Inborn errors of metabolite repair

Abstract

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 nonclassical 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. K E Y W O R D S1,5-anhydroglucitol-6-phosphate, D-2-hydroxyglutaric aciduria, enzyme promiscuity, G6PC3, G6PT, galactose, inborn errors of metabolism, metabolite repair, NADP(H)X, neutropenia, PGM1, SGLT2 inhibitor, UGP2Abbreviations: D2HGDH, D-2-hydroxyglutarate dehydrogenase; G6PC3, ubiquitous glucose-6-phosphatase; G6PT, glucose-6-phosphate translocase of the endoplasmic

An international classification of inherited metabolic disorders (ICIMD)

“…12. Disorders of metabolite repair/proofreading There is a growing number of diseases affecting metabolite repair or proofreading 14 ; enzymes deficient in these conditions do not have a function in a particular metabolic pathway but remove detrimental metabolites generated as side reactions of other enzymes. As the number of these diseases is expected to increase, we felt that they deserve "their own" category.…”

Enzyme promiscuity, metabolite damage, and metabolite damage control systems of the tricarboxylic acid cycle

“…Because disruption of metabolite damage control systems is the cause of several inborn errors of metabolism in humans [131], much work in this area has focused on mammalian systems. These studies have been instrumental in popularizing the concept of metabolite damage and repair over the past ~ 15 years and have made significant contributions to our understanding of human pathology and metabolism in general.…”

Hypothesis: A Novel Neuroprotective Role for Glucose-6-phosphatase (G6PC3) in Brain—To Maintain Energy-Dependent Functions Including Cognitive Processes

“…A critically-important function for G6PC3 in neutrophils was recently discovered in the elegant, rigorous studies by Veiga-da-Cunha et al [18,34] who investigated the metabolic basis for severe neutropenia in patients with mutations that inactivate G6PC3. They identified a novel physiological role for G6PC3 in neutrophils, i.e., serving as a metabolite repair enzyme (reviewed by [35][36][37]) to eliminate a toxic metabolite 1,5-anhydroglucitol-6-phosphate (AG6P) of the glucose analog 1,5-anhydroglucitol (AG) that causes neutrophil dysfunction and neutrophil death. Astrocytes in brain also express the G6PC3 isoform, implicating a novel function as a repair enzyme beyond hydrolysis of Glc-6-P.…”

“…Human chronic myelogenous erythroleukemia (K-562) cells also convert [U- 13 C]glucose to [U- 13 C]AG in extremely small amounts, 7 × 10 -7 mol AG per mole of glucose consumed in 48 h [71]; these cells also took up AF and rapidly converted it to AG indicating reductase activity. Low rates of generation of AF and AG from endogenous compounds are notable because metabolite repair enzymes remove toxic compounds generated in very small amounts by side reactions of enzymes of intermediary metabolism [35][36][37].…”

“…As discussed above, G6PT and G6PC3 in astrocytes and non-specific phosphatase activities in brain cells are too low to interfere with the DG/FDG method during the routine experimental interval. However, metabolite repair enzymes are capable of removing low concentrations of products of side reactions, and low G6PT/G6PC3 activities are sufficient unless there are mutations that eliminate their activity [35][36][37]145]. Astrocytes can take up and phosphorylate AG, and they can also hydrolyze AG6P.…”