TECR

TECR (trans-2,3-enoyl-CoA reductase) is a lipid-metabolic enzyme that catalyzes the reduction step in very-long-chain fatty acid synthesis, and its activity governs cellular processes ranging from neuronal function to vascular barrier integrity and cell death (PMID:21212097, PMID:35465346, PMID:40419770). A homozygous missense mutation (p.Pro182Leu) causes autosomal recessive non-syndromic intellectual disability, establishing TECR loss of function as a cause of Mendelian neurodevelopmental disease (PMID:21212097). In endothelial cells, TECR-dependent very-long-chain fatty acid synthesis sustains the omega-3 fatty acid content that suppresses caveolae formation; endothelial-specific deletion delays vascular sprouting and increases transcytosis across the blood-brain barrier without disrupting tight junctions (PMID:35465346). TECR also enables a nonapoptotic, non-ferroptotic cell death program triggered by tegavivint and CIL56 in sarcoma and other cancer cells, operating through synthesis of the saturated fatty acid palmitate (PMID:40419770).

1. 2011 Medium

   Establishing that TECR loss of function causes human disease moved it from a metabolic enzyme to a clinically relevant neurodevelopmental gene.

   Evidence Exome sequencing with linkage/homozygosity mapping and segregation analysis in an affected sibship

   PMID:21212097

   Open questions at the time

   • Single family with no functional rescue experiment
   • Mechanism linking enzyme deficiency to synaptic/neuronal dysfunction not defined
   • Effect of the mutation on enzymatic activity not directly measured
2. 2022 Medium

   Endothelial-specific deletion connected TECR's very-long-chain fatty acid synthesis to vascular barrier control, showing the enzyme regulates caveolae-mediated transcytosis via lipid composition rather than tight junctions.

   Evidence Endothelial-cell-specific conditional knockout in mice with lipidomics, single-cell transcriptomics, and vascular permeability assays

   PMID:35465346

   Open questions at the time

   • Single lab; molecular link between omega-3 content and caveolae suppression not fully resolved
   • Whether the same lipid mechanism operates in non-endothelial tissues unknown
3. 2025 Medium

   Loss-of-function studies placed TECR within a distinct cell death pathway, showing its palmitate-synthesis activity is required for a nonapoptotic, non-ferroptotic lethal program in cancer cells.

   Evidence Genetic TECR loss-of-function with cell death modality assays and lipid metabolite profiling in sarcoma and other cancer cells

   PMID:40419770

   Open questions at the time

   • Single lab; downstream effectors of palmitate-driven death not identified
   • Direct enzymatic role of TECR in generating the lethal lipid species not biochemically reconstituted
   • Generality across tumor types beyond those tested unknown

• How a single very-long-chain fatty acid reductase coordinates such divergent outcomes — neuronal function, BBB integrity, and cell death — through distinct lipid products remains unresolved.
• No unifying biochemical model linking TECR enzyme activity to its different downstream lipid species across contexts
• No structural characterization in the corpus