Metabolite damage

Many metabolites are chemically reactive and unstable and can react with other cell components or undergo unwanted modifications.

[1][2] Similarly to DNA and proteins, metabolites are prone to damage, which can occur chemically or through enzyme promiscuity.

[5] Typical types of chemical damage reactions that can occur to metabolites are racemization, rearrangement, elimination, photodissociation, addition, and condensation.

For example, the mitochondrial malate dehydrogenase reduces alpha-ketoglutarate to L-2-hydroxyglutarate 107 times less efficiently than its regular substrate oxaloacetate, but L-2-hydroxyglutarate can still accumulate to several grams per day in a human adult.

This compound is a dead-end metabolite and is not a substrate for any other enzyme in central metabolism, and its accumulation in humans causes L-2-Hydroxyglutaric aciduria.

[8] Directed overflow is a special case of damage pre-emption, where excess of a normal, but reactive metabolite could lead to toxic products.

[7] Mutations in the L2HGDH gene cause accumulation of L-2-hydroxyglutarate, which is a structural analog to glutamate and alpha-ketoglutarate and presumably inhibits other enzymes or transporters.

Examples of spontaneous chemical reactions a metabolite can undergo in vivo .
Damage-control systems for metabolites are similar to those for DNA or proteins. Damage reactions are represented by red arrows, whereas damage-control reactions are represented by blue arrows. The solid black arrow at the bottom indicates a normal enzyme reactions, and the dashed black arrow indicates a relatively slow spontaneous reaction. a) Damage by spontaneous reactions or enzymatic mistakes to macromolecules can be repaired by enzymatic control systems. b) The same principle applies to metabolites that are also prone to damage by enzymatic errors or spontaneous chemical reactions. Metabolite repair systems can either repair the damage or pre-empt it; directed overflow is a special case of damage pre-emption.