Metabolite Repair Enzymes Control Metabolic Damage in Glycolysis.

Hundreds of metabolic enzymes work together smoothly in a cell. These enzymes are highly specific. Nevertheless, under physiological conditions, many perform side-reactions at low rates, producing potentially toxic side-products. An increasing number of metabolite repair enzymes are being discovered that serve to eliminate these noncanonical metabolites. Some of these enzymes are extraordinarily conserved, and their deficiency can lead to diseases in humans or embryonic lethality in mice, indicating their central role in cellular metabolism. We discuss how metabolite repair enzymes eliminate glycolytic side-products and prevent negative interference within and beyond this core metabolic pathway. Extrapolating from the number of metabolite repair enzymes involved in glycolysis, hundreds more likely remain to be discovered that protect a wide range of metabolic pathways. Many noncanonical metabolites are produced under physiological conditions by side-activities of enzymes and by spontaneous reactions. Many of these noncanonical metabolites are repaired or reconverted to useful metabolites by metabolite repair enzymes. A single repair enzyme may catalyze several repair reactions. Metabolite repair reactions are sometimes catalyzed by a side-activity of a canonical enzyme (i.e., FBP1/2, PGK). Major pathways may require multiple metabolite repair enzymes. In the case of glycolysis, 10 canonical glycolytic enzymes are assisted by 10 repair enzymes (G6PC3, PGP, ACYP1, NAXD, NAXE, L2HGDH, GLO1, GLO2, FN3K, MDP-1) and a transporter (G6PT). Deficiencies in several of the metabolite repair enzymes can cause disease in humans or are lethal in higher vertebrates. [ABSTRACT FROM AUTHOR]