Polyketide synthases (PKSs) are remarkable molecular machines found in various organisms, including bacteria, fungi, and plants. These complex enzymatic systems assemble a vast array of natural products known as polyketides. Polyketides exhibit diverse chemical structures and a wide range of biological activities, making them a significant focus in scientific research.
Understanding Polyketide Synthases
Polyketide synthases are large, multi-domain enzymes or enzyme complexes that create polyketides. They function much like an assembly line, where each enzymatic domain performs a specific chemical reaction to build a complex molecule step-by-step. These enzymes utilize simple building blocks, primarily acetate units, linking them together in a precise order. The process involves repeated decarboxylative condensations of acyl-CoA substrates, resembling fatty acid biosynthesis.
PKSs play distinct biological roles across diverse organisms. For example, bacterial and fungal PKSs often produce compounds for defense or competition, while plant PKSs contribute to secondary metabolites like flavonoids and stilbenes, involved in pigmentation or defense. PKS complexity varies, from large, modular proteins with multiple catalytic domains to smaller, homodimeric enzymes. All PKSs contain core domains such as an acyl carrier protein (ACP), an acyltransferase (AT), and a ketosynthase (KS), which work together to assemble the growing polyketide chain.
The Diverse Molecules They Create
The compounds produced by PKSs, known as polyketides, exhibit significant structural diversity. This vast array includes molecules with powerful biological activities, often secondary metabolites not directly involved in an organism’s primary growth or reproduction. Over 10,000 polyketides have been identified, with approximately 1% showing potential for drug activity.
Examples include erythromycin, a macrolide antibiotic effective against bacterial infections. Rapamycin (sirolimus) is an immunosuppressant used in organ transplant patients to prevent rejection. Lovastatin, a cholesterol-lowering drug, also originates from a polyketide synthase. Beyond pharmaceuticals, polyketides can include compounds like aflatoxins, potent toxins produced by certain fungi.
Impact on Health and Industry
Polyketides have impacted human health and various industries. Many commonly used pharmaceuticals are derived from polyketides, including a significant portion of top-selling drugs with global revenues exceeding USD 18 billion annually. They serve as potent antibiotics, such as tetracycline, a broad-spectrum antibiotic used to treat numerous bacterial infections. Other examples include antifungals like amphotericin and nystatin, combating fungal infections.
Beyond antimicrobial uses, polyketides also contribute to anti-cancer agents like epothiolone B and doxorubicin, offering new avenues for chemotherapy. Their immunosuppressive properties, exemplified by tacrolimus (FK506) and sirolimus, are important in preventing organ transplant rejection and treating autoimmune diseases. In agriculture, polyketides find applications as pesticides and herbicides, protecting crops from pests and weeds. Some polyketides also serve industrial purposes, such as pigments.
Harnessing Polyketide Synthases for New Discoveries
Scientists are exploring and manipulating PKS systems to create novel molecules with improved properties. This field, often termed “combinatorial biosynthesis” or “synthetic biology,” involves modifying PKS enzymes or their biosynthetic pathways. By altering specific domains within the PKS assembly line, researchers can generate new-to-nature polyketides, expanding their chemical space.
The goal is to discover new drugs or enhance the effectiveness of existing ones. For instance, researchers can “plug and play” different PKS modules or domains to construct hybrid enzymes that produce modified polyketide structures. Advances in genetic engineering and bioinformatics tools enable the identification and characterization of new PKS pathways, even from uncharacterized bacterial sources, offering promising avenues for future drug discovery.