This web page was produced as an assignment for Genetics 564, an undergraduate course at UW‐Madison.
Chemical genetics is the investigation of proteins and signal transduction pathways by the screening of chemical libraries of small molecules. Chemical genetics utilizes small molecules (drug candidates) that can interact with proteins to affect their expression levels, by activating or inhibiting the targeted proteins. [1]
Forward chemical-genetics entails screening exogenous ligands in cells, selecting a ligand that induces a phenotype of interest, and identifying the protein target of this ligand. Reverse chemical-genetics entails overexpressing a protein of interest, screening for a ligand for the protein, and using the ligand to determine the phenotypic consequences of altering the function of this protein in a cellular context. [2] |
Figure 1. Chemical genetic approaches. CLICK TO ENLARGE. (Source)
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How does chemical genetics illustrate gene expression?
Chemical genetics can provide great insight of gene expression because it is possible to find a small molecule that alters only one or specific functions of a gene product with many functions,[3] via forward chemical genetics approach. Therefore, as opposed to simply knocking out all functions of a gene and not knowing which specific molecular activities account for the phenotype in interest, scientists can use small molecules to alter specific pathways, and examine which pathways are responsible for the phenotype of interest. Chemical genetics also enables scientists to study the structural functions of proteins. Chemical genetics alters gene expression rapidly, easily and reversibly. Compared to siRNA used in RNAi, small molecules used in chemical genetics can be delivered into cells more effectively as they are often small and stable in vivo.
Limitation of chemical genetics
A few limitations of chemical genetics as gene expression tool include:
- Availability of appropriate reagents is often limited.
- Small molecules do not silence the gene completely, as there will be some proteins that remain unbound.
- Off target effects might arise if the small molecules binds to other complementary proteins and affect the expression of an undesired gene.
Small molecules and MAOA
The results of past chemical genetic experiments can be searched in the PubChem and Chembank databases to find previously identified interaction partners that could be further explored or as a starting point for a focused chemical library. However, after searching PubChem and and Chembank, I was unable to find any potential small molecule that interact with MAOA. This was expected though, because the research on MAOA only started flourishing recently and medical intervention for aggression has not gained popular support.
Although small molecules that interact with MAOA are currently not available, there are some existing drugs that can regulate the levels of neurotransmitters degraded by MAOA, such as dopamine and serotonin. However, because the exact mechanism of MAOA underlying aggression is not understood, these drugs might have varying effectiveness and side effects. Since L-MAOA alleles cause reduced transcriptional activity of MAOA, resulting in build-up of neurotransmitters in the brain that leads to aggression, an alternative would be to look for potential drug candidates that can upregulate the production of MAOA proteins.
Although small molecules that interact with MAOA are currently not available, there are some existing drugs that can regulate the levels of neurotransmitters degraded by MAOA, such as dopamine and serotonin. However, because the exact mechanism of MAOA underlying aggression is not understood, these drugs might have varying effectiveness and side effects. Since L-MAOA alleles cause reduced transcriptional activity of MAOA, resulting in build-up of neurotransmitters in the brain that leads to aggression, an alternative would be to look for potential drug candidates that can upregulate the production of MAOA proteins.
Reference:
- Kubinyi H (2006). "Chemogenomics in drug discovery". In Weinmann H, Jaroch S. Chemical genomics small molecule probes to study cellular function. Berlin: Springer.
- Stockwell, B.R. (2000). Chemical genetics: ligand-based discovery of gene function. Nature Reviews Genetics 1, 116-125.
- Stockwell, B.R. (2004). Exploring biology with small organic molecules. Nature. 432(7019), 846.