Polyketides are a structurally varied class of natural products, which are organic compounds made by living organisms. These molecules are assembled from simple building blocks into complex architectures of many shapes and sizes. Their importance is rooted in the diverse roles they play in ecological interactions and human medicine, a direct result of their structural complexity.
Natural Origins and Roles
Polyketides are produced by a wide range of organisms, with bacteria, fungi, and plants being the most prolific sources. Among bacteria, those from the phylum Actinobacteria are particularly well-known for their ability to synthesize these compounds. These molecules are not directly involved in an organism’s normal growth or reproduction but serve other purposes. Their absence may not cause immediate death but can affect long-term survival or the ability to reproduce.
The functions of polyketides in nature are diverse. Many organisms use them as chemical defenses against predators or competing microbes. For example, some fungi produce polyketides with antifungal properties to gain an advantage over other fungi. These compounds can also act as signaling molecules for communication, play a role in symbiotic relationships, or serve as pigments and herbivore deterrents in plants.
An illustration of a polyketide’s role is the case of aflatoxins. These are toxic polyketides produced by certain Aspergillus fungi, which can contaminate crops like peanuts and corn. Aflatoxins are not used for medicine and are instead potent carcinogens and toxins. Their production is thought to be a defense mechanism for the fungus.
Medicinal Significance
The structural diversity of polyketides has led to the development of drugs for a wide range of diseases. Many pharmaceuticals are derived from these compounds, which are used as antibiotics, anticancer agents, and immunosuppressants.
A primary application of polyketides is in antibiotics. Erythromycin, for instance, is a macrolide antibiotic produced by the bacterium Saccharopolyspora erythraea. It works by inhibiting protein synthesis in bacteria, stopping their growth and allowing the immune system to clear the infection. Erythromycin and its derivatives are used to treat various bacterial infections, from skin conditions to respiratory illnesses.
Polyketides are also used to manage high cholesterol. Statin drugs, such as lovastatin, are a class of cholesterol-lowering medications derived from these compounds. Lovastatin was originally isolated from the fungus Aspergillus terreus and works by blocking a liver enzyme necessary for producing cholesterol. This action reduces cholesterol levels in the blood, which helps prevent cardiovascular disease.
In the fight against cancer, polyketides have provided potent chemotherapeutic agents. Doxorubicin is an anthracycline antibiotic used to treat cancers like breast, bladder, and lung cancer. It is produced by the bacterium Streptomyces peucetius and functions by interfering with the DNA of cancer cells, preventing them from replicating and leading to cell death.
Polyketides are also used to modulate the immune system. Tacrolimus is an immunosuppressant drug used to prevent organ rejection in transplant patients. Produced by the soil bacterium Streptomyces tsukubaensis, tacrolimus works by suppressing the activity of T-cells, a type of immune cell that plays a central role in organ rejection. This allows the transplanted organ to function without being attacked by the patient’s immune system.
The Biological Assembly Line
The diversity of polyketides stems from their creation method, which resembles a factory assembly line. This process is carried out by large enzyme complexes called polyketide synthases (PKSs). These enzymes use simple precursor molecules, such as acetyl-CoA and propionyl-CoA, as building blocks to construct the polyketide structure.
The PKS assembly line is organized into a series of modules, with each responsible for one cycle of chain extension and modification. Each module contains several domains, which are parts of the enzyme that perform specific tasks. A minimal module includes a ketosynthase (KS), an acyltransferase (AT), and an acyl carrier protein (ACP) domain. The AT domain selects the correct building block and attaches it to the ACP, which then shuttles it to the KS domain for addition to the growing polyketide chain.
After each extension step, other domains within the module can modify the newly added unit. These optional domains can perform reductions or dehydrations, tailoring the structure as it is built. The sequence and combination of these modules and domains determine the final structure of the polyketide. This modular nature allows for many combinations, explaining the structural diversity of these compounds.
The final step is the release of the completed polyketide chain from the PKS assembly line. This is carried out by a thioesterase (TE) domain, which cleaves the bond holding the polyketide to the enzyme. The TE domain often also catalyzes the cyclization of the molecule, forming the ring structures found in many polyketides, like macrolide antibiotics.
Harnessing Polyketide Production
Scientists are now working to create new polyketides through a field known as biosynthetic engineering. This involves modifying the genes that code for polyketide synthases (PKSs) to produce novel compounds. By altering the PKS assembly line, researchers can change the resulting polyketide’s structure, potentially leading to new drugs with improved properties.
The modular nature of PKSs makes them ideal for this genetic manipulation. Scientists can swap out entire modules or individual domains to change the building blocks used or the modifications made during synthesis. This “mix and match” approach allows for creating new polyketide structures that do not exist in nature. The goal is to design molecules with specific therapeutic properties, such as increased efficacy or reduced side effects.
A driver of this research is the growing problem of antibiotic resistance. By engineering new polyketides, scientists hope to develop novel antibiotics that can overcome resistance mechanisms in bacteria. This could lead to a new generation of drugs capable of treating infections that are currently untreatable with existing antibiotics.
This work is not without its challenges, as the large size and complexity of PKS genes can make them difficult to manipulate. However, advances in synthetic biology and genetic engineering are making it easier to work with these enzyme complexes. Continued understanding of PKSs will improve the ability to harness their biosynthetic power.