TECR

TECR is the sole mammalian trans-2,3-enoyl-CoA reductase that catalyzes the final NADPH-dependent reduction step of the very-long-chain fatty acid (VLCFA) elongation cycle, converting trans-2,3-enoyl-CoA intermediates to saturated acyl-CoAs (PMID:12482854). Beyond VLCFA synthesis, TECR functions in the sphingosine 1-phosphate degradation pathway by reducing trans-2-hexadecenoyl-CoA to palmitoyl-CoA, thereby linking sphingolipid catabolism to fatty acid elongation (PMID:25049234). A homozygous P182L missense mutation causes autosomal recessive non-syndromic intellectual disability, reduces enzymatic activity and protein stability, and depletes C24 sphingomyelin and ceramide species (PMID:21212097, PMID:24220030). In brain endothelial cells, TECR-dependent production of omega-3 fatty acids suppresses caveolae-mediated transcytosis and is required for blood–brain barrier integrity during development (PMID:35465346).

1. 2002 High

   The fundamental enzymatic identity of TECR was established: it catalyzes the trans-2,3-enoyl-CoA reduction that constitutes the fourth and final step of the VLCFA elongation cycle, resolving which mammalian gene encodes this activity.

   Evidence cDNA cloning, overexpression, and in vitro enzymatic assay measuring trans-2,3-enoyl-CoA reductase activity

   PMID:12482854

   Open questions at the time

   • Whether TECR is the sole trans-2,3-enoyl-CoA reductase in vivo or shares redundancy with paralogs
   • No structural model of substrate binding or NADPH cofactor interaction
   • Physiological consequences of loss of function in mammals unknown
2. 2011 Medium

   TECR was linked to human disease when a homozygous P182L missense mutation was identified as the cause of autosomal recessive non-syndromic intellectual disability, demonstrating that TECR function is essential for normal neurodevelopment.

   Evidence Exome sequencing combined with linkage/homozygosity mapping in a consanguineous family; segregation in five affected versus eight unaffected siblings

   PMID:21212097

   Open questions at the time

   • Based on a single family — no independent replication in additional kindreds at that time
   • Biochemical impact of P182L on enzyme activity and lipid composition not yet characterized
   • Neurodevelopmental mechanism (which lipid species, which cell types) undefined
3. 2013 High

   The molecular pathogenesis of the P182L mutation was resolved: it reduces trans-2,3-enoyl-CoA reductase activity and protein stability, impairs VLCFA synthesis, and depletes C24 sphingomyelin and ceramide, directly linking enzymatic loss of function to altered sphingolipid composition in patient cells.

   Evidence Yeast complementation (TSC13 deletion), mammalian cell transfection, enzymatic activity assays, and lipidomic profiling of patient-derived B-lymphoblastoid cells

   PMID:24220030

   Open questions at the time

   • Neuron- or brain-specific lipid changes not assessed
   • No in vivo mammalian model of the P182L mutation
   • Why C24 species are preferentially affected while shorter-chain species are spared is unclear
4. 2014 High

   TECR was shown to have a second metabolic role: it is the missing trans-2-enoyl-CoA reductase in the sphingosine 1-phosphate degradation pathway, reducing trans-2-hexadecenoyl-CoA to palmitoyl-CoA, thereby linking sphingolipid catabolism to the fatty acid elongation machinery.

   Evidence Yeast complementation of TSC13 deletion and siRNA knockdown in HeLa cells with lipid metabolite analysis

   PMID:25049234

   Open questions at the time

   • Relative contribution of this pathway versus VLCFA elongation to disease phenotype unknown
   • Tissue-specific importance of S1P degradation via TECR not defined
   • Kinetic parameters for trans-2-hexadecenoyl-CoA versus longer-chain substrates not compared
5. 2022 High

   An endothelial-specific role for TECR was uncovered: it is required for blood–brain barrier integrity and developmental angiogenesis by supplying omega-3 fatty acids that suppress caveolae-dependent transcytosis, shifting the understanding of TECR from a housekeeping lipid enzyme to a cell-type-specific regulator of vascular permeability.

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

   PMID:35465346

   Open questions at the time

   • Whether the BBB phenotype contributes to the intellectual disability seen in TECR patients is untested
   • Which specific omega-3 VLCFA species suppress caveolae formation is not defined at single-species resolution
   • Tight-junction independence of the phenotype needs confirmation in other BBB models

• Key unresolved questions include the neuronal versus endothelial contributions to TECR-linked intellectual disability, the structural basis of substrate specificity and the P182L defect, and whether TECR has additional cell-type-specific roles beyond brain endothelium and neurons.
• No high-resolution structure of mammalian TECR
• Neuron-specific knockout phenotype not reported
• No therapeutic strategies explored for TECR deficiency