RNA, Enzyme, Metabolites
It has been conventionally thought that eukaryotic cells have been able to evolve and adapt to their surroundings without the need for gene regulatory mechanisms. Recent studies have shown that in specific cases, this may not necessarily be true as these cases have shown connections between intermediary metabolism and the regulation of gene expression. Currently, there is evidence to show that there are interactions among the RNA, enzymes, and metabolites in gene regulation.
Enzymes Regulating RNA Expression
Hentze and Preiss listed several biological cycles which demonstrate that enzymes bind to RNA, which include the tricarboxylic cycle, glycolysis and pentose cycle, fatty acid metabolism, and pyrimidine synthesis. The examples that Hentze and Priess use are cystolic aconitase, GADPH, and the three enzymes used for the thymidylate synthesis cycle.
An example of an enzyme that can affect regulation of RNA expression is cytosolic aconitase. This enzyme acts by using its iron-sulfur group as a catalyst. However, cytosolic aconitase can also act as an RNA-binding protein (labeled IRP1) when the cytosolic aconitase loses its iron sulfur cluster. This is significant in that this protein has two mutually exclusive activities that are regulated by whether the iron-sulfur cluster is present or not.
The presence of iron-sulfur clusters, as mentioned above, affects what type of activity cytosolic aconitase can perform. This is an example of how metabolism and the resulting metabolites can regulate interactions between enzymes and RNA. A cell that is iron-deficient will result in cytosolic aconitase losing its iron-sulfur cluster, transforming it into the IRP1 protein that will bind to iron-responsive RNA elements (IRE); the IRE will then regulate the production of necessary compounds to maintain homeostasis in the cell.
GAPDH is an enzyme that has been shown to bind to several different types of RNA including, mRNAs, tRNA,s rRNA, and viral RNAs. Hentze and Priess state that this protein is thought to bind to the 3' side of untranslated regions of lymphokine mRNAs because of their richness in AU.
GAPDH is also involved in the GAIT complex, which is a γ-interferon-activated inhibitor of translation. In this complex, the GAPDH controls mRNA translation under the direction of the γ-interferon.
TS, SHMT, and DHFR
TS, SHMT (serine hydroxymethl-transferase and DHFR are enzymes involved in the thymidylate synthesis cycle. They are another example of proteins that are known to bind to RNA. These three enzymes regulate mRNA translation by binding to areas in the 5' untranslated regions.
RNA Regulation of Enzyme Activity
Hentze and Priess assert that enzymes' catalytic activity can be controlled by RNA binding when enzymatic and RNA functions are competing. The evidence for this activity is shown though the enzyme IDH (isocitrate dehydrogenase), which is a yeast mitocondrial protein that is NAD+ specific. IDH binds to the 5' end of mitochondrial mRNA to stop their activity. Although there is not conclusive evidence, Hentze and Preiss also suggest that noncoding RNAs could regulate enzymatic activity by directly binding to those proteins.
There are still vast amounts of research to be done on metabolites. Hentze and Priess assert that metabolites play the role of balancing RNA and enzymatic activity either directly or allosterically (binding a molecule to the active site of a protein). Changes in metabolism can change the body's metabolite concentrations, which will effect proteins with two different functions. One example would be how the cytosolic aconitase switches between its RNA binding role and its catalytic role. Another example of how metabolites are involved in this REM cycle is how the change in nucleotide levels would affect the function of GAPDH. Factors that disrupt nutrition, redox state, or oxygen tension could change the NAD+/NADH ratio, which will change protein functions.
Systematic Exploration of REM Networks
As mentioned above, REM regulation requires research for it to be fully explored. Hentze and Priess suggest two steps to begin the study. The first step would to be to catalogue different types of RNA-binding enzymes using corosslinking techniques. The second step would be to identify the different types of RNA that these enzymes bind with.
While the evidence (as well as other observations) points to the existence of this idea of REM gene regulation, it should be noted that there lacks a complete underlying concept. Regardless, the findings show that there exists much more in gene regulation than adaptation. This has significant implications, even for medicine; one may use the interactions among the RNA, enzymes, and metabolites to create drugs that specifically target a specific point that can directly affect gene regulation. For now, the RNA-binding enzymes, proteins, and RNAs, must be identified for further study on the REM phenomenon.