title: Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway.
abstract: The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic β-cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D.
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich 8091, Switzerland.|Center for Integrative Human Physiology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Irina
authors.initials: I
authors.lastname: Alecu
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck D-23562, Germany.
authors.forename: Alaa
authors.initials: A
authors.lastname: Othman
authors.affiliation: LIMES Life and Medical Sciences Institute, University of Bonn, Bonn 53115, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Penno
authors.affiliation: Institute for Chemistry, Humboldt Universität zu Berlin, Berlin D-12489, Germany.|Chemistry Department, Suez Canal University, Ismailia 41522, Egypt.
authors.forename: Essa M
authors.initials: EM
authors.lastname: Saied
authors.affiliation: Institute for Chemistry, Humboldt Universität zu Berlin, Berlin D-12489, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Arenz
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich 8091, Switzerland.|Center for Integrative Human Physiology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich 8091, Switzerland thorsten.hornemann@usz.ch.|Center for Integrative Human Physiology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D009154:Mutation; D010084:Oxidation-Reduction; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism*
chemical_list: C512110:Cyp4a10 protein, mouse; D013107:Sphingolipids; D003577:Cytochrome P-450 Enzyme System; D051102:Serine C-Palmitoyltransferase
keywords: diabetes; lipids/chemistry; mass spectrometry; metabolic pathway; neurotoxicity; obesity; sphingolipids