Scientists Found a Sugar That’s Sweet, Low-Calorie, and Rare

Sugar is often treated as a nutritional problem, but for chemists and biologists it is also a molecular opportunity. Subtle changes in how sugar molecules are arranged can dramatically alter how the body processes them, influencing sweetness, caloric value, and metabolic effects. Among these alternatives is D-tagatose, a naturally occurring sugar that tastes similar to sucrose but delivers fewer calories and produces a much smaller rise in blood glucose.

Despite its attractive properties, D-tagatose remains rare in the food supply. That scarcity is not due to lack of demand, but to the difficulty of making it efficiently. Traditional production methods rely on converting galactose into tagatose using specialized enzymes, a process that is costly, slow, and constrained by limited raw materials.

The new study tackles this challenge from an unexpected angle, by reengineering one of biology’s most familiar sugar pathways and running it in reverse.

The Leloir Pathway, a One-Way Street Until Now

For decades, the Leloir pathway has been taught as a textbook example of how cells metabolize galactose. Discovered in the mid-20th century, it describes a series of enzyme-driven steps that convert galactose into glucose-derived intermediates the cell can use for energy and biosynthesis.

In biology classrooms and biochemistry manuals, the pathway flows in a single direction. Galactose goes in, usable cellular fuel comes out. The reactions are considered effectively irreversible under physiological conditions, shaped by enzyme specificity and cellular energetics.

The researchers behind the new work questioned whether that apparent irreversibility was truly fundamental or simply a reflection of how cells normally operate. If the pathway could be coaxed into running backward, it might offer a way to transform abundant glucose into far rarer sugars such as tagatose.

Turning Metabolism Backward

To test this idea, the team designed a whole-cell system capable of reversing the Leloir pathway. Rather than isolating individual enzymes in a test tube, they engineered living microbial cells to express a carefully balanced set of enzymes that collectively pushed metabolic flux in the opposite direction.

This approach required more than simply adding enzymes. Cellular metabolism is tightly regulated, and pathways compete for substrates and energy. The researchers adjusted enzyme levels, optimized cofactor availability, and fine-tuned reaction conditions so that glucose would be redirected away from its usual metabolic fate.

Under these engineered conditions, glucose was converted step by step into D-tagatose inside intact cells. The result was not a trace reaction or a biochemical curiosity, but a measurable and sustained production of a rare sugar from one of the most common carbohydrates on Earth.

Why D-Tagatose Matters

D-tagatose occupies a distinctive niche among sweeteners. Chemically, it is a stereoisomer of fructose, differing only in the orientation of a single hydroxyl group. That small structural change has outsized physiological consequences.

The body absorbs tagatose less efficiently than sucrose or fructose, resulting in fewer calories. It also produces a lower glycemic response, making it attractive for applications where blood sugar control is important. These properties have fueled interest in tagatose as a functional sweetener rather than a simple sugar substitute.

However, the limited availability of tagatose has constrained its broader use. Production costs remain high, and existing methods depend heavily on galactose, itself less abundant and more expensive than glucose. A direct route from glucose could substantially lower these barriers.

From Chemical Isomerization to Cellular Engineering

Most existing tagatose production methods rely on chemical or enzymatic isomerization of galactose. While effective in principle, these approaches face practical limitations, including unfavorable reaction equilibria and the need for extensive downstream purification.

By contrast, the new study uses living cells as miniature chemical factories. Inside these cells, enzymes operate in a coordinated environment, with substrates channeled efficiently from one reaction to the next. This integrated system reduces the need for harsh reaction conditions and external catalysts.

The researchers demonstrated that reversing the Leloir pathway can yield tagatose directly from glucose without requiring galactose as a starting material. This shift simplifies the production pipeline and opens the door to using inexpensive, renewable feedstocks.

Challenging Assumptions About Metabolic Directionality

Beyond its practical implications, the work raises broader questions about how rigid metabolic pathways really are. Many biochemical routes are described as unidirectional because they proceed that way under normal cellular conditions. Yet those conditions are not fixed laws of nature.

By altering enzyme expression and cellular context, the researchers showed that even well-established pathways can be repurposed. The Leloir pathway, long considered a one-way system for galactose utilization, turned out to be more flexible than expected.

This insight has implications beyond sugar chemistry. It suggests that other metabolic pathways, traditionally viewed as irreversible, might also be redirected to produce valuable compounds if cellular constraints are carefully managed.

Efficiency Without Overstatement

Importantly, the study does not claim to have solved all challenges associated with rare sugar production. The reported system represents a proof of concept, demonstrating feasibility rather than immediate industrial readiness.

Yields, productivity, and long-term stability will require further optimization before the approach can be scaled. The researchers also note that metabolic balancing remains delicate, as pushing cells too far from their natural state can reduce viability or efficiency.

By acknowledging these limitations, the work maintains credibility while still highlighting a clear advance. The significance lies in opening a new metabolic route, not in claiming instant commercial transformation.

Implications for Food and Biotechnology

If refined and scaled, the strategy could influence multiple sectors. In food science, it may support more sustainable production of low-calorie sweeteners that closely mimic the taste of sugar. In biotechnology, it demonstrates a generalizable method for converting abundant substrates into higher-value molecules.

The approach also aligns with broader trends toward biomanufacturing, where microbes are engineered to produce chemicals traditionally made through petrochemical or resource-intensive processes. Using glucose, derived from plant biomass, as a starting point fits squarely within this framework.

A Subtle Shift With Broad Reach

At first glance, reversing a metabolic pathway might seem like an esoteric biochemical trick. Yet the study illustrates how reexamining long-standing assumptions can yield practical benefits. By questioning whether the Leloir pathway truly had to run in one direction, the researchers uncovered a new route to a molecule with real-world relevance.

The work stands as a reminder that even in well-mapped territory, biology still holds surprises. Sometimes, progress comes not from discovering entirely new pathways, but from learning how to travel familiar ones in reverse.

The research was published in Cell Reports Physical Science on December 17, 2025.