Eli Lilly Award in Biological Chemistry

Professor Neal K. Devaraj, University of California, San Diego

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

Professor Neal K. Devaraj is the recipient of the 2019 Eli Lilly Award in Biological Chemistry. One of the most challenging questions in chemical biology is how non-living matter, such as simple organic molecules, can assemble to form life. The Devaraj group is approaching this problem through the synthesis of artificial cells, developing coupling reactions that drive the self-assembly, growth and reproduction of lipid vesicle assemblies. To guide the work, they are developing chemical tools to blueprint the structure and function of modern cells. Using this combined approach, the lab strives to understand the prerequisite chemistry from which biology can emerge.

Devaraj and his lab synthesized the first artificial cell membrane that can sustain continual growth. Unlike natural membranes, biomimetic systems cannot maintain growth owing to an inability to replenish phospholipid-synthesizing catalysts that are diluted during lipid expansion. The Devaraj lab created an artificial cell membrane that continually synthesizes all of the components needed to form additional catalytic membranes. Membrane growth can proceed indefinitely as the catalyst required for vesicle growth also autocatalyzes its own synthesis.

Another direction of his lab seeks to develop new tools for labeling and manipulating RNA. Mainstream methods for studying RNA utilize non-covalent interactions between the probes and the RNA of interest, which limits their robustness, especially for less abundant RNA targets. The Devaraj lab devised a method for the site-specific covalent labeling of RNA with functional reporters in a single conjugation step by exploiting a bacterial tRNA modifying enzyme, tRNA-guanine transglycosylase (TGT), and unnatural analogs of its native substrate preQ1. RNA transglycosylation at guanosine (RNA-TAG) can incorporate a wide variety of probes targeted to a minimal 17-residue hairpin that can be encoded on any RNA. The use of covalent linkages will lead to robust methods to isolate RNA and label RNA.

Applying the lessons learned from their earlier work in chemoselective lipid synthesis, his lab has recently developed traceless chemistries to assemble lipid natural products from within living cells. This approach allows unequivocal association of specific lipids generated in vivo with their cellular function. His lab’s initial studies have focused on generating ceramides, one of the most enigmatic classes of molecules within the realm of bioactive lipids. The Devaraj lab found that delivery of fully saturated ceramides significantly reduces cell viability while there is no reduction in cell viability following delivery of monounsaturated ceramides. These observations highlight the importance of species-specific study of ceramides and demonstrate the power of chemical tools to circumvent the limitations of endogenous lipid synthesis pathways to uncover the function of individual lipid molecules in vivo.

Pfizer Award in Enzyme Chemistry

Professor Kenichi Yokoyama, Duke University

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

Professor Kenichi Yokoyama is the recipient of the 2019 Pfizer Award in Enzyme Chemistry in recognition of his contributions to the elucidation of complex mechanisms and novel functions of enzymes involved in the biosynthesis of cofactors and natural products. One area of focus of the Yokoyama group has been radical-mediated enzyme catalysis. In the past decade, the scope of free radical reactions in enzymology has expanded significantly. In particular, a multitude of enzymes in the radical S-adenosyl-L-methionine (SAM) superfamily have been found to catalyze highly diverse and chemically challenging reactions. The main focus of the Yokoyama lab has been radical SAM enzymes involved in C–C bond formation during the biosynthesis of the carbon skeletons of cofactors and natural products. One of their most significant areas of contribution is elucidation of the mechanism of pterin backbone construction during molybdenum cofactor (Moco) biosynthesis, a pathway linked to a fatal metabolic disorder in humans and bacterial pathogenicity. In this study, the Yokoyama group characterized the radical SAM enzyme, MoaA, along with MoaC, another enzyme in the pathway, and identified a structurally novel cryptic biosynthetic intermediate, 3’,8-cH2GTP. Together with subsequent mechanistic studies, their results elucidated the functions of both MoaA and MoaC for the first time in the >30 years-long history of the study of Moco biosynthesis. Another area of Yokoyama lab contribution is the functional characterization of the radical SAM enzyme NikJ in the biosynthesis of antifungal nucleoside antibiotics such as the nikkomycins and polyoxins. In this study, NikJ was found to catalyze formation of the unique bicyclic nucleotide, octosyl acid 5’-phosphate, through radical-mediated C-C bond formation involving a redox-active Cys residue. This revelation allowed the Yokoyama lab to perform bioinformatic analyses of related pathways, which suggested potentials for genome mining discovery of novel antifungal nucleoside natural products. In both of these studies, radical SAM enzymes were found to install C-C bonds in unique positions within precursors. The lab is currently extending their efforts to the other steps of the pathways and the mechanism of action of antifungal natural products. The Yokoyama lab studies have expanded our understanding of carbon skeleton construction in metabolic pathways and demonstrated the impact of identifying novel enzyme functions and mechanisms on future development of novel therapeutics for infectious and metabolic diseases.

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 Vern L. Schramm

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 Vern L. Schramm is the recipient of the 2018 Gordon Hammes ACS Biochemistry Lectureship. The Gordon Hammes Lecture Award is sponsored jointly by Biochemistry and the ACS Division of Biological Chemistry. The objective is to recognize and honor a single individual whose scientific contributions have had a significant impact on research at the interface of chemistry and biology. This year’s award goes to Professor Vern Schramm of the Albert Einstein College of Medicine.

“I am so incredibly thrilled that Vern has been selected as the winner of the Biochemistry 2018 Gordon Hammes Lectureship! The selection committee was unanimous and unanimously enthusiastic about his profound contributions to the field of biological chemistry”, says Alanna Schepartz, Editor-in-Chief of Biochemistry.

Schramm studied chemistry and microbiology for his B.S. at South Dakota State University. A scholarship for a master’s degree at the Harvard School of Public Health exposed him to nutrition and biochemistry. For his Ph.D. degree, he studied enzymatic mechanisms at the Australian National University with John Morrison during the time Morrison was deriving equations for tight-binding enzyme inhibitors.

Following an NRC-NSF postdoctoral fellowship at NASA Ames Research Center in California, Schramm began research in enzymatic reaction mechanisms and transition state analysis at the Department of Biochemistry, Temple University School of Medicine. In 1987 he was recruited to chair the Department of Biochemistry at the Albert Einstein College of Medicine, a position he held until 2015. He leads a research program in enzymology as Professor and Ruth Merns Chair of Biochemistry, the Schramm laboratory, which pioneered an approach to use intrinsic kinetic isotope effects combined with computational chemistry to understand the details of enzymatic transition states. Together with a team of chemistry collaborators in New Zealand, the Schramm laboratory designed and characterized the transition state analogs for a family of N-ribosyltransferases. These have proven to be powerful inhibitors. Three of the inhibitors designed by this approach have entered clinical trials, and others are in earlier development. Japan recently approved one analog for use in relapsed or resistant peripheral T cell lymphoma in Japan.

Schramm will present a talk and receive his award during the Gordon Hammes ACS Biochemistry Symposium during the Gordon Hammes ACS Biochemistry Symposium at the 256th ACS National Meeting & Exposition, held in Boston, Aug. 19-23, 2018.

Gordon Hammes ACS Biochemistry Scholar Award

Timothy Bumpus

To honor the young scientists resposible for the very best papers published in Biochemistry.

Timothy Bumpus is the recipient of the 2018 Gordon Hammes Scholar Award. The Gordon Hammes Scholar Award honors the young scientists responsible for the very best papers published in Biochemistry. Established in 2017 and awarded alongside the Gordon Hammes Lectureship Award, the Scholar Award seeks to recognize those at the bench – graduate students, postdocs, and undergraduates – for the outstanding work they do. The award is sponsored jointly by Biochemistry and the ACS Division of Biological Chemistry. Timothy Bumpus was selected as this year’s winner from a large applicant pool based on his first-author paper, “Ex Uno Plura: Differential Labeling of Phospholipid Biosynthetic Pathways with a Single Bioorthogonal Alcohol,” published earlier this year as part of the Future of Biochemistry Special Issue.

Bumpus is currently a National Science Foundation graduate research fellow in the Department of Chemistry & Chemical Biology at Cornell University studying under Professor Jeremy Baskin. After growing up on the East Coast, he moved to Iowa for his undergraduate studies and in 2015 received his bachelor’s degree from Luther College, with majors in chemistry, biology, and mathematics. There his thesis work focused on the design and synthesis of ecologically friendly bio-renewable and biodegradable plastics.

Bumpus says his current work focuses on “developing and implementing new chemical tools to study the role of lipid signaling in cell biology, particularly small-molecule probes which serve as substrate mimics and report on the enzymatic activity of phospholipase D. This will help elucidate the role of phosphatidic acid, the lipid product of phospholipase D, in cell signaling, and unravel the web of biosynthetic pathways which intersect at this pleiotropic lipid.”

Bumpus will present a talk describing his research and receive his award during the Gordon Hammes ACS Biochemistry Symposium at the 256th ACS National Meeting & Exposition, held in Boston, Aug. 19-23, 2018.

The ACS Chemical Biology Lectureship

Professor James A. Wells, University of California, San Francisco

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

James A. Wells is the Harry Wm. and Diana V. Hind Distinguished Professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco. Dr. Wells’ selection as the recipient of the 2018 ACS Chemistry Biology Lectureship recognizes his groundbreaking research in detecting and attacking cancer surface proteomes with recombinant antibodies. This research involves the development of enabling technologies for protein engineering and drug discovery to understand biology and pave roads to therapeutics. His lab uses both mass spectrometry based technologies and a new multiplexed antibody method to systematically understand how cancer cells remodel their surface-omes, then toxify the antibodies, or recruit immune cells to kill these cancer cells. The cell surface proteome is an essential platform for cell–cell communication. The cellular changes caused by oncogenesis may also impact this cell surface-ome, making it a potential therapeutic target in the treatment of various cancers. The Wells group has used a powerful combination of proteomic and transcriptomic techniques to profile changes to the cell surface proteome induced by the expression of oncogenic KRas. They also employ genetically barcoded antibodies for highly multiplexed surface-ome profiling. Together, these techniques allowed mapping of the KRas cell surface, enabling the identification of cell surface proteins that are unique to cancer cells and thus possible therapeutic targets. Wells and co-workers have also generated chemical-epitope-selective antibodies that can act as antibody-based chemically induced dimerizers for the regulation of human cancer cell therapies. Dr. Wells presented this work on March 20, 2018 at the 255th ACS National Meeting and Exposition held in New Orleans.

The Biopolymers Murray Goodman Memorial Prize

Professor William F. DeGrado, University of California, San Francisco

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

Professor William F. DeGrado is the recipient of the 2017 Biopolymers Murray Goodman Memorial Prize. The award is in recognition of Dr. DeGrado’s seminal contributions to the de novo design of peptides, proteins, and pharmaceutically active small molecules. He currently works as a Professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco. He received his Ph.D. from the University of Chicago. Thereafter he worked at the then named DuPont Merck Pharmaceutical Company and the University of Pennsylvania, before taking up his present position in 2011. He has co-authored over 370 articles, holds more than 25 patents, and has received several prestigious awards. These include the Protein Society’s Stein and Moore Award, the Rao Makineni Lectureship presented by the American Peptide Society, and the ACS Ralph F. Hirschmann Award in Peptide Chemistry. Dr. Degrado’s research group focuses on small molecule and protein design as an approach to understanding macromolecule structure and function. More specifically, the group carries out structural characterization of membrane proteins and de novo protein design in order to gain insight into biological processes relevant to human disease and to develop novel therapeutics. A recent example of their research reports the first ligand–binding protein designed from scratch, with the experimentally determined high-resolution structure matching the design with sub-angstrom accuracy. Dr. Degrado’s work has far-reaching implications for understanding human diseases, including HIV and Alzheimer’s disease.