Enzyme-malfunctioning in the light of pathway analysis An example from nucleotide metabolism

Many diseases occur as a consequence of enzyme deficiencies. The missing or incompletely operating enzyme can imply the interruption of a synthesis pathway and, thus, the lack of a product, or it can lead to the accumulation of an intermediate that is toxic when present in high concentration, for example, by inhibiting another essential enzyme. A clinical important and well known example is the enzyme hypoxanthine-guanine ribosyltransferase (HPRT, EC. 2.4.2.8) – an enzyme of the nucleotide metabolism. When this enzyme does not operate properly, uric acid accumulation, kidney stones, gout, and even the so-called Lesch-Nyhan syndrome occur, depending on the degree of malfunctionality [1]. For understanding the metabolic effects resulting from enzyme deficiencies, flux balance analysis, in particular the concept of elementary flux mode (EFM), can be of great help. Its advantage consists in coping with systems having available only the stoichiometric properties. An EFM represents a minimal set of enzymes that could operate at steady state with all irreversible reactions used in the right direction [2]. A biochemical system can be decomposed into a unique set of EFMs, which stand for all significant biochemical interconversions. A necessary step is to split the set of metabolites into external and internal metabolites. The source and the sink metabolites have to be external. Sometimes it is useful to consider also those metabolites as external which interconnect many different branches of metabolism The remaining metabolites are internal.