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 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.

Keywords: 1,5-anhydroglucitol-6-phosphate; D-2-hydroxyglutaric aciduria; G6PC3; G6PT; NADP(H)X; PGM1; SGLT2 inhibitor; UGP2; enzyme promiscuity; galactose; inborn errors of metabolism; metabolite repair; neutropenia.

Figure 1

Metabolite repair and diseases of metabolite repair. Panel A, many enzymes catalyse side reactions leading to the production of abnormal metabolites. These metabolites may be toxic because they inhibit other enzymes. Fortunately, they are destroyed by metabolite repair enzymes and become unable to exert their toxic effects. Panel B, mutations inactivating the metabolite repair enzymes lead to various diseases such as L‐2‐hydroxyglutaric aciduria, to the neutropenia found in G6PC3 and G6PT deficiency and to the neurodegenerative disorders that are due to the deficiency in NAD(P)HX dehydratase or NAD(P)HX epimerase, as explained in the main text. Abbreviation: GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase

Figure 2

Role of G6PC3 and G6PT to maintain a low level of 1,5‐anhydroglucitol‐6‐phosphate and thereby prevent the toxic effects of this compound in neutrophils. 1,5‐anhydroglucitol, which is normally present in the blood at ≈ 100 μM, is phosphorylated to 1,5‐anhydroglucitol‐6‐phosphate by side activities of low‐Km hexokinases and of ADP dependent glucokinase (ADPGK). The glucose‐6‐phosphate transporter G6PT and G6PC3 collaborate to hydrolyse 1,5‐anhydroglucitol‐6‐phosphate, thereby preventing it to inhibit low Km hexokinases. This explains the lower glucose phosphorylation rates observed in neutrophils from patients with G6PC3 or G6PT transporter deficiency. G6PC3 was previously assumed to act as a glucose‐6‐phosphatase64 but as can be understood from this scheme, if this were the case, suppression of hydrolysis of glucose‐6‐phosphate should increase the flux through glycolysis and the pentose‐phosphate pathway, not decrease it (from Reference 26 with the required permission)

Figure 3

Production of D‐2‐hydroxyglutarate and its metabolism by the FAD‐dependent D‐2‐hydroxyglutarate dehydrogenase. The mitochondrial enzyme D‐2 hydroxyglutarate dehydrogenase catalyses the irreversible oxidation of D‐2‐hydroxyglutarate and its inactivation by mutations causes D‐2‐hydroxyglutaric aciduria type I. D‐2‐hydroxyglutarate can be produced from α‐ketoglutarate by four different enzymes. Hydroxyacid‐oxoacid transhydrogenase (HOT) oxidises 4‐hydroxybuyrate using alpha‐ketoglutarate as an electron acceptor. 3‐P‐glycerate dehydrogenase, an enzyme involved in the pathway of serine synthesis (not shown), has a side activity on α‐ketoglutarate due to the structural similarity of the latter with 3‐phosphohydroxypyruvate, the normal product of this enzyme. Mutated forms of IDH1 and IDH2, as described in various cancers, particularly in glioblastomas,51, 52 and in D‐2‐hydroxyglutaric aciduria type II (mutations in IDH2) very efficiently catalyse the reduction of α‐ketoglutarate to D‐2‐hydroxyglutarate; in this condition, the metabolic capacity of D‐2‐hydroxyglutarate dehydrogenase is exceeded and D‐2‐hydroxyglutarate accumulates

Figure 4

Enzyme promiscuity explains that galactose supplementation can correct glycosylation defects in PGM1 deficiency. UDP‐glucose pyrophosphorylase (UGP2), known to form UDP‐glucose (UDPGlc) from glucose‐1‐phosphate (Glc1P) and UTP, has a side activity (shown as dashed green arrows in panel B) that allows it to make UDP‐galactose (UDPGal) from UTP and galactose‐1‐phosphate (Gal1P). This side activity is essential to explain that galactose supplements correct the metabolic problems in PGM1 deficiency (illustrated by the low concentrations of the metabolites shown in grey in panel A). When PGM1 is deficient, cells do not have the possibility of making UDP‐glucose and UDP‐galactose from glucose because they cannot make glucose‐1‐phosphate from glucose‐6‐phosphate (Glc6P). Galactose supplementation raises the concentration of galactose‐1‐phosphate. Panel A, In the absence of the side activity of UGP2, galactose‐1‐phosphate cannot be converted to UDP‐galactose (in grey), since the co‐substrate of GALT, UDP‐glucose (in grey), is deficient. Panel B, However, when the side activity of UGP2 is taken into account (shown in green dashed arrows), the small production of UDP‐galactose from galactose‐1‐phosphate and UTP initiates a virtuous cycle that inflates the pool of UDP‐hexoses and explains the clinical benefits of galactose supplementation