes. In collaboration with Prof. Rick Silverman (Northwestern), the Poulos group also is working in the area of NOS structure-based drug design in an effort to develop therapeutic agents for neurodegenerative diseases.

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The ACS Chemical Biology Lectureship

Professor Peter B. Dervan, California Institute of Technology

For contributions that have had a major impact on scientific research in the area of Chemical Biology.

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Professor Peter B. Dervan will present the 2014 ACS Chemical Biology Lecture at the Spring 2014 ACS National Meeting in recognition for his contributions to the field of chemical biology over the past four decades.  Py-Im polyamides are small molecules programmed to read the DNA double helix by a set of simple chemical principles.  Pairs of three aromatic amino acids distinguish the edges of the four Watson-Crick base pairs on the floor of the minor groove.  Hairpin oligomers achieve affinities comparable to DNA binding proteins, are cell permeable, bind chromatin, and modulate gene expression pathways.  Many human diseases are caused by dysregulated gene expression.  The oversupply or overactivity of one or more transcription factors may be required for the survival, growth, and metastatic behavior of human cancers.  A hairpin Py-Im polyamide targeted to the androgen receptor DNA binding element was found to exert antitumor effects against prostate cancer xenografts with no significant evidence of mouse toxicity at doses ≤10 mg/kg.