The enzyme in question is pyrimidine-nucleoside phosphorylase, or PyNP, from the bacterium Bacillus subtilis. PyNP participates in the production of nucleic-acid building blocks by cleaving and reassembling nucleosides, the sugar-and-base units that form the letters of DNA and RNA. Because the same reaction chemistry can be redirected to process synthetic nucleoside analogues, the enzyme is a workhorse in the design of anticancer, antiviral, and antibacterial drugs, and it is also used to manufacture artificial nucleosides, fluorescently labeled nucleosides, and stable-isotope-labeled nucleic acids for research and diagnostics. Despite decades of practical use, the molecular basis of how PyNP’s changing shape governs molecular recognition has remained unclear, leaving a gap between what chemists observe at the bench and what is actually happening at atomic resolution inside the active site.

Addressing that gap, a research team led by Professor Akihiko Hatano, together with researcher Kousei Takeshima of the Course of Chemistry and Biotechnology, Department of Materials Science and Chemistry, College of Engineering at Shibaura Institute of Technology, set out to test how different conformations of the enzyme influence ligand retention and sugar preference. Their strategy was to treat the enzyme not as one structure but as a family of structures. Using all-atom molecular dynamics simulations, the team sampled four distinct conformational states of PyNP, probed the active site with 13 structural probes, and accumulated molecular dynamics trajectories totaling 15.6 microseconds of simulation time. The findings were published online in the journal ACS Omega on September 12, 2026.

The motivation, Professor Hatano explains, grew out of years of bench work. His group has long used this enzyme to synthesize artificial nucleosides, and a recurring question kept surfacing: why does changing the sugar component of a substrate alter the reaction? Experiments could document the outcomes, but they could not directly expose the atomic-scale motions responsible. “We wanted to understand this question from the perspective of atomic-scale motions that experiments alone cannot reveal,” said Prof. Hatano. “This led us to examine how the enzyme and its bound molecules behave across different structural states.” In other words, the team wanted to watch the enzyme and its cargo in real time at the level of individual atoms, rather than infer behavior from static crystal structures.

The first result concerns the geometry of the active-site pocket itself. As the protein transitions between its most closed and most open conformational states, the pocket that cradles the ligand expands by approximately 1.4-fold. That is a substantial change for a recognition site whose job is to grip molecules precisely. A pocket that breathes to this degree cannot be characterized by a single volume or a single set of contact distances; the microenvironment experienced by a bound nucleoside depends on which conformational state the enzyme happens to occupy at any moment. This observation alone suggests that docking studies and structure-based drug design built on one static structure may systematically misjudge how ligands behave in the real, dynamic enzyme.

The simulations then connected this breathing motion directly to function. Across the trajectories, 75.6 percent of those in the closed group retained their ligands in a bound state, compared with only 55.1 percent in the open group. The difference is striking: simply shifting the enzyme’s conformation changed the odds that a bound molecule would stay in place by roughly twenty percentage points. Ligand retention, in this view, is not a fixed property of the enzyme-ligand pair but a joint product of molecular identity and enzyme shape. A compound that appears loosely bound in an open structure might be firmly anchored in a closed one, and vice versa, which has immediate implications for how inhibitors targeting PyNP should be evaluated.

The study also resolved the sugar-preference puzzle. Ribose- and 2′-deoxyribose-containing compounds, it turns out, do not show a universal preference for one sugar over the other. Instead, sugar preference depended on both the individual compound and the enzyme’s conformation, meaning there is no single rule of thumb that predicts which sugar PyNP will handle better. The simulations did, however, reveal a consistent geometric signature: ribose occupied the North, or C3′-endo, ring conformation for 64.3 percent of the sampled time, whereas 2′-deoxyribose occupied the South, or C2′-endo, conformation for 57.9 percent. This conformational divergence was strongest for the unsubstituted compound and became progressively smaller as the substituent at the 6-position of the base grew larger, indicating that bulky base modifications can partially override the intrinsic tendencies of the two sugars.

A single amino acid residue emerged as a key player in this dynamic picture. Tyrosine 165, or Tyr165, behaves as a moving lid over the active site, an effect that was particularly pronounced in the closed reference structure. To test whether this lid genuinely contributes to ligand capture, the researchers ran additional simulations in which the residue was removed. Ligand retention dropped in those simulations, supporting the proposed lid mechanism at the computational level. The authors are careful to note a caveat: the strongest Tyr165 signal came mainly from a closed structure belonging to a related species, so confirmation using a closed-state structure from B. subtilis itself is still needed before the lid mechanism can be considered fully established for this organism.

The broader implications reach well beyond one bacterial enzyme. Because PyNP is already used to synthesize fluorescently labeled nucleosides and stable-isotope-labeled nucleic acids, understanding how enzyme shape affects molecular capture could help researchers design more efficient enzymatic synthesis routes and select reaction conditions that favor the desired conformational behavior. The same understanding could guide the design of inhibitors that exploit the closed state or the lid residue, a strategy relevant to anticancer and antiviral drug development. There is also a sustainability angle: enzymatic synthesis performed in water at mild temperatures is an inherently greener manufacturing route than many conventional chemical syntheses, and improving its efficiency through conformation-aware enzyme engineering could amplify that advantage.

“Enzymes should not be viewed as single, static structures when we think about molecular recognition,” said Prof. Hatano. “Our results show that different conformations can change how compounds are retained and how sugar-related preferences emerge.” The study points toward future calculations and experiments aimed at connecting these dynamic binding behaviors to the actual chemical steps of the phosphorylase reaction, a link that remains to be established. What the work already demonstrates, however, is methodological as much as mechanistic: examining multiple enzyme conformations with molecular simulations can reveal binding behavior that any single static structure may miss. By showing that ligand retention and sugar preference depend jointly on molecular identity and enzyme shape, the research provides a framework for dynamic substrate recognition and opens concrete paths toward future enzyme engineering, rational inhibitor design, and sustainable biocatalytic synthesis of the nucleoside analogues on which modern medicine and biological research increasingly depend.

Subject of Research: Conformation-dependent ligand retention and sugar recognition in pyrimidine-nucleoside phosphorylase from Bacillus subtilis studied by molecular dynamics simulations

Article Title: Molecular simulations reveal how an enzyme’s shape guides molecular recognition

Article References: Molecular simulations reveal how an enzyme’s shape guides molecular recognition. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: pyrimidine-nucleoside phosphorylase, molecular dynamics simulations, Bacillus subtilis, molecular recognition, ligand retention, ribose, 2'-deoxyribose, active site, conformational states, enzyme engineering, nucleoside synthesis, ACS Omega

The scale of the problem the researchers are targeting is enormous. According to estimates by the World Health Organization, malaria was responsible for approximately 600,000 deaths in 2024, and Célia Regina da Silva Garcia, a professor in the Department of Clinical and Toxicological Analysis at FCF-USP, notes that an estimated 90 percent of those deaths are caused by P. falciparum. Effective treatments for malaria do exist, but the parasite has progressively developed resistance to frontline drugs such as chloroquine and artemisinin, the backbone of current therapy in most endemic regions. That erosion of drug efficacy has made the search for new chemical classes of antimalarials a global priority, and it is precisely the gap that the São Paulo team’s work is designed to fill.

The strategy the researchers pursued is known as drug repurposing, an approach that has gained traction across infectious disease research because it exploits compounds whose pharmacology, safety profiles, and synthetic routes are already partly understood. Rather than screening millions of novel chemicals, repurposing starts with molecules validated for another indication and asks whether they also act against a new target organism. In this case, the team synthesized and tested fourteen derivatives of an antineoplastic, or cancer-treating, drug against P. falciparum parasites cultured in the laboratory. The in vitro experiments were funded by the São Paulo Research Foundation (FAPESP) through a series of research grants and fellowships supporting the laboratory’s long-running program on parasite cell biology and chemotherapy.

The results were striking in two respects. First, the molecules proved effective at killing the parasite during its asexual stage, the phase in which Plasmodium invades and reproduces inside human red blood cells and produces the cyclical fevers that define clinical malaria. A drug that clears asexual parasites is, by definition, a treatment: it addresses the disease in the symptomatic patient. Second, and arguably more important from a public health perspective, the compounds also acted against gametocytes, the specialized sexual-stage parasites that are taken up by Anopheles mosquitoes during a blood meal and that make onward transmission possible. A therapy that eliminates gametocytes would not only cure the individual patient but could also block the passage of the parasite from humans back into the mosquito vector, interrupting transmission chains at the community level.

This dual-stage activity is rare among antimalarial candidates. Most existing drugs are optimized for the blood-stage parasites and have little or no effect on mature gametocytes, which is one reason malaria transmission can persist even in treated populations. A single molecule class capable of both curing the patient and reducing infectivity to mosquitoes would be a valuable addition to the therapeutic arsenal, particularly in regions pursuing malaria elimination rather than mere control. The São Paulo findings, while still confined to laboratory cultures, indicate that the 6-anilinopurine scaffold underlying these compounds deserves serious attention as a platform for exactly that kind of transmission-blocking chemotherapy.

Underlying the antiparasitic effect, the researchers believe, is a specific molecular target inside the parasite’s cell: histone deacetylase enzymes, and in particular an enzyme known as PfHDAC1. Histone deacetylases regulate gene expression by modifying the proteins around which DNA is wound, and they have long been recognized as important drug targets in cancer chemotherapy, which helps explain why compounds designed as anticancer agents would show activity against a parasite. By inhibiting the parasite’s version of the enzyme, the derivatives appear to disrupt essential developmental programs in Plasmodium. Garcia explains that the team’s experiments have strengthened the hypothesis that histone deacetylase enzymes are an important therapeutic target for malaria, and that this understanding has allowed the group to design new molecules that are increasingly potent and selective against the parasite.

That structure-activity analysis is the second major contribution of the study. The fourteen tested derivatives varied in their chemical structure, and by comparing how those structural differences changed antiparasitic potency, selectivity, and target engagement, the team gathered the information needed for rational drug design. As Garcia describes it, rational design allows chemists to refine a molecule’s structure in a targeted manner rather than relying on trial and error. In practical terms, the researchers can now adjust side chains and functional groups to maximize inhibition of the parasite enzyme while minimizing interaction with human cells, a balancing act that determines whether a laboratory hit can ever become a safe medicine.

Safety, in fact, remains the central caveat. Because the work so far has been conducted entirely in vitro, the potential side effects of the compounds in patients have not yet been assessed. Some of the tested derivatives showed reduced efficacy against human cells while retaining their effect on the parasites, an encouraging sign of selectivity that suggests a lower risk of serious adverse effects. Nevertheless, Garcia is candid about the concerns: molecules in that class can cause fatigue, nausea, vomiting, and hematological changes such as a decrease in platelets, and she acknowledges that it is natural for such concerns to exist. Only in vivo tests, in animal models and eventually in clinical trials, can confirm whether the therapeutic window observed in culture dishes holds up in a living body.

There is also a pharmacological hurdle specific to this chemical class that the team must overcome. Drugs of this type tend to degrade rapidly inside the body, which can undermine their effectiveness regardless of how potent they are in a test tube. In vivo studies will therefore serve a second purpose beyond safety: verifying whether the candidate molecules remain chemically stable long enough in a patient’s circulation to reach and clear the parasite. Stability, selectivity, and potency together form the triad of criteria that any successor compound emerging from the group’s rational design program will need to satisfy before it can advance toward preclinical and clinical development.

Looking further ahead, Garcia’s team intends to extend its testing to other malaria-causing parasite species, most notably Plasmodium vivax, which is the predominant malaria parasite in Brazil and across much of the equatorial world. P. vivax poses distinct challenges: it can cause relapses even after treatment because it produces latent liver-stage forms called hypnozoites that can reactivate months later, and it is more widespread in equatorial countries than P. falciparum. Garcia emphasizes that evaluating antimalarial drug candidates against different parasite species is essential to ensure they are effective in the various regions of the world where malaria burden is concentrated. If the 6-anilinopurine derivatives, or the optimized molecules designed from them, prove active against multiple Plasmodium species and safe enough for human use, the cancer research toolbox may yet deliver one of the most sought-after prizes in tropical medicine: a single therapy that treats the sick and stops the spread.

Subject of Research: Repurposing anticancer 6-anilinopurine derivatives as dual-stage antimalarial compounds targeting Plasmodium falciparum histone deacetylase

Article Title: Anti-cancer molecules show promise in the fight against malaria

Article References: Anti-cancer molecules show promise in the fight against malaria. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: malaria, Plasmodium falciparum, drug repurposing, anticancer compounds, histone deacetylase, gametocytes, University of São Paulo, FAPESP, ACS Omega, drug resistance, Plasmodium vivax, rational drug design

The study, published in the journal ACS Omega by Ahmed Badreldin, assistant professor of chemical engineering at the University of Mississippi, and Carter Racine, a mechanical engineering doctoral student at Texas A&M University, tackles one of the least glamorous but most consequential bottlenecks in the emerging carbon-recycling economy: manufacturing scale. The pair demonstrated a simpler, lower-cost route to producing carbon-recycling catalysts in batches far larger than the laboratory norm, addressing what both researchers describe as one of the biggest barriers to commercial adoption of electrochemical carbon dioxide conversion. Their work does not invent a new reaction so much as remove the practical obstacle that has kept an otherwise promising reaction confined to the bench.

The reaction in question is the electrochemical reduction of carbon dioxide to carbon monoxide. To a general audience, that transformation may sound like swapping one troublesome gas for another, since carbon monoxide is famously poisonous. In industrial chemistry, however, carbon monoxide is a foundational building block. It is used to manufacture synthetic fuels, plastics, pharmaceuticals and a wide range of other products. Mixed with hydrogen, it forms what the hydrocarbon industry calls synthesis gas, or syngas, the feedstock from which an enormous fraction of the modern chemical economy is built. As Racine explains, carbon monoxide is essentially the simplest form of carbon that chemistry can offer, and when paired with green hydrogen produced from renewable electricity, it can serve as the starting point for making chemicals that would otherwise require virgin fossil fuels.

Converting carbon dioxide into carbon monoxide electrochemically is already possible, and has been demonstrated in laboratories around the world for years. The problem has been the catalysts that make the reaction fast and selective. The most advanced designs are nanostructured materials, often based on silver, and they are typically synthesized in quantities measured in milligrams. Racine notes that many research groups work with batches of around 50 to 100 milligrams. At that rate, the arithmetic of industrial deployment becomes absurd. If a lab produces 100 milligrams per batch, he calculates, it would take a year or more to make enough catalyst to cover 10 square meters of electrode area, the kind of surface a commercial electrolyzer would plausibly require. Small batches also mean more repeated synthesis cycles, each one consuming time, energy and money, which drives up the effective cost of every gram produced.

Badreldin and Racine’s answer was to redesign the synthesis itself. Using a nickel-and-iron single-atom catalyst design, in which individual metal atoms dispersed on a support material perform the catalytic work, they showed that a single synthesis run can yield 75-gram batches without sacrificing the performance that makes single-atom electrocatalysts attractive in the first place. That is a jump of roughly three orders of magnitude over the milligram-scale batches typical of the field, achieved in one step rather than through hundreds of repetitions. The significance is easiest to see in Racine’s comparison: at 75 grams per batch, enough catalyst for a large commercial implementation of these technologies could be produced in a few days rather than a year or more.

Single-atom catalysts are worth pausing over, because they represent a distinctive strategy in modern catalysis. In a conventional heterogeneous catalyst, only a fraction of the metal atoms, those sitting on the surface of nanoparticles, actually participate in the reaction, while the rest sit buried inside particles doing nothing. By dispersing metal atoms individually across a support, single-atom designs maximize the use of every atom, which matters enormously when the metals involved, such as nickel, iron or silver, carry real cost. The challenge has always been keeping those isolated atoms stable and uniformly distributed while scaling production beyond the small batches that careful laboratory procedures allow. Demonstrating that the dispersion and performance survive a 75-gram synthesis is precisely the kind of evidence that separates a laboratory curiosity from a manufacturable product.

The economic implications follow directly from the manufacturing gain. According to the researchers’ analysis, the new catalyst could reduce the cost of recycling carbon dioxide to about $145 per ton, some $255 below the current market price, while generating roughly 25 percent fewer emissions than current methods. In a field where techno-economic analyses routinely show promising chemistry failing on cost, a double-digit reduction in both price and carbon intensity is the kind of result that gets the attention of investors and industrial partners. Racine frames the decisive question bluntly: how much electricity the process requires is the biggest consideration, and being able to run the synthesis in larger batches proves the logistics and feasibility of doing it at scale.

There is also a strategic dimension that Badreldin argues may be the strongest near-term driver. Because the technology would let the United States convert domestically captured carbon dioxide into fuels and essential chemicals, it could establish a domestic supply chain for products that are currently vulnerable to global market disruptions and concentrated production elsewhere. Most of the world’s chemical industries, he notes, are centralized in a handful of locations, but this technology opens the possibility of decentralizing that production. The electrochemical setup is modular, which means a company can size its carbon recycling capacity to its own needs rather than building a giant plant. A manufacturer that needs ethylene or ethanol for a production line, Badreldin suggests, could install an electrolyzer stack just large enough to produce the required volume, something the conventional centralized model does not permit.

That modularity could reshape who participates in the carbon-recycling economy. Instead of a few enormous facilities serving national markets, the technology points toward distributed production at breweries, cement plants, chemical works and other sites that emit concentrated streams of carbon dioxide, each converting its own emissions into feedstock on site. The infrastructure for electrochemical energy conversion is, as Badreldin observes, already in place at many startups in the field; what they lack is catalyst supply at a price and scale that make commercial operation viable. A synthesis route that delivers kilogram-scale batches of high-performing single-atom catalysts at lower cost directly unblocks that bottleneck, potentially accelerating the timeline for carbon dioxide electrolysis to move from pilot demonstrations to revenue-generating plants.

One hurdle remains before any of this reaches industrial reality: durability. Racine is candid that the last challenge is making the process stable enough for continuous industrial use. Large oil and gas plants and other industrial facilities run around the clock for roughly 350 days a year, shutting down for only about a week of maintenance. For carbon-conversion technology to slot into that operating rhythm, the catalyst and the electrolyzer system must be able to run for nearly a year without significant degradation. Figuring out that long-term stability, he says, is what his team and everyone else in the field are working on now. If that problem falls, the vision sketched by this study, in which the carbon dioxide billowing from industry becomes the carbon monoxide feeding it, moves a decisive step closer to being ordinary industrial practice rather than an ambitious promise.

Subject of Research: Large-scale synthesis of single-atom catalysts for electrochemical conversion of carbon dioxide to carbon monoxide

Article Title: Researchers turn climate pollution into usable material

Article References: Researchers turn climate pollution into usable material. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: carbon dioxide, carbon monoxide, single-atom catalysts, electrochemistry, nickel-iron catalyst, carbon recycling, synthesis gas, green hydrogen, catalyst scale-up, ACS Omega, climate change, chemical manufacturing