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Departments: Enzymes Involved in Glycoconjugate Metabolism

Ryan Weiss

jennbryant on July 20, 2021

Short Biography:
Dr. Ryan Weiss received his B.S. in chemistry in 2008 at Point Loma Nazarene University in San Diego, CA. He then received his Ph.D. in chemistry in 2015 at the University of California, San Diego under the supervision of Prof. Yitzhak Tor. He then moved to the Department of Cellular and Molecular Medicine at the University of California, San Diego, where he worked as a postdoctoral fellow in the laboratory of Prof. Jeffrey Esko. Dr. Weiss began his independent career as an assistant professor in the Department of Biochemistry and Molecular Biology at the University of Georgia in January 2021. His current research interests include drug discovery and using genomic tools to understand the regulation of glycosylation in human diseases.

Research Interests:
Complex carbohydrates play important roles in many cellular processes and their dysregulation has been implicated in many disease states, including cancer, pathogen infection, and rare genetic disorders. The mammalian glycome contains extensive structural and functional heterogeneity that can vary temporally and spatially during development and in different tissues. Currently, little is known about the regulation of the non-template driven assembly of these ubiquitous post-translational modifications. My current research interests are focused on studying the structure, function, and genomic regulation of complex carbohydrates in human biology and disease. In particular, my laboratory is focused on identifying the transcriptional and epigenetic programs responsible for temporal and spatial control of glycosylation using genome-wide, molecular, and chemical approaches. In addition, we are dedicated to developing pharmacological and cell-based tools to aid in the discovery of novel targets and therapies for modulating glycan and glycoprotein expression in human diseases.

  • Functional Genomics of Glycosaminoglycan Biosynthesis

In the Weiss lab, we utilize pooled genome-wide CRISPR screening approaches, genetic engineering, and bioinformatic tools to identify the molecular mechanisms responsible for the regulation of glycosaminoglycan biosynthesis in human cells.

 

  • Drug Discovery for Rare Genetic Disorders

Many human diseases are caused by rare mutations in genes involved in the biosynthesis and/or catabolism of glycans. In the Weiss lab, genetic engineering, high-throughput drug screening, and cell-based disease models are utilized to uncover novel drug targets and therapeutic agents to treat these rare genetic disorders.

 

  • Epigenetic and Transcriptional Regulation of Glycan Assembly

Epigenetic changes alter the physical structure and organization of DNA, and transcription factors regulate the expression of their genomic targets. Currently, little is known about the genomic regulation of glycosylation. The Weiss lab aims to use state-of-the-art genomic tools and pharmacological agents to identify and modulate novel regulatory pathways responsible for controlling glycosylation in mammalian cells.

Lance Wells

jennbryant on July 12, 2021

Short Biography:
Dr. Wells received his B.S. in Chemistry, with a minor in Psychology, in 1991 from the Georgia Institute of Technology, and after spending two years working at the Microchemical Facility, his Ph.D. in Biochemistry and Molecular Biology in 1998 from the Emory University School of Medicine. A postdoctoral research fellowship at the Johns Hopkins School of Medicine in Biological Chemistry followed, which was supported by a National Research Service Award from the National Cancer Institute of the NIH. Dr. Wells joined the CCRC in August of 2003. Full publications: 98.

Research Interests:
Using a combination of methodologies, including mass spectrometry, protein biochemistry, cell biology, genetics, proteomics, and molecular biology, we study the role of PTMs (primarily O-glycosylation) in a variety of pathophysiological processes including cancer, diabetes, viral infection, neurological disorders, and congenital muscular dystrophy. Our research is aimed at increasing our understanding of how increased functional diversity leads to finer control of biological processes. The hope is that by understanding the role of PTMs, we will not only more accurately describe fundamental biological processes but will also elucidate novel therapeutic targets in disease states where these processes have become dysregulated.

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Breeanna Urbanowicz

jennbryant on July 12, 2021

Short Biography:
Dr. Urbanowicz received her B.S. in Biology in 2001 from Purdue University and her Ph.D. in 2008 from Cornell University. Prior to her junior faculty position at the Complex Carbohydrate Research Center, Dr. Urbanowicz was a Postdoctoral Fellow (2008-2013) in the Department of Biochemistry and Molecular Biology at the University of Georgia.

Research Interests:
Biological molecules, including proteins, polysaccharides, and nucleic acids, are assembled to create complex structures with biochemical and biomechanical properties that are greater than the sum of their parts. My current research focuses on understanding the structure and function of plant carbohydrate active enzymes involved in polysaccharide biosynthesis and modification. Plant cell walls are complex macrostructures comprised of cellulose, hemicellulose, and pectins, together with lesser amounts of protein and phenolic molecules. These components assemble and interact with one another to produce dynamic structures with many capabilities, including providing mechanical support to plant structures and determining the size and shape of plant cells.
The research of my group focuses on understanding the integral steps in the molecular pathways used by plants to synthesize complex polysaccharides. A key area of interest is development of methods to express and analyze recombinant plant enzymes, which has allowed us to investigate plant biochemical pathways in vitro. We have now generated a large collection of recombinant enzymes that are able to catalyze highly specific, covalent modifications of polysaccharides, which we utilize as nature-inspired molecular tools for targeted functionalization and labeling of glycopolymers that greatly expand our toolkit for producing glycopolymer-based products with valuable properties.

• High throughput expression of plant biocatalysts. In collaboration with Kelley Moremen at the CCRC, we have designed and evaluated over 75 constructs for heterologous expression in HEK293 cells encoding plant glycosyltransferases (GTs) from diverse families in addition to both polysaccharide O-methyltransferases (O-MTs) and O-acetyltransferases (O-AcTs). Assessment of these constructs for both protein expression levels and retention of in vitro activity determined that this is a robust heterologous expression system for plant derived enzymes. We have applied this system to the in vitro synthesis of decorated hemicellulosic polymers, resulting in the first proof-of-concept generation of enzymatically synthesized, high degree of polymerization (DP), substituted plant polysaccharides in vitro (Urbanowicz et al., 2014).

• Polysaccharide Methyltransferases. We have shown that Arabidopsis GXMT1 encodes a glucuronoxylan (GX)-specific 4-O-methyltransferase responsible for methylating 75% of the GlcA residues in GX isolated from mature Arabidopsis inflorescence stems. Reduced methylation of GX in gxmt1-1 plants is correlated with altered lignin composition and increased release of GX by mild hydrothermal pretreatment (Urbanowicz et al., 2012). The ability to selectively manipulate polysaccharide O-methylation may provide new opportunities to modulate biopolymer interactions in the plant cell wall. We are currently investigating the role of other members in this family on polysaccharide methyletherfication.

• Investigating the mechanism of polysaccharide O-acetylation. Despite the high degree of O-acetyl substituents found in plant glycopolymers, the biochemical and mechanisms of polysaccharide O-acetylation employed by plants are still lacking. An unsolved question is the source of the acetyl group used by acetyltransferases. We have developed robust methods to biochemically analyze O-acetyltransferases and are applying these techniques to investigate the molecular details of polysaccharide methylation.

Christine Szymanski

jennbryant on July 12, 2021

Short Biography:

Dr. Szymanski has been exploring bacterial glycomics for three decades, working on food pathogens since the early 1990s, with a particular emphasis on Campylobacter jejuni. She combines her expertise in food safety and animal health with novel therapeutic diagnostic platforms developed during her postdoctoral fellowship at the Naval Medical Research Center vaccine program (1996-2000), the key findings while employed at the National Research Council of Canada (2000-2008), and the translational advances during her tenure as an Alberta Innovates Technology Futures Scholar at the University of Alberta (2008-2016). She was the first to demonstrate that bacteria are capable of N-glycosylating proteins and is now exploiting these systems to create glycoconjugate vaccines and oral therapeutics through recombinant expression in Escherichia coli. Dr. Szymanski was also the first to demonstrate that viruses specific for bacteria express proteins that can be used as novel therapeutics in addition to their recognized diagnostic value. These viruses (bacteriophages) are the most abundant biological entity on earth (10+31) and are therefore a limitless resource for exploitation, especially in the area of glycomics.

Research Interests:

The Szymanski laboratory is a microbial glycobiology laboratory using multidisciplinary techniques and relevant model systems to: 1) characterize bacterial glycoconjugate pathways, 2) exploit bacteriophage recognition proteins that bind these structures, and 3) understand the protective benefits of host milk oligosaccharides to develop novel therapeutics and vaccines for the prevention of diarrheal diseases and post-infectious neuropathies such as Guillain-Barré Syndrome. These studies have also expanded our knowledge of carbohydrate metabolism by the gut microbiota and the transfer of antibiotic resistance between bacteria.

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Kelley Moremen

jennbryant on July 12, 2021

Short Biography:

Dr. Moremen received his B.S. in Biology and Chemistry (1978) from Dickinson College and his Ph.D. in Molecular Biology (1984) from Vanderbilt University. Prior to joining the faculty at the CCRC in 1991, he spent five years as a Postdoctoral Fellow at Massachusetts Institute of Technology. Dr. Moremen has served as chair of the Glycobiology Gordon Research Conference, President, Board of Directors, and Secretary of the Society for Glycobiology. He directed efforts on an NIH funded multi-investigator ‘Resource for Integrated Glycotechnology’, served as a senior investigator on the NIH-funded ‘National Center for Biomedical Glycomics’, and is a lead Principal Investigator or Senior Investigator on eight additional grants from the NIH and Department of Energy. In 2018 he launched a biotech startup, Glyco Expression Technologies, Inc., as a part of the UGA Innovation Gateway. He has served on editorial boards of Journal of Biological Chemistry, Glycobiology, and Glycoconjugate Journal, numerous NIH grant review panels, and Scientific Advisory Boards of four biotech companies. In 2014 Dr. Moremen was appointed the Distinguished Research Professorship in Biochemistry and Molecular Biology at the University of Georgia and in 202 was awarded the Karl Meyer Lectureship from the Society for Glycobiology. Dr. Moremen has 10 patents and over 180 publications.

Research Interests:

Research in the Moremen lab focuses on the biochemistry, structure, and regulation of enzymes involved in the biosynthesis, recognition, and catabolism of mammalian glycoproteins. Carbohydrate structures on glycoproteins contribute to many biological recognition events during development, oncogenic transformation, and cell adhesion. Large numbers of intracellular and extracellular proteins contain covalently bound glycans and alterations in the synthesis and degradation of these structures can occur in human genetic diseases and cancer. Many questions remain regarding the regulation of glycosylation pathways, the structures and functions of the processing enzymes, and the specificity and regulation of protein-carbohydrate interactions during development. Research in the Moremen lab is focused on developing novel strategies to address contemporary problems in the regulation, roles, mechanism, and machinery of mammalian protein glycosylation with efforts in four main areas:

1) Structures, specificities and mechanisms of mammalian glycosylation enzymes: Studies on the mammalian glycosylation enzymes in the Moremen lab have expanded in recent years with the development of a unified design and expression platform (Repository of Glycan-related Expression Constructs) for recombinant production of all mammalian glycosyltransferases, glycosidases, and sulfotransferases (target gene list of >400 coding regions) in bacteria, baculovirus, and mammalian cells. This multi-investigator effort, initiated and coordinated within the Moremen lab, is focused on production of these recombinant enzymes and has led to new enzyme structures and insights into the structural basis for enzymatic glycan synthesis. This project has led to numerous additional applications in chemoenzymatic synthesis, biochemical and structural studies, and development of technologies for enzymatic modification of glycoproteins and glycolipids in cellular environments to monitor molecule redistribution in the course of disease. The goals of these studies are to provide a biochemical and structural understanding of glycan biosynthesis and catabolism as well as providing enzymatic catalysts for chemoenzymatic synthesis. This project has been funded by an NIH P01 grant (P01GM107012, Mammalian Glycosyltransferases for Use in Chemistry and Biology) and presently by a multi-investigator NIH R01 grant (R01GM130915, Origin of N-Glycan Site-Specific Heterogeneity). For further information please see: glycoenzymes.ccrc.uga.edu.

2) Protein-carbohydrate interactions: Cell-surface and extracellular glycoproteins and glycolipids play unique and critical roles in mammalian physiology. One of the major glycan classes at the cell surface and within the extracellular matrix are the proteoglycans (PGs) that play diverse roles as co-receptors for cell surface signaling, scaffolds for cell-matrix interactions, ligands that create morphogen or chemokine gradients in development and inflammation, and numerous other contributions to signaling and cell surface structure. Little is known about the details of PG interactions with binding partners or their mechanisms of biological function. The Moremen lab directs a multi-investigator project with goals to develop a novel, integrated technologies that will address the challenges of PG structures, interactions, and biological functions by leveraging advances in analytical, synthetic, structural, biochemical and biological tools. This project has been funded by an NIH P41 grant (P41GM103390, Resource for Integrated Glycotechnology). For further information please see: glycotech.uga.edu.

3) Regulation of glycosylation machinery in mammalian systems: The Moremen lab is also involved in a collaborative project focused on determining the structures and regulation of glycans associated with glycoproteins and glycolipids in animal systems. The overall aims of the program are to examine the changes glycan structures during development with a particular focus on embryonic stem cell differentiation. The Moremen lab has developed platforms for analysis of glyco-gene transcript abundance using a custom real-time RT-PCR strategy as well as next-generation RNA-Seq methods. Integration of the transcript abundance data with the glycan structure analysis developed by other research groups in the CCRC will be accomplished through the bioinformatics group associated with the research program. This project has been funded by an NIH P41 grant (P41GM103490, National Center for Biomedical Glycomics). For further information please see: glycomics.uga.edu

4) Structure and biochemistry of glycan trimming enzymes involved in glycoprotein biosynthesis and catabolism: The fourth area of focus in the Moremen lab is on the enzymes involved in glycan trimming in the secretory pathway that are essential for N-glycan maturation as well as playing a role in the catabolism of misfolded nascent glycoproteins in the endoplasmic reticulum (ER-associated degradation).

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