Researchers Map Marine Bacterial Enzyme to Tweak Therapeutic Red Pigments

Many important medicines and agricultural compounds have origins in natural products made by microorganisms. One such compound is prodigiosin, a vivid red pigment produced by certain bacteria. Beyond its color, prodigiosin and related compounds known as prodiginines have attracted scientific interest because they have shown antibacterial, anticancer, immunosuppressive, antifungal, and plant-protection activities. 

However, natural compounds usually cannot be used directly as medicines or applied products. Researchers often need to adjust their chemical structures and compare many related versions before identifying which properties are useful. Even small changes to a molecule's side chains can affect how it binds to biological targets, dissolves, remains stable, or behaves in living systems. 

A research team from Taipei Medical University has now provided new insight into HapC, an enzyme from the marine bacterium Hahella chejuensis. The study, led by Professor Andrew H.-J. Wang, University Chair Professor at Taipei Medical University, was published in The FEBS Journal.  

The Solution: Testing HapC's Flexibility 

HapC catalyzes the final joining step in prodiginine biosynthesis. To test how flexible the enzyme is, the TMU team used modified short-chain versions of one key chemical building block and examined whether HapC could join them with another precursor to form new prodiginine compounds. 

The enzyme successfully produced six non-native prodiginines in the laboratory. Importantly, two of them-3,4-dimethyl-6-methoxyprodiginine and 2-ethyl-6-methoxyprodiginine-had not previously been successfully produced by any prodigiosin-forming enzyme. One of these, the 2-ethyl variant, had shown no activity when tested with the more commonly studied related enzyme PigC, highlighting HapC's distinct catalytic potential. 

This is meaningful because it shows that HapC is not only another enzyme in a known pathway. It may serve as a flexible biological tool for building chemical structures that were previously difficult to access. Such enzyme-guided synthesis could help researchers expand prodiginine libraries more efficiently than relying only on complex chemical synthesis. 

Understanding How the Enzyme Works 

The study also investigated the mechanism behind HapC's activity. Because no experimentally solved crystal structure of HapC is currently available, the team built a structural model and used docking simulations to examine how the enzyme binds ATP, reaction intermediates, and prodiginine products. 

We wanted to understand how nature builds these red-pigment molecules, not only by looking at the final product, but by following the enzyme's working steps. HapC works like a molecular assembly station. It brings together small chemical building blocks, uses ATP to activate the reaction, and then guides the final joining step. By testing different building blocks and modeling how they fit inside the enzyme, we could see both what HapC can make and why it can make them." 

Andrew H.-J. Wang, University Chair Professor, Taipei Medical University

Their analysis supports a three-phase catalytic cycle. First, HapC binds ATP, the energy-carrying molecule that helps activate the reaction. Second, the enzyme positions the substrate and transfers a phosphate group through a conserved histidine residue, H859. Third, the newly formed prodiginine product is released, allowing the enzyme to reset for another reaction cycle.  

What this Could Enable Next 

The new compounds are not being presented as medicines. Their value is that they give researchers more prodiginine analogs to test and compare, especially short-chain variants that may influence how these molecules interact with biological targets while preserving important chemical features. 

With a clearer model of HapC's active sites and catalytic cycle, researchers can now explore whether the enzyme can be engineered to accept more building blocks and produce larger compound libraries. The next step is to test the biological activity of these analogs and assess whether HapC can become a useful tool for natural-product discovery in medicine, biotechnology, or agricultural biocontrol.