Iis There Any Paper Containing The Methodology Of Choke-Point Reaction Analysis ?

Question

[rezwan.02]

is there any paper containing the methodology of chokepoint reaction anlysis ?

Answer 1

[Malachi Griffith]

For anyone else that was wondering:

A “chokepoint reaction” is a reaction that either uniquely consumes a specific substrate or uniquely produces a specific product in the Entamoeba metabolic network (Figure 1). As described by Yeh and colleagues [7] it is expected that the inhibition of an enzyme that consumes a unique substrate result in the accumulation of the unique substrate which is potentially toxic to the cell and the inhibition of an enzyme that produces a unique product to result in the starvation of the unique product which potentially cripple essential cell functions. Thus, it is believed that chokepoint enzymes may be essential to the parasite and are therefore potential drug targets. ... Chokepoint analysis has several advantages. First, it allows us to test the consistency between experimental data and assumptions about the organization and regulation of the biochemical pathway and of its interdependencies with other processes. Second, it can be used to predict the consequences of various mutations or inhibitors. [Choke point analysis of metabolic pathways in E.histolytica: a computational approach for drug target identification.]

This paper claims to describe the method:

We have constructed PlasmoCyc, a PGDB for Plasmodium falciparum 3D7, using its annotated genomic sequence. In addition to the annotations provided in the genome database, we add 956 additional annotations to proteins annotated as “hypothetical” using the GeneQuiz annotation system. We apply a novel computational algorithm to PlasmoCyc to identify 216 “chokepoint enzymes.” ... The association between a protein and a specific reaction is captured in an enzymatic-reaction frame, which allows us to specify inhibitors and cofactors for a specific enzyme's catalysis of a specific reaction (Fig. 1). Encoding these relationships in a computational data structure allows us to perform systematic analyses over the entire system, including complex queries and checks for data inconsistency within the pathway database. ... Chokepoint analyses are particularly straightforward to perform with a computational representation of metabolism, due to the constraints placed on the representation, and would be difficult to perform on a flat list of enzymatic reactions (due to synonyms for reactions and compounds). There are certain reactions that we excluded from our chokepoint analysis, namely proteolytic reactions (as we do not capture the specificity of these reactions), reactions that do not have clearly defined substrates (e.g., protein disulfide isomerase), and reactions with important side effects (many ATPases). Although these enzymes could be good drug targets, we did not expect the rationale of our method to apply in these cases. We identified 216 of 303 distinct enzymatic activities (71.3%) as catalyzing chokepoint reactions, assuming each enzyme has only one active site, unless annotated as multifunctional.

Figure 4 provides a diagrammatic depiction of chokepoints.