This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
What is Chemical Genomics?
Chemical genomics is an area of study that aims to understand how genes and proteins interact with small molecules. This is investigated by using a screening libraries of chemicals. The scientist takes a phenotype of interest, exposes the organisms with the interesting phenotype to a chemical library, and investigates if any of the chemicals get rid of the interesting phenotype to restore wild type function.[1] The most common use for this technique is to screen for drugs that may be effective in reversing disease phenotypes. A basic example of this is demonstrated in figure one below.
Chemical Genomics and MTHFR
PubChem is a public database that contains thousands of chemicals and their observed activities in biological assays. This database was used to identify known chemical interactions with MTHFR and spina bifida. Although there are no known drugs that rescue the spina bifida disease phenotype, there is a drug that up-regulates the amount of folate in the serum. [2]
NAT1 is an acetyl-transferase that acetylates folate in the body. This functions to catabolize folate, thus decreasing its availability within the body. [3]
NAT1 is also implicated in cell division and cancer. Increases in NAT1 activity have also been implicated in the exacerbation of low folate and the development of neural tube defects. [4] The drug trichostatin A (TSA) is a histone deacetylase inhibitor. This means that is functions to prevent the removal of acetyl residues from histones, thus promoting gene expression. This drug up-regulates NAT1 expression. These effects are wide-spread because NAT1 is expressed in most tissues in the body. [3] |
Discussion
The understanding that histone deacetylase inhibitors can increase NAT1 activity and by extent the catabolism of folate is an important consideration for family planning. Histone deacetylase inhibitors are a treatment sometimes used for cancer due to their apoptotic effects. It is important to investigate the long-term effects of NAT1 over-expression on folate levels. This may inform the cancer treatments offered to women who would like to eventually start a family.
This chemical screen also brought to light the fact that NAT1 over-expression can lower folate levels. MTHFR mutation has a similar effect later in the folate metabolic pathway. It would be interesting to look at the combined contribution that mutations in these genes can have toward the risk of developing neural tube disorders.
This chemical screen also brought to light the fact that NAT1 over-expression can lower folate levels. MTHFR mutation has a similar effect later in the folate metabolic pathway. It would be interesting to look at the combined contribution that mutations in these genes can have toward the risk of developing neural tube disorders.
References:
[1] Macbeath, G. (2001). Chemical genomics: What will it take and who gets to play? Genome Biology, 6, commment2005.1-comment2005.6.
[2] https://pubchem.ncbi.nlm.nih.gov/
[3] Patterson, S., Sin, K.L., Tiang, J.M., Minchin, R.F. & Butcher, N.J. Histone deacetylase inhibitors increase human arylamine N-acetyltranferase-1 expression in human tumor cells. Drug Metabolism and Disposition, 39, 77-82.
[4] Jensen, L.E., Hoess, K., Whitehead, A.S. & Mitchell, L.E. (2005). The NAT1 c1095A polymorphism, maternal multivitamin use and smoking, and the risk of spina bifida. Clinical and Molecular Teratology, 73, 512-516.
Images:
Header: https://medicalfuturist.com/pharmacogenomics-the-science-of-personalizing-drugs-based-on-dna
Figure 1: https://www.omicsonline.org/articles-images/2327-5146-1-112-g002.html
Figure 2: https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0096370.g004
[1] Macbeath, G. (2001). Chemical genomics: What will it take and who gets to play? Genome Biology, 6, commment2005.1-comment2005.6.
[2] https://pubchem.ncbi.nlm.nih.gov/
[3] Patterson, S., Sin, K.L., Tiang, J.M., Minchin, R.F. & Butcher, N.J. Histone deacetylase inhibitors increase human arylamine N-acetyltranferase-1 expression in human tumor cells. Drug Metabolism and Disposition, 39, 77-82.
[4] Jensen, L.E., Hoess, K., Whitehead, A.S. & Mitchell, L.E. (2005). The NAT1 c1095A polymorphism, maternal multivitamin use and smoking, and the risk of spina bifida. Clinical and Molecular Teratology, 73, 512-516.
Images:
Header: https://medicalfuturist.com/pharmacogenomics-the-science-of-personalizing-drugs-based-on-dna
Figure 1: https://www.omicsonline.org/articles-images/2327-5146-1-112-g002.html
Figure 2: https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0096370.g004