Eli Lilly Award in Biological Chemistry

Professor Brad Pentelute, Massachusetts Institute of Technology

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

 

Professor Brad Pentelute is the recipient of the 2018 Eli Lilly Award in Biological Chemistry. Throughout evolution, Nature has developed molecular machines to rapidly manufacture, tailor, and deliver large functional biopolymers such as proteins into specific cells. Inspired by these mechanisms of nature, the Pentelute Lab has aimed to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins. he invention of new chemistry is sought to modify Nature’s proteins to enhance their therapeutic properties for human medicine. This goal has posed immense challenges because proteins contain 20 amino acids that present different reactive functional groups and have a 3D shape that is moderately stable. In light of these obstacles, the newly developed chemistry needs to be protein compatible, site-selective, quantitative, and carried out in water at reasonable temperatures to maintain protein integrity and function. The Pentelute Lab has met these challenges and has developed a series of highly efficient and selective chemistries that can modify the amino acid cysteine and lysine within peptides and proteins. These newly developed chemistries can be catalyzed by enzymes or even promoted by a motif discovered by Pentelute’s group, which is coined a ‘pi-clamp’. This extensive protein modification toolkit has enabled the production of some powerful molecules including peptide macrocycles that cross cell membranes to disrupt cancer or antibody drug conjugates to kill breast cancer cells.

The Pentelute group is also focused on the delivery of large biomolecules into the cell cytosol. The group has developed a chemical approach for the systematic investigation of a nontoxic form of anthrax toxin, which transports enzymes into cells via a protective antigen-protein pump. The Pentelute Lab has recently discovered that the protein pump can deliver a wide range of cargo molecules into cells including antibody mimics, mirror-image proteins, small molecules, and enzymes. Once in the cytosol, the cargo activates biologically and in certain cases perturbs protein-protein interactions that drive cancer. The Pentelute group made a noteworthy cell biology discovery with this biomolecular delivery platform: the act of simply installing a single D-amino acid on an otherwise large L-protein turns off a key mechanism for cytosolic protein degradation. This discovery will aid in the development of durable cell-based protein therapeutics.

The Pentelute group has also invented a fully automated fast-flow machine to accelerate the chemical manufacture of polypeptides. It has built the world’s fastest and most efficient machine that can produce thousands of amide-bonds orders of magnitude faster than commercially available instruments. The machine is inspired by Nature’s ribosome that can incorporate 9 amino acids into a polypeptide chain per second. While the Pentelute group’s fast-flow technology is not as fast as the ribosome, it can form one amide bond in 7 seconds. This technology not only facilitates rapid polypeptide generation but also has enabled the group to carry out an entire D-scan of proteins to investigate protein folding and functions. This technology may solve the manufacturing problem for personalized peptide cancer vaccines.

Pfizer Award in Enzyme Chemistry

Professor Mohammad Seyedsayamdost, Princeton University

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

Professor Mohammad R. Seyedsayamdost is the recipient of the 2018 Pfizer Award in Enzyme Chemistry in recognition of his contributions to the discovery of new enzymatic transformations in microbial systems. His research blends approaches from microbiology, bacterial genetics, natural products chemistry, and mechanistic enzymology to characterize the structures, functions, and biosynthesis of bacterial secondary metabolites. These metabolites are of importance to microbial communities, such as the human microbiome, and play decisive roles in human health and disease. One area of focus in the Seyedsayamdost group has been the identification of new metalloenzymes that catalyze unusual transformations during secondary metabolite biosynthesis. Specifically, his group characterized streptide, the founding member of a novel class of peptide natural products produced by the probiotic bacterium Streptococcus thermophilus. Structural elucidation of streptide revealed an unprecedented post-translational modification consisting of an intramolecular carbon-carbon crosslink between the side-chains of lysine and tryptophan. Further investigations showed that a new subfamily of radical SAM metalloenzymes install this unique modification in a single step, the mechanistic basis of which has been delineated in detail. Moreover, his group has examined the biosynthesis of the antibiotic drug-of-last resort, vancomycin, and demonstrated the involvement of cytochrome P450 metalloenzymes in creating some of the aromatic macrocycles, which endow the antibiotic with exquisite biological activity. Together, these studies have expanded our knowledge regarding the capabilities of metalloenzymes in synthesizing complex molecules; they have important implications for the utility of enzymes in the creation of designer natural products with desired biological functions.

The Repligen Award in Chemistry of Biological Processes

Professor Michael Gelb, University of Washington

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

 

Prof. Michael Gelb is the winner of the 2018 Repligen Corporation Award in the Chemistry of Biological Processes in recognition of his research contributions in the area of enzymology applied to medicine. Major accomplishments have been made in 4 areas. The first is two decades or work with the late Mahendra Jain (Univ. of Delaware) and Otto Berg (Univ. of Uppsala) on developing the fundamental paradigm for studying the action of enzymes at the membrane-water interface (interfacial enzymology). This work has led to methods for the proper evaluation of enzyme inhibitors and substrate specificity of interfacial enzymes, most notably phospholipases. More recent work in this area have helped to understand the role of phospholipases A2 in pro-inflammatory eicosanoid cascades relevant to asthma and arthritis.

In the late 1980s, the Gelb lab in collaboration with the late John Glomset (Univ. of Washington) discovered a post-translational protein modification in eukaryotic cells called protein prenylation. The discovery that Ras proteins are farnesylated led to a massive campaign in pharma to develop novel anticancer drugs. Gelb and Glomset also discovered that most G-proteins are bound to membranes via 15-carbon farnesyl or 20-carbon geranylgeranyl groups.

The third area of research in the Gelb lab is aimed at discovery of new drugs for treating neglected diseases caused by parasites (malaria, African sleeping sickness, Chagas, and Leishmaniasis). Some of the top ranking pre-clinical drug candidates in this area have been put forward by the Gelb lab in collaboration with parasitologists Fred Buckner and Wes Van Voorhis (Univ. of Washington).

The final area, and the one that is prominent in Gelb’s lab now, is the use of mass spectrometry for quantitative proteomics and clinical chemistry. The Gelb lab developed Isotope-Coded Affinity Tag reagents (ICAT) in collaboration with Frank Turecek and Ruedi Aebersold (Univ. of Washington). As a team, Gelb, Turecek and C. Ronald Scott (Univ. of Washington) have advanced the use of tandem mass spectrometry for screening of newborns to detect inborn errors of metabolism, most notably lysosomal storage diseases. This work has led to the first worldwide effort to screen for these disorders and is rapidly becoming part of the newborn screening panels in each state’s newborn screening laboratory in the USA. With newborn screening in place, treatments for these diseases can be initiated before the onset of irreversible symptoms and lead on to a greatly improved quality of life for infants and children.


Gordon Hammes ACS Biochemistry Lectureship

Professor John A. Gerlt

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

Professor John A. Gerlt is the recipient of the 2017 Gordon Hammes ACS Biochemistry Lectureship in recognition of his contributions to understanding the mechanisms of enzyme-catalyzed reactions, the evolution of functions in enzyme superfamilies, and the assignment of functions to uncharacterized enzymes discovered in genome projects. His mechanistic work has focused on a variety of reactions, including phosphoryl transfer, formation of enolate anions, and decarboxylation. His laboratory devised methods for the synthesis and configurational analysis of oxygen chiral phosphodiesters (16O, 17O, and 18O) and applied these to nucleotidyl transfer and phosphodiester hydrolysis reactions. He was among the first to use site-directed mutagenesis to probe the mechanisms of enzyme-catalyzed reactions, initially focusing on Staphylococcal nuclease. His laboratory cloned the gene for mandelate racemase, which lead to the discovery of the enolase superfamily, the first mechanistic diverse enzyme superfamily, in collaborative work with Patricia Babbitt, George Kenyon, Gregory Petsko, and John Kozarich. His studies of mandelate racemase established that the active site stabilizes an enolate anion intermediate, previously thought to be too unstable to exist, by coordination to an essential divalent metal ion; this catalytic strategy applies to all reactions catalyzed by members of the enolase superfamily. His work on the evolution of function in the enolase, crotonase, and OMP decarboxylase superfamilies generated his interest in devising methods to predict and assign functions to uncharacterized enzymes discovered in genome projects. He has lead three large-scale multidisciplinary projects in this area, with these demonstrating that a combination of enzymology, structure determination (with Steven Almo), and both homology modeling and ligand docking (with Matt Jacobson) provided a powerful approach for predicting the functions of uncharacterized enzymes in novel metabolic pathways. As these studies continue, he is developing community-accessible web tools to analyze sequence-function space in enzyme families as well as their genome context. Gerlt has followed his Ph.D. mentor’s (Frank H. Westheimer) advice to choose interesting problems and follow them, irrespective of how they evolve.

The ACS Chemical Biology Lectureship

Professor Benjamin Cravatt, The Scripps Research Institute

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

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Professor Ben Cravatt is the distinguished recipient of the 2017 ACS Chemical Biology Lectureship. The award is in recognition of Prof. Cravatt’s ground-breaking development of activity-based protein profiling technology, which enables the functional annotation of enzymes using active site-directed chemical probes. Through post-genomic profiling of the functional state of enzymes in complex proteomes, Prof. Cravatt has identified key mammalian enzymes involved in regulation of lipid signaling pathways in cancer. Utilizing his activity-based profiling technology in conjunction with advanced mass spectrometry methods, Prof. Cravatt has generated global-scale maps of lipid-binding proteins, amino acid reactivities, and novel functional residues within the proteome. Prof. Cravatt’s technologies have been adopted by academic and industrial labs worldwide for broad-scale functional characterization of enzymes within biological systems, thus having far-reaching implications for our understanding of mammalian physiology and disease.

The Biopolymers Murray Goodman Memorial Prize

Professor Jennifer Doudna, University of California, Berkeley

For outstanding accomplishments in one or more of the areas of biochemistry, biophysical chemistry, biophysics, and/or chemical biology.

 JenniferDoudna

Professor Jennifer A. Doudna is the recipient of the 2016 Biopolymers Murray Goodman Memorial Prize. Doudna’s research focuses on determining how non-coding RNAs function in living systems. Following her pioneering work on the structures and catalytic mechanisms of ribozymes, Dr. Doudna made exceptional advances in understanding how small RNAs are produced and used to control gene expression in mammals and bacteria. This line of research led to the breakthrough discovery of an RNA-programmed DNA endonuclease, Cas9, which functions as part of a CRISPR-based acquired immunity system in bacteria. By determining the molecular mechanism by which Cas9 uses RNA to recognize and cleave double-stranded DNA at specific sites, Doudna and collaborator Emmanuelle Charpentier showed how the system could be readily adapted for use in human and other cells and organisms. This transformative technology has influenced fundamental and clinical biology by enabling genetic experiments that were previously difficult or impossible to conduct. As Doudna’s research revealed, the CRISPR-Cas9 enzyme functions by using a 20-nucleotide RNA sequence within a dual-guide RNA structure to base pair with a complementary target sequence within doubled-stranded DNA. By showing how the dual-guide RNA could be redesigned as a single-guide RNA with the necessary structure to bind Cas9 and to direct site-specific Cas9-mediated DNA cleavage, Doudna and Charpentier’s findings almost immediately became a transformative tool for molecular biologists. The CRISPR-Cas9 system has been used for site-specific genome editing in human somatic and pluripotent stem cells, mice, rats, plants, fruit flies, nematodes and fungi. This versatile system is useful in organisms and cell lines, and also in various ex vivo experiments where excision of specific segments of chromosomes is desirable. The CRISPR-Cas9 technology is likely to create new therapeutic strategies as well as impacting the fields of plant and synthetic biology.