Mitochondrial trans-2-enoyl-CoA reductase (MECR) is an enzyme that in humans is encoded by the MECR gene. It belongs to the enzyme class of oxidoreductases and catalyzes the last step of mitochondrial fatty acid synthesis (mtFAS). In doing so, MECR makes the fatty acyl chain bound to mitochondrial acyl carrier protein (mtACP) available again for elongation. MECR thereby contributes to mitochondrial respiration and oxidative phosphorylation. Beyond its mitochondrial role, a cytosolic and nuclear isoform (cMECR) has been linked to PPARα-dependent transcription. Pathogenic variants in the MECR gene cause MEPAN syndrome.
Structure The MECR gene is located on chromosome 1 at locus p35.3 and contains 18 exons. Through alternative splicing, it produces nine protein-coding mRNA transcripts, which encode five isoforms of mitochondrial trans-2-enoyl-CoA reductase (MECR). The cMECR isoform lacks the N-terminal mitochondrial targeting sequence and localizes to the cytosol and nucleus.
MECR forms a dimer with a bent substrate-binding cavity between the two monomers that accommodates acyl substrates with carbon chain lengths from C4 to C16.
Reaction The reaction catalyzed by MECR can be summarized as follows: trans-2-enoyl-mtACP + NADPH + H+ → acyl-mtACP + NADP+
Function
The MECR gene encodes mitochondrial trans-2-enoyl-CoA reductase, which catalyzes the last step of mitochondrial fatty acid synthesis (mtFAS). Condensation in mtFAS produces an unsaturated fatty acyl chain bound to mtACP. It must undergo reduction and dehydration reactions to become saturated, making it available again for the next elongation cycle. MECR completes this process by reducing the trans double bond between carbon atoms 2 and 3, yielding a saturated acyl-mtACP species. NADPH, whose availability in mitochondria depends on NADK2, provides the required reducing power. Through repeated elongation cycles, mitochondrial fatty acid synthesis generates acyl-mtACP species with chain lengths from C2 to C16. Octanoyl-mtACP (C8) serves as the precursor for lipoic acid biosynthesis and subsequent protein lipoylation, which is essential for several mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, the branched-chain alpha-keto acid dehydrogenase complex, the 2-oxoadipate dehydrogenase complex, and the glycine cleavage system. Longer-chain acyl-mtACP species interact with LYRM proteins that are required for iron–sulfur cluster biogenesis and respiratory-chain assembly. In addition, mtFAS has been linked to mitochondrial translation and to levels of polyamines, including spermidine and spermine, as well as bioactive lipids such as lysophospholipids and sphingolipids.
MECR has also been reported to bind transcription factors of the PPAR family and activate transcription, suggesting a possible link between nuclear gene regulation and mtFAS.
Clinical significance Pathogenic variants in the MECR gene cause MEPAN syndrome, a rare autosomal recessive mitochondrial metabolic disorder characterized by childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. A later-onset phenotype with LHON-like optic neuropathy but without movement disorder or basal ganglia signal abnormalities has also been reported.
See also ACSF3 MCAT Combined malonic and methylmalonic aciduria (CMAMMA)
References
Further reading