Pathway analysis

The goal of this post is to utilize the Ingenuity pathway analysis (IPA) to evaluate our gene of interest ACADM.  In previous posts I have described this gene locus and the disease associated with it.  The IPA will be used to search for drugs that may interact with the product of the gene locus and review pathways associated with the locus and its products.

Using the "Genes and Chemicals" search tool and the identifier "ACADM" the entry of our gene of interest was located.  Unfortunately there were no drugs associated with the gene as seen below in the far right cell:

 Additionally linking out to the gene information page also showed the missing drugs table.  This is not surprising given the mechanism of action of the gene and it disease Medium-chain acyl-coenzyme A dehydrogenase deficiency or MCADD.  The disorder manifests itself when periods of fasting occur and the body attempts to utilize fatty acids as a source of energy.  The failure to produce the ACADM protein results in a failure to generate energy and the metabolism starts to fall apart.  This can be prevented through the use of glucose and simple carbohydrates.  As diet has been show to be enough to manage the disease the would be little incentive for a drug targeting this site to be developed.


To begin the analysis of the pathways ACADM was added to a new pathways construct, and using the "build" panel, and selecting the "grow" tools, molecules were limited to on those that have direct interactions, found in humans, and had the molecule types [biologic drug, chemical(8)] excluded.  All molecules both upstream and downstream were allowed, the limit was left at 10 for the first pass of the analysis, but this proved not to be a limiting factor as only two molecules were returned, PPARGC1A and ESRRA, (no trimming was required) as seen here on the left using the "auto-layout".  On the right we see the sub-cellular layout indicating that both molecules act from the nucleus into the cytoplasm on ACADM:

Both of the observed molecules were of the [E] type or expression, meaning that activity by these two protiens act to increase the RNA expression, and the blocking of the activity of these proteins reduced the amount of RNA seen from this locus.  No activation, no inhibition, and no Protein-Protein interaction was seen.
Switching to the "Overlay" tab and selecting Canonical Pathways showed a number of pathways recognized, as seen below:

However only 2 were from ACADM, the Fatty Acid B-oxidation I, and Leucine Degradation I.  As failure of the Fatty Acid B-oxidation I is what actually causes the disease MCADD it was chosen for further analysis.  The view of the pathway can bee seen here:

With ACADM as the purple triangle.  Both of the pathways passing through ACADM are of the type RE, meaning they are enzymatic reaction, part of the break down of fatty acids into energy.  The report for this pathway it is indicated that "Although enzymes of the pathway handle both short and long chain fatty acids, it is the long chain compounds that induce the enzymes of the pathway. Each turn of the cycle removes two carbon atoms until only two or three remain. When even-numbered fatty acids are broken down, a two-carbon compound remains, acetylCoA. When odd number fatty acids are broken down, a three-carbon residue results, propionylCoA. link".  As indicated with the gene itself, no drugs are indicated that interact with this pathway.