So I’m done with pharmacology courses forever, which is a good thing – not because I don’t like them, but because they’re hard! It was, however, in my medicinal chemistry courses where I learned the term ‘ternary complex.’ I’ve decided to name my blog after this because the concept has taken on a lot of meaning for me, in all aspects of my life. So I’ll try to define it for you in terms that non-chemists can understand. Strictly defined, a ternary complex is any tripartite combination. Defined chemically, it means the combination of an enzyme, cofactor and substrate or an enzyme and two cofactors (in a multisubstrate enzyme). Let me give you an example:
One classic example of a ternary complex in medicinal chemistry is the interaction of the chemotherapeutic agent topotecan (Hycamtin®) with the enzyme topoisomerase IB. When a cell is dividing (which occurs very rapidly in cancerous tumors), the DNA has to be copied. In order for this to occur, the DNA must be unwound from its supercoiled state to allow access for the replication machinery. Have I lost you yet? The TopoIB enzyme (green in the picture below) is responsible for the removal of the loops in DNA which arise when the DNA is uncoiled (think of trying to uncoil an old telephone cord — you get a lot of loops). The TopoIB protein binds to the DNA molecule, clamps around it and cuts one of the two DNA strands, allowing the DNA to untwist. Then it joins the untwisted broken ends together, allowing the replication machinery (gray in the picture) to proceed.
That’s what occurs normally. However, in chemotherapy, we try to disrupt normal cell division in the hopes of killing rapidly dividing cells (such as tumor cells). When the cancer drug topotecan (shown in red) is administered, it slides into the DNA, binds to it, and forms a ternary drug-enzyme-DNA complex. This stabilizes the DNA in its broken form, effectively blocking further DNA religation. This results in accumulation of DNA loops and the prevention of the DNA replication machinery (shown in gray) from continuing, disturbing cell division and causing the cancer cell to malfunction and ultimately die. Topotecan is frequently used to treat a number of tumors, including those in some ovarian cancers and small cell/non-small cell lung cancers. Also important here is that the binding affinity of the drug to the enzyme-DNA complex is much higher than to the enzyme or DNA separately.
So why does this chemistry concept have so much significance to me? Well, I see myself as the green enzyme just floating around exerting my influence on the DNA, the world around me. Without the red topotecan, I behave one way. With the topotecan, I behave much differently. If you’ve read Hard to Be Humble, you’re familiar with my motif of “the intrusion of others,” or what I now prefer to call “the presence of a third.” My interaction with another person changes considerably when I know I’m being watched or if there’s someone else in the room. I love this model of the ternary complex because it helps me to remember that the name of Jesus should always be on my lips. His presence in my heart changes my interaction with everyone around me. Without Him as my ‘topotecan,’ the cancer in my life spreads rapidly. With Him there, I can keep it in check, and have a positive influence on others. And although the drug can bind the enzyme while not attached to the DNA, it binds much tighter if all three are present. When I am alone, God is working in my life, but He wants me to be interacting with others. He wants me to be connected to other people.
It all makes sense to me at least. I hope you could take something from it too! Enjoy the rest of my blog! This could be fun…
Photo caption: A Topoisomerase IB protein (green) is hindered in unwinding DNA loops by the cancer inhibitor topotecan (red). The DNA polymerase protein (gray), a protein which duplicates DNA, is hindered by the DNA loops. (Credit: TU Delft/Tremani)
Reference: Koster DA, Palle K, Bot ES, Bjornsti MA, Dekker NH. Antitumour drugs impede DNA uncoiling by topoisomerase I. Nature 2007;448:213-7.
