I’m studying for my second qualifying exams (the exam which, should I pass, will officially qualify me as a PhD candidate). In an effort to bolster my general knowledge of all things RNA-related, I’m reading a textbook called the “Molecular Biology of RNA.”
This book as an entire chapter devoted to catalytic RNAs. Since my days as an AP Biology student I’ve known that some RNA molecules can behave as enzymes and catalyze reactions, but this chapter opened up the world of ribozymes as I’ve never understood them before.
A Ribozyme is an RNA molecule that can catalyze a reaction. The ribosome is probably the most famous ribozyme, which catalyzes peptide bond formation, but other RNAs exist that also behave as true catalysts. A true catalyst is not destroyed or changed by the reaction it speeds up.
Some RNAs with enzymatic activity ARE exhausted by the reactions they catalyze, and the chemistry here is equally fascinating. These include self-splicing RNA introns and self-cleaving viral genomes.
Most catalytic RNAs use acid-base chemistry and leverage the heightened reactivity of the ribose sugar via the 2′-OH functional group.
Let’s take a step back. To understand how RNA can act as an RNA-cutting enzyme, we need to know two things. 1) how structure and function are intimately related in biology, and 2) how generally unstable RNA is as a polymer.
1) Structure and Function:
This is something I also learned in high school biology that I took for granted until late in college. Primary sequences of proteins and RNAs are closely tied to secondary or tertiary structures, and these are intimately related to how a molecule functions. In the case of RNAs, primary sequence influences base-pairing or secondary structure, and RNA molecules can fold up into tertiary structures that bring reactive groups into close proximity. All you need is an environment that encourages this folding and can stabilize the reactive groups in this close proximity.
2) RNA instability
RNA is less stable than DNA. The namesake ribose sugar has an extra functional group (-OH) attached to carbon #2. This functional group is reactive, and particularly so when de-protonated. The partially-negatively charged oxygen can attack the phosphate in RNA’s phosphate backbone, triggering cleavage of the backbone.
(I understand pictures would be greatly useful here…I’ll get on that)
So for enzymatic RNAs to function, all we need is creation of an active site by RNA-folding, and then stable acid-base chemistry to trigger cleavage. This can occur within the RNA sequence itself (self-cleavage) or by sequence-recognition in a separate RNA molecule (site-specific cleavage).