Our work is focused on the elucidation of inborn errors of metabolism, i.e. diseases due to a genetic defect making that an enzyme of intermediary metabolism is deficient. In this context, one of our goals is to identify the gene encoding enzymes for which this identity is unknown. Another goal is to identify new enzymes, most particularly ‘metabolite repair enzymes’.
Our cells are chemical factories that make hundreds of compounds thanks to enzymes, each of which allows a specific chemical reaction to proceed. Enzymatic reactions are organized in ‘pathways’, that allow the conversion of a major molecule into another one. A well-known example of metabolic pathway is glycolysis, which allows us to extract energy from glucose while converting it to pyruvate thanks to ten successive enzymatic reactions. All together, enzymatic reactions and the metabolic intermediates they form make up what is known as intermediary Metabolism.
Diseases of intermediary metabolism are known as inborn errors of metabolism. Each of them is due to mutations in the gene that encodes an enzyme involved in intermediary metabolism. In most cases, the mutations make that the enzyme is inactive or less active than normal. This enzyme deficiency interrupts the flow of metabolites in the metabolic pathway to which the enzyme belongs. Just as when a dam is built in a river, the water level will increase upstream and will decrease downstream, the metabolites upstream of the enzymatic block accumulate and those downstream of the block become scarce. The accumulation of some metabolites may have toxic effects. The absence of the endproduct of the pathway may also be a problem, which in some cases can be solved by providing supplements of the endproduct. Thus, defects in the synthesis of the amino acid L-serine can be treated by providing supplements of this amino acid in the food. All this shows how important it is to determine the exact location of the metabolic block in a patient with an inborn error of metabolism, because this information is of tremendous help for his/her treatment.
Diagnosis of enzyme defects relies more and more on the identification of mutations in the genome : if we know the function of the enzyme that is mutated, we have a diagnosis. Unfortunately, for quite a few enzymes that we know to be present in our cells, we simply do not know the encoding gene. Even worse, we are probably still ignoring the existence of numerous enzymes that participate in intermediary metabolism. Filling these two gaps is the goal of our research. As an example, we have identified the gene encoding the enzymes that destroy L-2-hydroxyglutarate, D-2-hydroxyglutarate, and phosphohydroxylysine, and the enzyme that makes N-acetylaspartate. Thanks to this information, the corresponding metabolic diseases, in which L-2-hydroxyglutarate, D-2-hydroxyglutarate, and phosphohydroxylysine accumulate or N-acetylaspartate is deficient, can be diagnosed by mutation search on genomic DNA.
Identifying totally new enzymes is our other goal. In that respect, we have recently discovered what we have called ‘metabolite repair’ enzymes. The starting point of this discovery was a metabolic disease, L-2-hydroxyglutaric aciduria, in which a metabolite (L-2-hydroxyglutarate) that does not belong to a classical metabolic pathway accumulates. It turned out that this metabolite is made by a ‘side activity’ of an enzyme that serves to make another metabolite (L-malate). As we cannot prevent this enzyme from making this mistake, we have a ‘metabolite repair’ enzyme that destroys the abnormal metabolite. If this enzyme is missing, L-2-hydroxyglutarate accumulates and damages the brain. Knowing that numerous enzymes (slowly) catalyze side-reactions, we have searched for new metabolite repair enzymes. We have in this way discovered several new enzymes.
Am J Hum Genet. 2021; 108(6):1151-1160.
Blood. 2020; 136(9):1033-1043.
J Inherit Metab Dis. 2020; 43(1):14-24.
Trends Biochem Sci. 2020; 45(3):228-243.
Peracchi A, Veiga-da-Cunha M, Kuhara T, Ellens KW, Paczia N, Stroobant V, Seliga AK, Marlaire S, Jaisson S, Bommer GT, Sun J, Huebner K, Linster CL, Cooper AJL, Van Schaftingen E.
Proc Natl Acad Sci USA. 2017; 114(16):E3233-42.
Nat Chem Biol. 2016; 12(8):601-7.
Rzem R, Achouri Y, Marbaix E, Schakman O, Wiame E, Marie S, Gailly P, Vincent MF, Veiga-da-Cunha M, Van Schaftingen E.
PLoS One. 2015; 10(3):e0119540.
Van Schaftingen E, Veiga-da-Cunha M, Linster CL.
J Inherit Metab Dis. 2015; 38(4):721-7.
Barbier T, Collard F, Zúñiga-Ripa A, Moriyón I, Godard T, Becker J, Wittmann C, Van Schaftingen E, Letesson JJ.
Proc Natl Acad Sci U S A. 2014; 111(50):17815-20.
Veiga-da-Cunha M, Chevalier N, Stroobant V, Vertommen D, Van Schaftingen E.
J Biol Chem. 2014; 289(28):19726-36.
Marbaix AY, Tyteca D, Niehaus TD, Hanson AD, Linster CL, Van Schaftingen E.
Biochem J. 2014; 460(1):49-58.
Gerin I, Noël G, Bolsée J, Haumont O, Van Schaftingen E, Bommer GT.
Biochem J. 2014; 458(3):439-48.
Drozak J, Veiga-da-Cunha M, Kadziolka B, Van Schaftingen E.
FEBS J. 2014; 281(6):1585-97.
Marlaire S, Van Schaftingen E, Veiga-da-Cunha M.
J Inherit Metab Dis. 2014; 37(1):13-9.
Kraoua I, Wiame E, Kraoua L, Nasrallah F, Benrhouma H, Rouissi A, Turki I, Chaabouni H, Briand G, Kaabachi N, Van Schaftingen E, Gouider-Khouja N.
Neuropediatrics. 2013; 44(5):281-5.
Linster CL, Van Schaftingen E, Hanson AD.
Nat Chem Biol. 2013; 9(2):72-80.
Van Schaftingen E, Rzem R, Marbaix A, Collard F, Veiga-da-Cunha M, Linster CL.
J Inherit Metab Dis. 2013; 36(3):427-34.
Tahay G, Wiame E, Tyteca D, Courtoy PJ, Van Schaftingen E.
Biochem J. 2012; 441(1):105-12.
Veiga-da-Cunha M, Hadi F, Balligand T, Stroobant V, Van Schaftingen E.
J Biol Chem. 2012; 287(10):7246-55.
Linster CL, Noël G, Stroobant V, Vertommen D, Vincent MF, Bommer GT, Veiga-da-Cunha M, Van Schaftingen E.
J Biol Chem. 2011; 286(50):42992-3003.
Marbaix AY, Noël G, Detroux AM, Vertommen D, Van Schaftingen E, Linster CL.
J Biol Chem. 2011; 286(48):41246-52.
Kranendijk M, Struys EA, van Schaftingen E, Gibson KM, Kanhai WA, van der Knaap MS, Amiel J, Buist NR, Das AM, de Klerk JB, Feigenbaum AS, Grange DK, Hofstede FC, Holme E, Kirk EP, Korman SH, Morava E, Morris A, Smeitink J, Sukhai RN, Vallance H, Jakobs C, et al.
Science. 2010; 330(6002):336.
Collard F, Stroobant V, Lamosa P, Kapanda CN, Lambert DM, Muccioli GG, Poupaert JH, Opperdoes F, Van Schaftingen E.
J Biol Chem. 2010; 285(39):29826-33.
Veiga-da-Cunha M, Tyteca D, Stroobant V, Courtoy PJ, Opperdoes FR, Van Schaftingen E.
J Biol Chem. 2010; 285(24):18888-98.
Drozak J, Veiga-da-Cunha M, Vertommen D, Stroobant V, Van Schaftingen E.
J Biol Chem. 2010; 285(13):9346-56.
Wiame E, Tyteca D, Pierrot N, Collard F, Amyere M, Noel G, Desmedt J, Nassogne MC, Vikkula M, Octave JN, Vincent MF, Courtoy PJ, Boltshauser E, van Schaftingen E.
Biochem J. 2009; 425(1):127-36.
Veiga-da-Cunha M, Vleugels W, Maliekal P, Matthijs G, Van Schaftingen E.
J Biol Chem. 2008; 283(49):33988-93.
Veiga da-Cunha M, Jacquemin P, Delpierre G, Godfraind C, Théate I, Vertommen D, Clotman F, Lemaigre F, Devuyst O, Van Schaftingen E.
Biochem J. 2006; 399(2):257-64.
Rzem R, Veiga-da-Cunha M, Noël G, Goffette S, Nassogne MC, Tabarki B, Schöller C, Marquardt T, Vikkula M, Van Schaftingen E.
Proc Natl Acad Sci U S A. 2004; 101(48):16849-54.
METABOLITE REPAIR AND INBORN ERRORS OF METABOLISM