Inborn errors of metabolite repair

It is traditionally assumed that enzymes of intermediary metabolism are extremely specific and that this is sufficient to prevent the production of useless and/or toxic side‐products. Recent work indicates that this statement is not entirely correct. In reality, enzymes are not strictly specific, they often display weak side activities on intracellular metabolites (substrate promiscuity) that resemble their physiological substrate or slowly catalyse abnormal reactions on their physiological substrate (catalytic promiscuity). They thereby produce non‐classical metabolites that are not efficiently metabolised by conventional enzymes. In an increasing number of cases, metabolite repair enzymes are being discovered that serve to eliminate these non‐classical metabolites and prevent their accumulation. Metabolite repair enzymes also eliminate non‐classical metabolites that are formed through spontaneous (ie, not enzyme‐catalysed) reactions. Importantly, genetic deficiencies in several metabolite repair enzymes lead to ‘inborn errors of metabolite repair’, such as L‐2‐hydroxyglutaric aciduria, D‐2‐hydroxyglutaric aciduria, ‘ubiquitous glucose‐6‐phosphatase’ (G6PC3) deficiency, the neutropenia present in Glycogen Storage Disease type Ib or defects in the enzymes that repair the hydrated forms of NADH or NADPH. Metabolite repair defects may be difficult to identify as such, because the mutated enzymes are non‐classical enzymes that act on non‐classical metabolites, which in some cases accumulate only inside the cells, and at rather low, yet toxic, concentrations. It is therefore likely that many additional metabolite repair enzymes remain to be discovered and that many diseases of metabolite repair still await elucidation.