title: Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis.
abstract: X-linked adrenoleukodystrophy (X-ALD) is a neurometabolic disease that is caused by mutations in the ABCD1 gene. ABCD1 protein deficiency impairs peroxisomal very long-chain fatty acid (VLCFA) degradation resulting in increased cytosolic VLCFA-CoA levels, which are further elongated by the VLCFA-specific elongase, ELOVL1. In adulthood, X-ALD most commonly manifests as a gradually progressive myelopathy (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1. Although, in a clinical trial, bezafibrate was unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients, inhibition of ELOVL1 remains an attractive therapeutic option. In this study, we investigated the kinetic characteristics of ELOVL1 using X-ALD fibroblasts and microsomal fractions from ELOVL1 over-expressing HEK293 cell lines and analyzed the inhibition kinetics of a series of fibrates. Our data show that the CoA esters of bezafibrate and gemfibrozil reduce chain elongation by specifically inhibiting ELOVL1. These fibrates can therefore serve as lead compounds for the development of more potent and more specific inhibitors for ELOVL1.
authors.affiliation: Genetic Metabolic Diseases, Department of Pediatrics/Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Martin J A
authors.initials: MJ
authors.lastname: Schackmann
authors.affiliation: Genetic Metabolic Diseases, Department of Pediatrics/Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Ofman
authors.affiliation: Genetic Metabolic Diseases, Department of Pediatrics/Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Inge M E
authors.initials: IM
authors.lastname: Dijkstra
authors.affiliation: Genetic Metabolic Diseases, Department of Pediatrics/Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.affiliation: Genetic Metabolic Diseases, Department of Pediatrics/Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Electronic address: s.kemp@amc.uva.nl.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000326:Adrenoleukodystrophy / Q000201:enzymology* / Q000235:genetics; D001629:Bezafibrate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000096:biosynthesis*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D015248:Gemfibrozil / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D014162:Transfection
chemical_list: C000630949:ELOVL1 protein, human; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D015248:Gemfibrozil; D001629:Bezafibrate
keywords: Adrenoleukodystrophy; Fatty acids; Fibrates; Peroxisome; Substrate-reduction