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

Ernst R Werner,Sabrina Sailer,Katrin Watschinger,Johannes Berger,Martin Hermann,Katharina Lackner,Georg Golderer,Stefan Coassin,Gabriele Werner-Felmayer,Jakob Koch,Nicolas Hulo,Raphael A Zoeller,Markus A Keller

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.

Highlights

A significant fraction of the glycerophospholipids in the human body is composed of plasmalogens, in the brain, cardiac, and immune cell membranes
We present evidence that the transmembrane protein 189 gene (TMEM189; Tmem189 for the murine gene) encodes PEDS activity, that the conserved eight histidines found in a conserved motif occurring in TMEM189 proteins are essential for PEDS enzymatic activity, and that mice homozygous for an inactivated Tmem189 gene have dramatically lower plasmalogen levels
We show that the TMEM189 gene is essential for the introduction of the alk-1′-enyl ether bond to form plasmalogens

Summary

Introduction

A significant fraction of the glycerophospholipids in the human body is composed of plasmalogens, in the brain, cardiac, and immune cell membranes. SELENOI, which encodes ethanolamine phosphotransferase 1, has been found to play a crucial role in plasmalogen biosynthesis [15]; the gene coding for the enzyme generating the first plasmalogen in the pathway, plasmanylethanolamine desaturase (PEDS, E.C. 1.14.99.19), has not yet been identified This enzymatic reaction is specific for plasmalogen biosynthesis. We assign one of those predicted membrane proteins (transmembrane protein 189; TMEM189) to one of the enzymatic reactions with an uncharacterized gene (plasmanylethanolamine desaturase). This enzyme catalyzes the final step in the biosynthesis of plasmalogens, an abundant class of glycerophospholipids that is depleted in such diseases as Alzheimer’s. BIOCHEMISTRY phosphocholine head group class) are not substrates of the enzyme and must be synthesized from plasmenylethanolamines [2]

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