A5085462355- Glycosylation and Glycoproteins Research
- Carbohydrate Chemistry and Synthesis
- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Parkinson's Disease Mechanisms and Treatments
- Peptidase Inhibition and Analysis
- Galectins and Cancer Biology
- Proteoglycans and glycosaminoglycans research
- Alzheimer's disease research and treatments
- Protein Degradation and Inhibitors
- Endoplasmic Reticulum Stress and Disease
- Biochemical and Molecular Research
- Lysosomal Storage Disorders Research
- Heat shock proteins research
- Monoclonal and Polyclonal Antibodies Research
- Virus-based gene therapy research
- Protein Structure and Dynamics
- Advanced biosensing and bioanalysis techniques
- Polysaccharides and Plant Cell Walls
- Sphingolipid Metabolism and Signaling
- Microbial Metabolic Engineering and Bioproduction
- Cancer Research and Treatments
- Cell death mechanisms and regulation
- Protein Kinase Regulation and GTPase Signaling
University of Southern California
2015-2024
Convergent Science (United States)
2024
Southern California University for Professional Studies
2021
University of Michigan
2019
Rockefeller University
2007-2009
University of Arizona
2006
University of California, Berkeley
2002-2005
Adamas Pharmaceuticals (United States)
2004
Howard Hughes Medical Institute
2002-2003
Lawrence Berkeley National Laboratory
2002-2003
Significance Preventing the aggregation of toxic proteins in neurodegenerative diseases is both an important biological function and a potential therapeutic strategy. Here, we examine consequences O-GlcNAcylation on toxicity α-synuclein, aggregating protein Parkinson’s disease. α-Synuclein modified by O-GlcNAc at least nine different positions vivo, but most these modifications are unknown. use synthetic chemistry to prepare six O-GlcNAcylated forms α-synuclein show that they have largely...
Abstract Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer’s Parkinson’s disease, can form different fibril structures or strains with distinct toxic properties, seeding activities pathology. Understanding the determinants contributing to formation of amyloid features could open new avenues for developing disease-specific diagnostics therapies. Here we report that O-GlcNAc modification monomers results core structure, as revealed by cryogenic electron...
The dynamic modification of nuclear and cytoplasmic proteins by the monosaccharide N -acetyl-glucosamine (GlcNAc) continues to emerge as an important regulator many biological processes. Herein we describe development alkynyl-modified GlcNAc analog (GlcNAlk) a new chemical reporter O-GlcNAc in living cells. This strategy is based on metabolic incorporation reactive functionality into biosynthetic pathway. When combined with Cu(I)-catalyzed [3 + 2] azide-alkyne cycloaddition, this allowed for...
Metabolic chemical reporters (MCRs) of glycosylation are analogues monosaccharides that contain bioorthogonal functionalities and enable the direct visualization identification glycoproteins from living cells. Each MCR was initially thought to report on specific types glycosylation. We others have demonstrated several MCRs metabolically transformed enter multiple pathways. Therefore, development selective remains a key unmet goal. demonstrate here 6-azido-6-deoxy-N-acetyl-glucosamine...
The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety post-translational modifications. One such modification, O-GlcNAcylation, has been found on some these prone proteins, α-synuclein, the major protein that plays causative role in synucleinopathies like Parkinson's disease. We previously used synthetic chemistry to prepare α-synuclein bearing homogeneous O-GlcNAc modification at threonine 72 and showed this inhibits...
Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, genetically ablated GFAT1 in human cell lines, which completely blocked proliferation vitro and led to death. In contrast, knockout did not preclude growth tumor xenografts mice,...
Post-translational modification of histones plays an integral role in regulation genomic expression through modulation chromatin structure and function. Chemical preparations bearing these modifications allows for comprehensive vitro mechanistic investigation into their action to deconvolute observations from genome-wide studies vivo. Previously, we reported the semisynthesis ubiquitylated histone H2B (uH2B) using two orthogonal expressed protein ligation reactions. Semisynthetic uH2B, when...
The process of neurodegeneration in Parkinson's Disease is intimately associated with the aggregation protein α-synuclein into toxic oligomers and fibrils. Interestingly, many these aggregates are found to be post-translationally modified by ubiquitin at several different lysine residues. However, inability generate homogeneously each site has prevented understanding specific biochemical consequences. We have used semisynthesis nine site-specifically derivatives demonstrated that...
Aspirin (acetylsalicylic acid) is widely used for the acute treatment of inflammation and management cardiovascular disease. More recently, it has also been shown to reduce risk a variety cancers. The anti-inflammatory properties aspirin in pain-relief, cardio-protection, chemoprevention are well-known result from covalent inhibition cyclooxygenase enzymes through nonenzymatic acetylation key serine residues. However, any additional molecular mechanisms that may contribute beneficial effects...
Synthetic proteins bearing site-specific posttranslational modifications have revolutionized our understanding of their biological functions in vitro and vivo. One such modification, O-GlcNAcylation, is the dynamic addition β-N-acetyl glucosamine to side chains serine threonine residues proteins, yet impact O-GlcNAcylation remains difficult evaluate vivo because potential for enzymatic removal by endogenous O-GlcNAcase (OGA). Thioglycosides are generally perceived be enzymatically stable...
Palmitoylation is a 16-carbon lipid post-translational modification that increases protein hydrophobicity. This form of fatty acylation emerging as critical regulatory for multiple aspects cellular interactions and signaling. Despite recent advances in the development chemical tools rapid identification visualization palmitoylated proteins, palmitoyl proteome has not been fully defined. Here we sought to identify compare proteins murine fibroblasts dendritic cells. A total 563 putative...
Glycosylation events play an invaluable role in regulating cellular processes including enzymatic activity, immune recognition, protein stability, and cell-cell interactions. However, researchers have yet to realize the full range of glycan mediated biological functions due a lack appropriate chemical tools. Fortunately, past 25 years has seen emergence modified sugar analogs, termed metabolic reporters (MCRs), which are metabolized by endogenous enzymes label complex structures. Here, we...
The development of rapid screening methods for probing glycosyltransferase activities is essential advancing the field glycobiology. While assays specific glycosyltransferases exist, there no generalizable method that can be applied across enzyme superfamily. Herein we describe a novel assay exploits their unnatural substrate tolerance and unique chemical reactivity azide. We this "azido-ELISA" to family polypeptide α-N-acetylgalactosaminyltransferases (ppGalNAcTs), all which were able...
Mycobacteria contain high levels of the disaccharide trehalose in free form as well within various immunologically relevant glycolipids such cord factor and sulfolipid-1. By contrast, most bacteria use solely a general osmoprotectant or thermoprotectant. Mycobacterium tuberculosis smegmatis possess three pathways for synthesis trehalose. Most only one biosynthesis pathway do not elaborate into more complex metabolites, suggesting distinct role mycobacteria. We disabled key enzymes required...