2. Academic Validation
  3. The TMEM189 gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens

The TMEM189 gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens

  • Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):7792-7798. doi: 10.1073/pnas.1917461117.
Ernst R Werner 1,  Markus A Keller 2,  Sabrina Sailer 3,  Katharina Lackner 3,  Jakob Koch 2,  Martin Hermann 4,  Stefan Coassin 5,  Georg Golderer 3,  Gabriele Werner-Felmayer 3,  Raphael A Zoeller 6,  Nicolas Hulo 7,  Johannes Berger 8,  Katrin Watschinger 1
Affiliations

Affiliations

  • 1 Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, A-6020 Innsbruck, Austria; ernst.r.werner@i-med.ac.at katrin.watschinger@i-med.ac.at.
  • 2 Institute of Human Genetics, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
  • 3 Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
  • 4 University Clinic for Anesthesiology and General Intensive Care Medicine, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
  • 5 Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
  • 6 Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118.
  • 7 Institute of Genetics and Genomics, University of Geneva, 1211 Geneva 4, Switzerland.
  • 8 Department of Pathobiology of the Nervous System, Medical University of Vienna, 1090 Vienna, Austria.
PMID: 32209662 DOI: 10.1073/pnas.1917461117
Abstract

A significant fraction of the glycerophospholipids in the human body is composed of plasmalogens, particularly in the brain, cardiac, and immune cell membranes. A decline in these lipids has been observed in such diseases as Alzheimer's and chronic obstructive pulmonary disease. Plasmalogens contain a characteristic 1-O-alk-1'-enyl ether (vinyl ether) double bond that confers special biophysical, biochemical, and chemical properties to these lipids. However, the genetics of their biosynthesis is not fully understood, since no gene has been identified that encodes plasmanylethanolamine desaturase (E.C. 1.14.99.19), the Enzyme introducing the crucial alk-1'-enyl ether double bond. The present work identifies this gene as transmembrane protein 189 (TMEM189). Inactivation of the TMEM189 gene in human HAP1 cells led to a total loss of plasmanylethanolamine desaturase activity, strongly decreased plasmalogen levels, and accumulation of plasmanylethanolamine substrates and resulted in an inability of these cells to form labeled plasmalogens from labeled alkylglycerols. Transient expression of TMEM189 protein, but not of Other selected desaturases, recovered this deficit. TMEM189 proteins contain a conserved protein motif (pfam10520) with eight conserved histidines that is shared by an alternative type of plant desaturase but not by Other mammalian proteins. Each of these histidines is essential for plasmanylethanolamine desaturase activity. Mice homozygous for an inactivated Tmem189 gene lacked plasmanylethanolamine desaturase activity and had dramatically lowered plasmalogen levels in their tissues. These results assign the TMEM189 gene to plasmanylethanolamine desaturase and suggest that the previously characterized phenotype of Tmem189-deficient mice may be caused by a lack of plasmalogens.

Keywords

ether lipid; plasmalogen; plasmanylethanolamine desaturase; transmembrane protein 189.

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