The connection between sugar biology and type 2 diabetes (T2D) has been studied for decades, yet actionable mechanistic details at the level of individual glycan modifications on insulin signaling proteins remain surprisingly incomplete. That gap leads to a major biomedical problem: without knowing precisely which carbohydrate-linked proteins are modified, on which residues, and under what metabolic conditions, intervention strategies are less effective and prone to side effects.

This post covers what chemical biology approaches reveal about glycan modifications and insulin resistance, with a particular focus on O-GlcNAcylation as a regulatory mechanism in insulin signaling pathways. After all, O-GlcNAc is the sugar sensor of the cell! It stands out as a key modulator of insulin sensitivity vs. resistance.

Why Glycan Modifications Matter in Insulin Signaling

Glycosylation is not a passive decoration. Post-translational modifications by monosaccharides — especially O-linked N-acetylglucosamine (O-GlcNAc) — actively regulate protein function. As a key mechanism, O-GlcNAc on serine and threonine sites can compete directly with phosphorylation, the known driver of insulin signal transduction. Several core insulin signaling proteins, including IRS-1, AKT, and PDK1, carry O-GlcNAc modifications at serine and threonine residues that overlap with phosphorylation sites, making these hotspots for how aberrantly high levels of O-GlcNAc reduce insulin sensitivity and activity!

When O-GlcNAcylation occupies those sites, downstream signaling through the PI3K-AKT axis is attenuated. The result is reduced GLUT4 translocation, impaired glucose uptake in skeletal muscle and adipose tissue, and the metabolic phenotype we recognize as insulin resistance.

Hyperglycemia itself increases flux through the hexosamine biosynthetic pathway (HBP), producing more UDP-GlcNAc — the donor substrate for O-GlcNAc transferase (OGT). The result is a feed-forward loop: high glucose increases O-GlcNAcylation, which impairs insulin signaling, which worsens glycemic control.

O-GlcNAcylation as a Metabolic Sensor

OGT and its counterpart OGA (O-GlcNAcase, the single human enzyme that removes these modifications) together control the dynamic cycling of O-GlcNAc on hundreds of nuclear and cytoplasmic proteins. In type 2 diabetes, re-adjusting the balance between their activities is a meaningful medical target.

For decades, research has shown that genetic elevation of OGT activity in mouse models produces insulin resistance. Pharmacological OGT inhibition partially restores insulin sensitivity under hyperglycemic conditions. OGA inhibition, which raises O-GlcNAc levels, can do the opposite…it can exacerbates insulin signaling defects. It should be noted that there is some controversy there, depending on which OGA inhibitor is used – some are safe!

What has been harder to establish is the site-specific picture: which O-GlcNAc modifications on which proteins are functionally consequential, and which are simply bystanders elevated because UDP-GlcNAc is abundant? That is where our chemical biology tools and advanced metabolic disease studies we do in the Fehl Lab become essential.

Chemical Tools Defining the Intervention Points

Metabolic Labeling and Bioorthogonal Chemistry

Metabolic labeling with GlcNAc analogs bearing bioorthogonal handles — such as GalNAz, Ac4GlcNAz, and our PhotoSugar tools — allow us to tag O-GlcNAcylated proteins in living cells, then enrich, identify, and quantify them using click chemistry. We apply these tools in insulin-responsive cell lines like muscle cells or adipocytes under hyperglycemic conditions, to map the O-GlcNAc proteome in a metabolic context.

The limitation is selectivity. Metabolic labeling itself elevates the entire global O-GlcNAc proteome, not the subset of modifications that causally drive insulin resistance. Distinguishing cause from correlation at the proteome level requires additional chemical strategies. We are always seeking to improve our approaches to catch these nuanced details, as an active research area in our lab.

Site-Specific Mutagenesis and Synthetic Glycopeptides

Replacing individual serine or threonine residues on IRS-1 or AKT with alanine, or introducing non-hydrolyzable O-GlcNAc mimetics at defined positions, allows direct testing of whether a specific modification impairs signaling. Synthetic glycopeptides carrying defined O-GlcNAc modifications serve as substrates for kinase assays and antibody development.

This work has confirmed that O-GlcNAcylation at Thr-308 of AKT — a canonical activating phosphorylation site — directly reduces kinase activity. The mechanistic link at this residue is now well-established. Analogous studies on IRS-1 have identified multiple competing glycosylation-phosphorylation sites, though the relative contribution of each in human tissue remains an active question.

OGT and OGA Inhibitor Toolkits

Small molecule inhibitors of OGT and OGA have matured considerably. OSMI-4 and related compounds offer selective OGT inhibition with improved cell permeability over earlier generations, though OGT tools still struggle for activity in live animal models and preclinicla studies. For OGA, Thiamet-G remains widely used, and next generation analogs have been developed to further reduce off-target effects in human clinical trials!

These tools are not therapeutics in their current form (none have been FDA approved yet), but they are essential for establishing causality in cell and animal models. A key methodological point: inhibitor studies work best when paired with proteomics to confirm on-target engagement, and when dose-response relationships are characterized carefully enough to avoid interpreting non-specific toxicity as a glycobiology phenotype.

Machine Learning and Pathway-Level Analysis

One of the persistent challenges in this field is that O-GlcNAcylation affects hundreds of proteins simultaneously. Understanding how those changes collectively alter insulin signaling requires moving beyond single-protein studies to pathway-level analysis.

Machine learning approaches are beginning to address this. Predictive models trained on O-GlcNAc site databases can identify sequence features that make specific residues likely OGT substrates, helping prioritize which modifications to validate experimentally. Network-level analysis of O-GlcNAc proteomics data can identify which modified proteins cluster within the insulin signaling network versus other pathways.

At the Fehl Lab, we integrate machine learning with chemical biology strategies precisely to address this kind of complexity. The goal is not to generate more data — it is to define which glycobiology pathways are actionable and to design chemical tools targeted to those specific nodes. In the context of insulin resistance, that means moving from a global picture of O-GlcNAcylation to a mechanistically grounded map of the modifications that matter most.

Open Questions in 2026

Despite real progress, several questions remain genuinely open.

Tissue specificity. O-GlcNAcylation profiles differ across skeletal muscle, liver, and adipose tissue — all of which contribute to whole-body insulin sensitivity. Most mechanistic studies use cell lines. Understanding which modifications are relevant in primary human tissue, and whether they differ by disease stage, is a priority for the field, and our lab.

Crosstalk with other protein modifications. O-GlcNAcylation is not the only glycan modification relevant to insulin signaling. N-glycosylation of the insulin receptor affects receptor trafficking and ligand binding. Sialylation patterns on cell-surface glycoproteins shift in obesity. How these modifications interact with O-GlcNAcylation at the systems level is largely uncharacterized. We are also actively looking at phospho-GlcNAc crosstalk under insulin resistance conditions via our latest NIH NIDDK-funded grant!

Temporal dynamics. Insulin signaling operates on a timescale of minutes. O-GlcNAc cycling is slower. Understanding how the timing of glycan modifications intersects with the kinetics of insulin signaling is a methodological challenge that current tools only partially address. Our Lab’s PhotoSugars and GlycoID tools were designed with this exact challenge and application in mind, so we are poised to address this challenge.

Intervention selectivity. Even if OGT is a valid target in insulin resistance, systemic inhibition carries real risks — O-GlcNAcylation is essential for normal cellular function across many tissues. Selectively targeting OGT activity toward specific substrate proteins, rather than inhibiting it globally, would require a new generation of chemical tools. This is another key space for the Fehl Lab!

Join our group!

The mechanistic picture of how glycan modifications drive insulin resistance is clearer in 2026 than it was five years ago, but the most important questions are still open. Answering them will require more precise chemical tools and better strategies for interpreting complex glycoproteomics data at the pathway level.

If your research intersects with glycobiology and metabolic disease, contact Charlie Fehl to collaborate at fehl-lab.com.

Choosing a PhD program one of the most consequential decisions you will make as a scientist. The department, the city, the funding environment — all of it matters. But nothing shapes your doctoral experience more than the lab you join and the questions it asks.

If you are considering Wayne State University chemistry for graduate study and you are drawn to chemical biology, this article gives you a picture of what that path actually looks like — specifically inside a our lab that focuses at the intersection of glycobiology and targeting metabolic disease processes, including cancers.

What the Wayne State University Chemistry Department Offers

Wayne State University’s Department of Chemistry is embedded in a major research university in Detroit, a city with deep ties to applied science and industrial research. The department operates within the Detroit hospital network of 13 hospitals, allowing unprecedented access to biomedical samples, collaborations, and training opporutnities.

For chemical biology students, our lab and program fosters a combination of synthetic chemistry, biochemistry, and cell biology skills that we tailor to each of our researcher’s specific projects. Our students and postdocs are not siloed into one technique or one disease area…but rather can apply our bio/chemical tools to many cellular processes! The expectation is that you will build a toolkit broad enough to ask questions that cross disciplines.

What “Chemical Biology” Actually Means in Practice

Chemical biology is not biochemistry with better branding (see below for a related post!). It is the precision design and application of chemical tools — probes, inhibitors, reporters, and biosensors — to answer biological questions that traditional genetic, pharmacological, or phenotypic methods alone cannot address.

In a chemical biology PhD, your days look different from those of a synthetic organic chemist or a cell biologist. You might spend a morning running a synthesis, an afternoon working through mass spectrometry data, and a week figuring out how a new probe behaves in live cells. The work is inherently interdisciplinary, and that breadth is the point. We are increasingly using machine learning and AI-coding to analyze our datasets…and find synergies in our projects that we ourselves might even miss!

The questions tend to be mechanistic: not just “does this pathway matter in disease?” but “how does it work, who are the molecular actors, and can we design a tool to perturb it precisely?”

Research Focus: Glycobiology and Metabolic Disease

In the Fehl Lab, our central focus is carbohydrate-linked proteins and their roles in cellular metabolism. Sugars attached to proteins — glycans — regulate a remarkable range of cellular processes, from protein stability and location to immune signaling and metabolic sensing, or even regulating enzyme activity like in glycolysis. Yet glycobiology remains one of the most technically demanding and underexplored areas in molecular biology.

The lab targets glycobiology pathways implicated in cancer, diabetes, obesity, and neurodegeneration. These are not abstract disease categories. They represent some of the most pressing and mechanistically complex health problems we face, and the molecular tools to study them with real precision are still being built.

Graduate students in our lab work on designing those tools — chemical probes that can selectively label, track, or inhibit specific glycan-protein interactions inside living cells.

Machine Learning as a Research Method, Not a Buzzword

One thing that sets the Fehl Lab apart from many academic chemical biology groups is the active integration of machine learning into the research workflow. We encourage our students to attend coding workshops for R and python, and use those to create new ways to analyze, visualize, and take a deep-dive into our data! And many of our students and our Lab Manager, Yimin, become specialized in certain types of analyses.

What does that mean for a PhD student? It means developing fluency in both wet-lab chemistry and computational analysis. You will learn to use machine learning not as a black box but as a tool for pattern recognition in complex biological datasets — identifying which molecular features predict activity, which pathway members are functionally linked, and where chemical intervention is most likely to be informative.

That combination is genuinely rare. Most glycobiology groups skew either chemistry-heavy or biology-heavy. Very few integrate machine learning at the level of research design. For a graduate student, that rarity translates into real value on the job market, whether you are heading toward academia, biotech, or pharmaceutical R&D.

The Training Environment

The Fehl Lab maintains active roles for graduate students, postdoctoral scholars, and undergraduate researchers. Current lab members include are found here (with our alumni!) — a team that reflects the lab’s commitment to multi-stage, hands-on training.

What does day-to-day training actually look like?

Scientific Independence

You are expected to develop your own scientific voice. That means reading the primary literature critically, forming hypotheses, designing experiments, and interpreting results without waiting to be told what to think. Your advisor is a resource and a collaborator — not a supervisor in the industrial sense. The Fehl Lab’s dedicated Roadmap to PhD is a program we developed to develop YOU as an independent scientist.

Methodological Range

Because the work spans chemical synthesis, biochemical assays, cell biology, and computational analysis, you will not graduate as a narrow specialist. You will be able to move between methods as the scientific question demands. That flexibility is what chemical biology training is supposed to produce – highly interdisciplinary, collaborative researchers!

Publication and Communication

Graduate students in active research labs are expected to publish. Writing papers, presenting at conferences such as the ACS and Gordon Research Conferences, and communicating science to audiences with varying levels of expertise are all part of the PhD. These are skills built through practice, not assumed from the start. We have a dedicated Roadmap to PhD to bring you here, starting early once you join the lab.

Collaboration

Chemical biology research rarely succeeds in isolation. We benefit immensely from our collaborations and publications with disease experts. Many of our projects offer the opportunity for collaboration, research shadowing, and even brief research secondments to offer new ways to learn skills and expand your network.

What to Consider Before Applying

A few honest considerations for our prospective students:

Research fit matters more than prestige. The best PhD is the one where your scientific questions align with your advisor’s research program. Read the lab’s publications. Look at the projects on the lab website. Ask yourself whether the problems being worked on are problems you want to spend five years on.

Talk to current lab members. Graduate students will tell you things the lab website cannot. Ask about mentorship style, project timelines, and what the day-to-day culture actually feels like. This is ESSENTIAL for picking the right fit!

Think about career trajectory. A lab that trains you in both chemical biology and machine learning, with a focus on metabolic disease, positions you well across multiple paths. Academic research, biotech R&D, pharmaceutical science, and computational biology are all realistic outcomes. That range is worth weighing. Prof. Charlie Fehl has a broad network in both academia and industy, and is happy to tailor your training for either.

Detroit is a real city with a real research ecosystem. Wayne State is embedded in Detroit’s broader scientific and medical community. The city has a history of applied science and is home to active biomedical research institutions. We are proud of our city, and also work hard to serve the people who live here with our programs that analyze patient volunteers (see our NIDDK RC2 project for details!) right here in our city.

Why Glycobiology Is Worth Your PhD

The glycobiology market is projected to reach $4.66 billion by 2030. More importantly, the science is genuinely unfinished. We just don’t know what we do about glycans the way that the nucleic acids and proteins have been dissected. The tools to study glycan biology with the precision that protein biology now enjoys are still being developed. That means the field is open — fundamental questions remain unanswered, and the researchers who build the right tools will be the ones who answer them.

If you are drawn to problems where the methodology itself is part of the contribution, glycobiology chemical biology is a field where that kind of work is not only valued but necessary.

FAQs

What is the difference between chemical biology and biochemistry as a PhD focus?
Biochemistry typically studies biological molecules and their functions using established methods. Chemical biology involves designing new chemical tools — probes, inhibitors, reporters — to interrogate biological systems in ways those methods cannot. A chemical biology PhD emphasizes synthesis and tool design alongside biological application. FYI…we also dabble in Medicinal Chemistry, to add one more buzzword to the pile!

What research areas does the Fehl Lab focus on?
The lab studies carbohydrate-linked proteins and glycobiology pathways implicated in cancer, diabetes, obesity, and neurodegeneration. A defining feature of the approach is integrating machine learning with chemical biology to define and target specific biological pathways, since the sugars we study respond in real-time to nutrients, metabolic conditions, and disease pathways involved in diabetes, cancer, and other disease types.

Do I need a background in machine learning to join a lab that uses it?
No prior machine learning experience is typically required. Graduate training is designed to build skills you do not yet have. What matters more is intellectual curiosity and a willingness to work across disciplines. The lab develops computational fluency alongside wet-lab skills over the course of the PhD. We also harness AI-driven coding agents to help us with our R and python analyses all the time. That really breaks the barrier down.

What kinds of positions do chemical biology PhD graduates pursue?
Graduates move into academic research (postdocs and faculty positions), pharmaceutical and biotech R&D, computational biology, science policy, and science communication. A background combining chemical tool design with machine learning and metabolic disease research is competitive across all of these paths. See our lab alumni! We have folks who have gone on straight to industry, into tenure-track faculty positions, further research, and beyond!

How do I find out if this lab is a good fit before applying?
Read our recent publications to get a feel for the experiments we do…but keep in mind our most cutting-edge science isn’t yet published! You can also reach out to Charlie Fehl and our current Lab Members by email or appointment in the Wayne State Chemistry building.

What is the Wayne State University Department of Chemistry’s research environment like?
The department is part of a major research university within the Detroit health system (Detroit Medical Center, Henry Ford Hospital System, and the Karmanos Cancer Institute), with access to shared instrumentation, collaborative networks, and strong institutional resources. Detroit’s broader biomedical research (and patient) community adds unique context and opportunities for interdisciplinary work.

When should I contact a PI about joining their lab?
Many of our successful applicants reach out Charlie Fehl even before or during the application process. Once you are admitted, it is time to schedule an appointment with Charlie Fehl to discuss potential projects. Demonstrating that you have read our work is the fastest way to start a good, meaningful conversation with our lab members!

Every protein in your cell has the potential to be fined-tuned by chemical modifications. Phosphorylation of serine, threonine, and tyrosine gets most of the attention since it has been studied for decades, but another modification happens just as frequently—one that we as a field are only just now beginning to functionally decode.

O-GlcNAc transferase, or OGT, attaches a single sugar molecule to hundreds of proteins in a given human cell. In doing so, OGT controls how those proteins behave…in a glucose-responsive manner! That means that OGT becomes overactive in metabolic diseases that have too much (or too little) sguar, including cancer, and diabetes (hyperactive OGT) and neurodegeneration (hypoactive OGT). These functional changes in OGT activity have consequences for the hundreds of pathways that its substrate proteins make up. That makes it one of the most compelling enzyme targets in modern chemical biology, in our opinion in the Fehl Lab!

What OGT Actually Does

OGT catalyzes the addition of N-acetylglucosamine (GlcNAc) to serine and threonine residues on proteins. This modification—O-GlcNAcylation—is reversible. A second enzyme, O-GlcNAcase (OGA), removes the sugar. Together, they function like a molecular switch, cycling GlcNAc on and off proteins in response to changing cellular conditions, such as high vs. low glucose.

What makes OGT unusual is its substrate range. Most enzymes work within a narrow, well-defined set of targets. OGT modifies more than a thousand proteins—transcription factors, metabolic enzymes, cytoskeletal proteins, cell cycle components. It is not a specialist. It is a broad regulator that reads the metabolic state of the cell and translates that information into protein-level changes.

By the numbers, OGT is one, if not THE, most promiscuous enzymes in humans. I can’t think of another that has up to 10,000 substrates (according to the fantastic O-GlcNAc Databank at https://www.oglcnac.mcw.edu/overview/).

The sugar donor OGT uses is UDP-GlcNAc, a metabolite produced through the hexosamine biosynthesis pathway. That pathway sits at the intersection of glucose, glutamine, fatty acid, and nucleotide metabolism. When nutrients are abundant, UDP-GlcNAc levels rise, OGT becomes more active, and more proteins get glycosylated. When nutrients are scarce, the opposite happens. In a very real sense, OGT is a nutrient sensor.

The Structural Basis of OGT Function

OGT is encoded by a single gene in humans, but its architecture is anything but simple. The enzyme carries a long series of tetratricopeptide repeat (TPR) units at its N-terminus and a catalytic domain at its C-terminus. Those TPR repeats are not just scaffolding—they mediate protein-protein interactions, helping OGT find and engage its substrates. Different substrates interact with different regions of the TPR array, which partly explains how one enzyme can modify so many different proteins while still maintaining some degree of selectivity.

The catalytic domain houses the active site where UDP-GlcNAc binds and the sugar transfer reaction takes place. Structural studies have shown this site to be well-defined, which matters for drug discovery. A tractable active site is a meaningful starting point.

There is also a short isoform called sOGT that lacks most of the TPR repeats and localizes to the mitochondria, while the full-length form handles cytoplasmic and nuclear substrates. This compartmentalization adds another layer of regulation that researchers are still working to fully characterize.

Why OGT Dysregulation Matters in Disease

Cancer

In many cancers, O-GlcNAcylation levels are elevated—and not by coincidence. Tumor cells consume glucose at high rates, which feeds the hexosamine pathway and drives up UDP-GlcNAc. Elevated OGT activity then stabilizes oncoproteins, promotes proliferation, and helps tumor cells evade apoptosis. Several transcription factors central to cancer biology, including MYC and p53, are O-GlcNAcylated, and the modification alters how they function. Reducing OGT activity in cancer cell models generally slows growth, which has made the enzyme an attractive target.

Diabetes and Metabolic Disease

The hexosamine pathway has long been implicated in insulin resistance. When glucose flux through the pathway is chronically elevated—as it is in type 2 diabetes—OGT-driven glycosylation of insulin signaling proteins disrupts normal signaling. IRS-1, a key node in that pathway, is one example of a protein whose function is altered by O-GlcNAcylation. The relationship is complex and context-dependent, but the key point is that OGT sits at the interface of nutrient sensing and metabolic regulation, and that interface breaks down in metabolic disease.

Neurodegeneration

The connection between O-GlcNAcylation and neurodegeneration is particularly striking because of tau. Tau is the protein that aggregates into neurofibrillary tangles in Alzheimer’s disease, and O-GlcNAcylation and phosphorylation compete for the same sites on it. When O-GlcNAcylation decreases, tau becomes hyperphosphorylated and more prone to aggregation. This has led to the hypothesis that boosting OGT activity—or inhibiting OGA to prevent sugar removal—could be protective in Alzheimer’s. The picture is nuanced, but it illustrates how centrally OGT sits within a disease-relevant regulatory network. Other proteins, including alpha-syncuclein in Parkinson’s disease and TDP43 in ALS are also O-GlcNAcylated, expanding the roles of this key sugar in neurodegeneration. This relationship becomes more complicated, because here we actually want to INCREASE O-GlcNAc (vs. decrease O-GlcNAc in hyperglycemic diseases), so some tissue specificity will be needed when developing OGT inhibitors. The likely way is to ensure these drugs do NOT enter the brain 🙂

The Case for an O-GlcNAc Transferase Inhibitor

Given OGT’s role in cancer and metabolic disease, there has been sustained interest in developing a selective O-GlcNAc transferase inhibitor. The logic in cancer is clear: if tumor cells depend on elevated O-GlcNAcylation to sustain their proliferative and survival programs, blocking OGT should disrupt those programs.

Several small molecule inhibitors have been developed and characterized. OSMI-1 and its more potent successors—OSMI-2, OSMI-3, and OSMI-4—are among the most widely used research tools. These compounds bind the active site of OGT and compete with UDP-GlcNAc. They have been valuable for probing OGT function in cells, but they remain research tools rather than clinical candidates.

The challenge in developing a clinical O-GlcNAc transferase inhibitor comes down to selectivity and tolerability. Because OGT modifies so many proteins, broad inhibition could have wide-ranging effects on normal cell function. The goal is to find compounds potent and selective enough to be therapeutically useful—or to identify disease contexts where OGT inhibition is particularly well-tolerated or particularly effective.

One emerging strategy is to target OGT indirectly by disrupting its interactions with specific adapter proteins that direct it toward disease-relevant substrates. This would allow more targeted interference without globally suppressing O-GlcNAcylation across the proteome. One of our projects in the Fehl Lab is working on just this goal!

Chemical Biology Approaches to Studying OGT

Drugging OGT requires first understanding it—and that requires tools capable of detecting and tracking O-GlcNAcylation across the proteome. Chemical biology has produced several.

Metabolic labeling with unnatural sugars is one approach. Cells take up modified GlcNAc analogs bearing bioorthogonal handles, which OGT incorporates into its substrates. Researchers can then attach fluorescent dyes or affinity tags to those handles, enabling visualization or enrichment of O-GlcNAcylated proteins. This approach has been used to map the O-GlcNAc proteome and to study how glycosylation shifts in response to metabolic perturbations. Our Photo-GlcNAc probes, which are light-controlled, spatiotemporal tools to activeate OGT, can help us understand these dynamics.

Chemoenzymatic methods offer another route. Engineered versions of OGA can transfer modified sugars onto O-GlcNAcylated proteins, enabling selective labeling of the modified proteome. We apply chemoenzymatic labeling to find new roles of OGT and O-GlcNAc proteins in a variety of tissues, cell types, and conditions.

Machine learning is increasingly useful for predicting OGT substrates and identifying the sequence and structural features that make a site a good candidate for glycosylation. Combining computational predictions with experimental validation accelerates the work of mapping how OGT activity changes in disease states. We are increasingly using ML approaches to understand our datasets!

This is precisely the kind of work happening at the Fehl Lab, where chemical biology strategies and machine learning come together to study carbohydrate-linked proteins and their role in cellular metabolism.

Open Questions and Where the Field Is Heading

OGT is not a simple enzyme with a simple story. It sits at the convergence of metabolism, signaling, and gene regulation, and its dysregulation threads through some of the most prevalent diseases of our time. Developing the tools to study it precisely—and eventually the molecules to modulate it therapeutically—is one of the more important problems in chemical biology right now. If you want to follow that work, the Fehl Lab is a good place to start.

Despite real progress, many fundamental questions about OGT remain open. How does the enzyme select among its thousands of substrates? What governs the stoichiometry of modification at any given site? How does O-GlcNAcylation interact with phosphorylation, ubiquitination, and other modifications at a systems level? Can we safely inhibit OGT in the periphery, avoiding CNS effects?

Answering these questions will require better tools, better models, and tighter integration between chemistry and biology. More potent and selective O-GlcNAc transferase inhibitors will be part of that effort—both as research tools and as potential therapeutics.

These are our favorite things to think about and work on in the Fehl Lab, so stay tuned for our upcoming publications!

Many of our rotation graduate students and potential undergraduate researchers ask us what the difference is between ” chemical biology” and “biochemistry.” There is a great Venn diagram here, with much shared overlap. And we do both in our lab…though we prefer the chemical biology side of the Venn.

These two fields share significant overlap, and many people tend to use the terms interchangeably in ways that don’t help. But seeing both sides will help you choose a lab that fits best for you!

Here’s a clear breakdown.

Our Short Answer

Biochemistry asks: what are the molecules in living systems, and how do they function?

Chemical biology asks: how can we design new chemical tools to probe, control, or modify those molecules — and what does that tell us about disease?

Biochemistry tends to work with the molecules biology gives us. Chemical biology builds new molecules and biomolecules (which we call “probes”) to ask questions that existing, natural systems can’t answer.

What Biochemistry Studies

Biochemistry is the study of the chemical processes that occur in living organisms. It focuses on understanding naturally occurring molecules — proteins, nucleic acids, lipids, carbohydrates — and the reactions they participate in.

A biochemist might characterize the kinetics of an enzyme, map a metabolic pathway, or identify how a mutation alters protein folding. The orientation is largely descriptive and mechanistic: here is how this system works.

Biochemistry sits firmly within biology departments at most universities, though it shares methods with molecular biology, cell biology, and structural biology. The questions tend to start with the organism and move toward the molecule.

What Chemical Biology Does Differently

Chemical biology starts from a different position. Rather than observing biology as it exists, chemical biologists design synthetic tools — small molecules, probes, modified substrates, and engineered proteins or nucleic acids — to interrogate biological systems in ways that natural molecules and biomolecules (protein, DNA, RNA) cannot.

The orientation is intentionally to perturb a system to learn from it. We build something new, introduce it into a biological context, and use its behavior to reveal something about the system that would otherwise stay hidden!

Chemical biology approaches are particularly powerful for studying processes that are hard to observe directly. Protein glycosylation is a perfect example. The addition of sugar molecules to proteins (O-GlcNAc modification, for instance) plays a significant role in how cells respond to metabolic stress, yet studying it with conventional biochemical tools is technically difficult. Also, glycans and O-GlcNAc are NOT genetically encoded the way the RNA and proteins are, so they are much more difficult to predict (although machine learning helps us).

Chemical biologists design probes that can tag, track, or block specific glycosylation events to understand what those events actually do in cancer, diabetes, and neurodegeneration.

How the Tools Differ

Both fields use mass spectrometry, cell-based assays, and structural techniques. The difference is less about the instruments and more about the starting question and the tools designed to answer it.

Where They Overlap

The boundary between biochemistry and chemical biology is quite open. Many research groups use both approaches, and the best chemical biology work is grounded in solid biochemical understanding.

Biochemistry informs chemical biology by defining which pathways and proteins matter. Chemical biology returns the favor by generating tools that make biochemical questions answerable at higher resolution or in more physiologically relevant contexts.

Molecular biology overlaps with both, particularly around gene expression and nucleic acid function. Pharmacology shares chemical biology’s interest in small molecules but focuses more on therapeutic application than on tool development for basic research.

Also, we tend to validate the observations we make with our chemical biology tools in a natural, wild-type, biochemical system in order to make sure we did not introduce a chemical artifact into our biological finding. So…we end up doing both types of experiments anyway!

What This Looks Like in Metabolic Disease Research

At the Fehl Lab at Wayne State University’s Department of Chemistry, we work primarily in chemical biology. We design chemical tools to study carbohydrate-linked proteins and the glycobiology pathways connected to cancer, diabetes, obesity, and neurodegeneration.

We combine those tools with machine learning to identify patterns in glycobiology data that would be difficult to detect otherwise. That combination — custom chemical tools plus computational analysis — lets us ask precise questions about how sugar modifications on proteins drive metabolic disease.

This is exactly the kind of work that sits outside the scope of traditional biochemistry. We’re not just characterizing what exists; we’re building the instruments to see what’s been invisible.

If you’re a new graduate student, potential undergraduate researcher, or early-career researcher thinking about which direction to pursue, chemical biology is worth serious consideration if you’re drawn to building things, working at the chemistry-biology interface, and connecting molecular-level work directly to human disease outcomes.

Learn more about our research and current projects at fehl-lab.com.

Which Field Is Right for You?

Consider biochemistry if you:

• Want to deeply understand how natural biological systems work
• Prefer mechanistic, systems-level questions
• Are drawn to structural biology, enzymology, or metabolomics

Consider chemical biology if you:

• Want to design tools to probe biology, not just observe it
• Are comfortable working across chemistry and biology
• Want your research to connect directly to disease intervention and drug design

Neither path is narrower than the other. Both are rigorous, both publish in top journals, and both contribute to understanding human disease. The difference is in how you prefer to ask the question. And sometimes time…since you need to learn the skills of both chemistry AND biology to answer our research questions!

Sugars control the cell!

Sugar biology is more powerful than most researchers expect. One modification in particular — the addition of a single sugar called O-GlcNAc to serine and threonine residues on proteins — sits at the center of some of the most consequential metabolic decisions a cell makes.

O-GlcNAc modification is not a peripheral regulatory event. It directly shapes how cells sense nutrients, how tumors sustain growth, and how insulin signaling breaks down in type 2 diabetes. Understanding it is one of the most important open problems in metabolic disease research right now.

This article explains what O-GlcNAc modification does to cell metabolism, why it matters in cancer and diabetes specifically, and why we make precision chemical tools to study this critical sugar in live cell settings.

What Is O-GlcNAc Modification?

O-GlcNAc (O-linked N-acetylglucosamine) is a monosaccharide added post-translationally to proteins inside the cell. Unlike N-glycosylation, which occurs in the endoplasmic reticulum and Golgi, O-GlcNAcylation happens in the cytoplasm, nucleus, and mitochondria. That location matters: it puts this modification directly in contact with signaling proteins, transcription factors, and metabolic enzymes.

The modification is dynamic. It cycles on and off proteins in response to nutrient availability, stress, and cellular context. This makes it a real-time sensor of metabolic state, not a static structural tag.

The substrate for O-GlcNAc is UDP-GlcNAc, the end product of the hexosamine biosynthetic pathway (HBP). The HBP integrates inputs from glucose, glutamine, acetyl-CoA, and UTP — meaning O-GlcNAc levels reflect the overall nutritional status of the cell. When glucose flux is high, UDP-GlcNAc rises, and more proteins get O-GlcNAcylated. The cell is, in effect, reading its own sugar supply through this modification.

The Enzymes Behind the Switch: OGT and OGA

Two enzymes control O-GlcNAc cycling. OGT (O-GlcNAc transferase) adds the modification. OGA (O-GlcNAcase) removes it.

OGT is a single gene in mammals, yet it modifies thousands of protein substrates. It does this with remarkable selectivity, guided by its TPR domain and by interacting proteins that direct it to specific targets. Dysregulation of OGT is documented in multiple cancers and in insulin-resistant tissues.

OGA is the eraser. Inhibiting OGA raises global O-GlcNAc levels and has been explored as a therapeutic strategy in neurodegeneration, where tau hyperphosphorylation competes with O-GlcNAcylation at overlapping sites. The same competitive relationship between phosphorylation and O-GlcNAcylation appears in metabolic signaling pathways relevant to diabetes.

Understanding how OGT selects substrates, and how that selectivity shifts in disease states, is one of the central questions driving chemical biology research in this space.

How O-GlcNAc Rewires Metabolism in Cancer

Cancer cells reprogram their metabolism to support rapid proliferation. The Warburg effect — preferential use of glycolysis even in the presence of oxygen — is one well-known example. O-GlcNAc modification is woven into this reprogramming at multiple levels.

Elevated O-GlcNAcylation is a consistent feature of many tumor types. Several mechanisms explain why:

• Glucose flux drives HBP activity. Tumors consume glucose at high rates, which raises UDP-GlcNAc and pushes more O-GlcNAcylation onto proteins.
• O-GlcNAc stabilizes oncoproteins. Modification of proteins like c-Myc and HIF-1α at specific sites protects them from proteasomal degradation, sustaining pro-growth transcriptional programs.
• Metabolic enzyme activity shifts. O-GlcNAcylation of glycolytic enzymes including phosphofructokinase-1 (PFK1) alters flux through glycolysis, redirecting intermediates toward biosynthetic pathways that support nucleotide and lipid synthesis.
• Mitochondrial function is altered. O-GlcNAcylation of electron transport chain components and mitochondrial proteins affects oxidative phosphorylation, contributing to the metabolic flexibility that makes tumors resilient.
• Cancer Stem-Like Cells (CSCs). We found that enhanced O-GlcNAcylation directly reprogram breast tissue cells into cancer stem-like cells…the “seed” that allows cancers to start, then to metastasize through the body, and even to resist chemotherapy to come back as recurrent cancer! Check out our paper, here: https://pubmed.ncbi.nlm.nih.gov/37231419/

Taken together, O-GlcNAc modification does not simply respond to cancer metabolism — it actively maintains it and allows it to spread faster in high glucose conditions like metabolic disease (diabetes, obesity, polycystic ovary syndrome). That makes OGT a compelling target, and it makes the ability to map O-GlcNAc sites on specific proteins in tumor cells a high-priority methodological need.

The Role of O-GlcNAc in Diabetes and Insulin Signaling

In type 2 diabetes, chronic nutrient excess drives sustained elevation of O-GlcNAc levels in metabolic tissues. This has direct consequences for insulin signaling.

Insulin receptor substrate proteins (IRS-1 and IRS-2) are O-GlcNAcylated at sites that overlap with activating phosphorylation sites. When O-GlcNAc occupies these positions, the downstream PI3K-Akt pathway is blunted. The cell becomes less responsive to insulin — a molecular description of insulin resistance.

The relationship between O-GlcNAc and glucose toxicity is also relevant to pancreatic beta cells. Chronic hyperglycemia elevates HBP flux in beta cells, increasing O-GlcNAcylation of transcription factors that regulate insulin gene expression and beta cell survival. Over time, this contributes to beta cell dysfunction.

This creates a feedback loop: high glucose raises O-GlcNAc, O-GlcNAc impairs insulin signaling and beta cell function, which worsens glucose control, which raises O-GlcNAc further. Breaking this loop requires understanding exactly which proteins are modified, at which sites, and how that changes in the transition from insulin resistance to overt type 2 diabetes.

Why O-GlcNAc Is Hard to Study — and How Chemical Tools Help

O-GlcNAc research faces a persistent methodological challenge. The modification is substoichiometric on most proteins, labile under standard proteomics conditions, and competes with phosphorylation at overlapping residues. Standard antibody-based detection is limited in site-specificity and coverage.

Chemical biology tools address these limitations directly. Metabolic labeling strategies using unnatural sugar analogs — including GalNAz and Ac4GlcNAz — allow researchers to tag O-GlcNAcylated proteins selectively and enrich them for mass spectrometry analysis. Bioorthogonal chemistry makes it possible to visualize O-GlcNAc dynamics in living cells without disrupting normal biology.

In the Fehl Lab, we design precisely this kind of chemical tool. We combine custom probe design, large datasets, and machine learning algorithms to identify which glycobiology pathways are most active in disease-relevant contexts, and to prioritize which protein-modification events are worth pursuing as targets. This approach lets us move from broad pathway observation to specific, testable hypotheses about how O-GlcNAc drives cancer and diabetes.

You’re in the right place to learn about our ongoing research…check out our Publications!

What This Means for Metabolic Disease Research

O-GlcNAc sits at the intersection of nutrient sensing, signal transduction, and gene regulation. That position makes it relevant not just to cancer and diabetes, but also to obesity and neurodegeneration — disease areas where metabolic dysregulation is a shared underlying mechanism.

For researchers working on metabolic reprogramming, O-GlcNAc is not a side story. It is a central regulatory axis that connects the cell’s sugar supply to its most consequential decisions about growth, survival, and stress response.

Mapping that axis precisely, and building tools that make it tractable, is work that matters for patients. We design those tools at the Fehl Lab. If you are working on related questions and want to explore collaboration, contact Charlie Fehl at Wayne State University’s Chemistry Department!

FAQs

What is O-GlcNAc modification?
O-GlcNAc modification is the addition of a single N-acetylglucosamine sugar to serine or threonine residues on intracellular proteins. It is dynamic, cycling on and off in response to nutrient availability, and it regulates a wide range of signaling and metabolic proteins.

How does O-GlcNAc affect cancer cell metabolism?
Elevated O-GlcNAcylation in cancer cells stabilizes oncoproteins, alters glycolytic enzyme activity, and supports biosynthetic pathways needed for rapid proliferation. High glucose consumption by tumors drives increased UDP-GlcNAc production, which sustains this elevated modification state. Stopping OGT activity with inhibitors is a proven way to slow down this proliferation, and importantly the cancer stem-like cell pathway we found in breast cancer tumors.

What is the connection between OGT enzyme activity and diabetes?
OGT modifies insulin receptor substrate proteins at sites that overlap with activating phosphorylation residues. When O-GlcNAc occupies these sites — as happens in chronic nutrient excess — insulin signaling through the PI3K-Akt pathway is reduced, contributing to insulin resistance. We think that OGT is an excellent target for restoring insulin sensitivity in diabetic patients.

Why is O-GlcNAc difficult to study with standard proteomics methods?
O-GlcNAc is substoichiometric on most target proteins, labile under typical mass spectrometry conditions, and competes with phosphorylation at overlapping sites. Standard antibody reagents lack the site-specificity needed to map modification events comprehensively across the proteome. Precision chemical tools can address this gap.

What chemical tools are used to study O-GlcNAc in living cells?
Metabolic labeling with unnatural sugar analogs such as our PhotoSugar analogs (light-controlled metabolic chemical reporters!), combined with bioorthogonal chemistry, allows selective tagging and enrichment of O-GlcNAcylated proteins. These approaches enable site-specific proteomics and real-time imaging of O-GlcNAc dynamics in live cells. Our GlycoID system is another cell-based platform that labels O-GlcNAc in live cells under physiologically neutral conditions!

Does O-GlcNAc modification play a role in neurodegeneration?
Yes. O-GlcNAcylation of tau protein competes with phosphorylation at overlapping sites. Reduced O-GlcNAc on tau is associated with hyperphosphorylation and aggregation on tau and alpha-synuclein, which are hallmarks of Alzheimer’s disease and Parkinson’s pathology, respectively. OGA inhibition has been explored as a strategy to restore this balance. Stay tuned for new chemical probes from the Fehl Lab that can potentially address this space.

How does the Fehl Lab approach O-GlcNAc research?
The Fehl Lab at Wayne State University’s Department of Chemistry designs custom chemical tools to study carbohydrate-linked proteins, including O-GlcNAcylated substrates, in metabolic disease contexts. The lab integrates machine learning with chemical biology to identify and target specific glycobiology pathways in cancer, diabetes, and other metabolic diseases. Learn more at fehl-lab.com.

Some thoughts, opinions, and ideas about how to study human metabolic diseases via changing sugar patterns. Enjoy!