for catalysis). Isozyme specific regions Though the majority of the overall structure of the aldolase enzyme is conserved amongst the three isozymes, four regions of the generic aldolase enzyme have been identified to be highly variable among isozymes. Such regions have been denoted isozyme-specific regions (ISR1-4). These regions are thought to give isozymes their specificities and structural differences. ISRs 1-3 are all found in exon 3 of the ALDOB gene. ISR 4 is the most variable of the four and is found at the c-terminal end of the protein. ISRs 1-3 are found predominantly in patches on the surface of the enzyme. These patches do not overlap with the active site, indicating that ISRs may change specific isozyme substrate specificity from a distance or cause the C-terminus interactions with the active site. A recent theory suggests that ISRs may allow for different conformational dynamics in the aldolase enzyme that account for its specificity. Physiology Aldolase B plays a key role in carbohydrate metabolism as it catalyzes one of the major steps of the glycolytic-gluconeogenic pathway. Though it does catalyze the breakdown of glucose, it plays a particularly important role in fructose metabolism, which occurs mostly in the liver, renal cortex, and small intestinal mucosa. When fructose is absorbed, it is phosphorylated by fructokinase to form fructose 1-phosphate. Aldolase B then catalyzes F1P breakdown into glyceraldehyde and DHAP. After glyceraldehyde is phosphorylated by triose kinase to form G3P, both products can be used in the glycolytic-gluconeogenic pathway, that is, they can be modified to become either glucose or pyruvate. Though the mechanism aldolase B regulation is unknown, increased ALDOB gene transcription in animal livers has been noticed with an increase in dietary carbohydrates and decrease in glucagon concentration. Interactive pathway map Pathology Genetic mutations leading to defects in aldolase B result in a condition called hereditary fructose intolerance. Due to the lack of functional aldolase B, organisms with HFI cannot properly process F1P, which leads to an accumulation of F1P in bodily tissues. In addition to being toxic to cellular tissues, high levels of F1P traps phosphate in an unusable form that does not return to the general phosphate pool, resulting in depletion of both phosphate and ATP stores. The lack of readily available phosphate causes the cessation of glycogenolysis in the liver, which results in hypoglycemia. This accumulation also inhibits gluconeogenesis, further reducing the amount of readily available glucose. The