ECHS1 explained

Enoyl Coenzyme A hydratase, short chain, 1, mitochondrial, also known as ECHS1, is a human gene.^[1]

The protein encoded by this gene functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. It catalyzes the hydration of 2-trans-enoyl-coenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs. The gene product is a member of the hydratase/isomerase superfamily. It localizes to the mitochondrial matrix. Transcript variants utilizing alternative transcription initiation sites have been described in the literature.^[2]

Structure

The ECHS1 gene is approximately 11 kb in length, and is composed of eight exons, with exons I and VIII containing the 5'- and 3'-untranslated regions, respectively. There are two major transcription start sites, located 62 and 63 bp upstream of the translation codon, were mapped by primer extension analysis. The 5'-flanking region of the ECHS1 gene is GC-rich and contains several copies of the SP1 binding motive but no typical TATA or CAAT boxes are apparent. Alu repeat elements have been identified within the region -1052/-770 relative to the cap site and in intron 7.^[3] The precursor polypeptide contains 290 amino acid residues, with an N-terminal mitochondrial targeting domain (1-27,28,29) leading to a ragged mature N-terminus. The mRNA has a 5'-untranslated sequence of 21 bp and a 3'-untranslated sequence of 391 bp.^[4]

Function

Enoyl-CoA hydratase (ECH) catalyzes the second step in beta-oxidation pathway of fatty acid metabolism. The enzyme is involved in the formation of a β-hydroxyacyl-CoA thioester. The two catalytic glutamic acid residues are believed to act in concert to activate a water molecule, while Gly-141 is proposed to be involved in substrate activation. There are two potent inhibitors of ECHS, which irreversibly inactivate the enzyme via covalent adduct formation.^[5]

Clinical significance

Enoyl-CoA hydratase short chain has been confirmed to interact with STAT3, such that ECHS1 specifically represses STAT3 activity by inhibiting STAT3 phosphorylation.^[6] STAT3 can act as both an oncogene and a tumor suppressor. ECHS1 itself has shown to occur in many cancers, particularly in hypatocellular carcinoma (HCC) development;^[7] both exogenous and endogenous forms of ECHS1 bind to HBs and induce apoptosis as a result. This means that ECHS1 may be used in the future as a therapy for patients with HBV-related hepatitis or HCC.^[8]

Further reading

• Hochstrasser DF, Frutiger S, Paquet N . Human liver protein map: a reference database established by microsequencing and gel comparison. . Electrophoresis . 13 . 12 . 992–1001 . 1993 . 1286669 . 10.1002/elps.11501301201 . 23518983 . etal.
• Dawson SJ, White LA . Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin. . J. Infect. . 24 . 3 . 317–20 . 1992 . 1602151 . 10.1016/S0163-4453(05)80037-4 .
• Li J, Norwood DL, Mao LF, Schulz H . Mitochondrial metabolism of valproic acid. . Biochemistry . 30 . 2 . 388–94 . 1991 . 1988037 . 10.1021/bi00216a012 .
• Jackson S, Schaefer J, Middleton B, Turnbull DM . Characterisation of a novel enzyme of human fatty acid beta-oxidation: a matrix-associated, mitochondrial 2-enoyl-CoA hydratase. . Biochem. Biophys. Res. Commun. . 214 . 1 . 247–53 . 1995 . 7669045 . 10.1006/bbrc.1995.2281 .
• Kanazawa M, Ohtake A, Abe H . Molecular cloning and sequence analysis of the cDNA for human mitochondrial short-chain enoyl-CoA hydratase. . Enzyme and Protein. 47 . 1 . 9–13 . 1994 . 8012501 . 10.1159/000468650. 2024-06-08 . etal.
• Janssen U, Davis EM, Le Beau MM, Stoffel W . Human mitochondrial enoyl-CoA hydratase gene (ECHS1): structural organization and assignment to chromosome 10q26.2-q26.3. . Genomics . 40 . 3 . 470–5 . 1997 . 9073515 . 10.1006/geno.1996.4597 .
• Hubbard MJ, McHugh NJ . Human ERp29: isolation, primary structural characterisation and two-dimensional gel mapping. . Electrophoresis . 21 . 17 . 3785–96 . 2001 . 11271497 . 10.1002/1522-2683(200011)21:17<3785::AID-ELPS3785>3.0.CO;2-2 . 42538820 .
• Jiang LQ, Wen SJ, Wang HY, Chen LY . Screening the proteins that interact with calpain in a human heart cDNA library using a yeast two-hybrid system. . Hypertens. Res. . 25 . 4 . 647–52 . 2003 . 12358155 . 10.1291/hypres.25.647 . free .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . etal . 2002PNAS...9916899M. free .
• Deloukas P, Earthrowl ME, Grafham DV . The DNA sequence and comparative analysis of human chromosome 10. . Nature . 429 . 6990 . 375–81 . 2004 . 15164054 . 10.1038/nature02462 . etal. 2004Natur.429..375D . free .
• Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
• Bruneel A, Labas V, Mailloux A . Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis. . Proteomics . 5 . 15 . 3876–84 . 2006 . 16130169 . 10.1002/pmic.200401239 . 26007149 . etal.
• Ewing RM, Chu P, Elisma F . Large-scale mapping of human protein-protein interactions by mass spectrometry. . Mol. Syst. Biol. . 3 . 1. 89 . 2007 . 17353931 . 10.1038/msb4100134 . 1847948 . etal.
• Takahashi M, Watari E, Shinya E . Suppression of virus replication via down-modulation of mitochondrial short chain enoyl-CoA hydratase in human glioblastoma cells. . Antiviral Res. . 75 . 2 . 152–8 . 2007 . 17395278 . 10.1016/j.antiviral.2007.02.002 . etal.

Notes and References

1. Web site: Entrez Gene: ECHS1 enoyl Coenzyme A hydratase, short chain, 1, mitochondrial.
2. Web site: Entrez Gene: ECHS1 enoyl Coenzyme A hydratase, short chain, 1, mitochondrial.
3. 9073515. 1997. Janssen. U. Human mitochondrial enoyl-CoA hydratase gene (ECHS1): Structural organization and assignment to chromosome 10q26.2-q26.3. Genomics. 40. 3. 470–5. Davis. E. M.. Le Beau. M. M.. Stoffel. W. 10.1006/geno.1996.4597.
4. 8012501. 1993. Kanazawa. M. Molecular cloning and sequence analysis of the cDNA for human mitochondrial short-chain enoyl-CoA hydratase. Enzyme & Protein. 47. 1. 9–13. Ohtake. A. Abe. H. Yamamoto. S. Satoh. Y. Takayanagi. M. Niimi. H. Mori. M. Hashimoto. T. 10.1159/000468650. 2024-06-08.
5. 12467702. 2003. Agnihotri. G. Enoyl-CoA hydratase. Reaction, mechanism, and inhibition. Bioorganic & Medicinal Chemistry. 11. 1. 9–20. Liu. H. W. . 10.1016/s0968-0896(02)00333-4.
6. 23416296. 2013. Chang. Y. ECHS1 interacts with STAT3 and negatively regulates STAT3 signaling. FEBS Letters. 587. 6. 607–13. Wang. S. X.. Wang. Y. B.. Zhou. J. Li. W. H.. Wang. N. Fang. D. F.. Li. H. Y.. Li. A. L.. Zhang. X. M.. Zhang. W. N.. 10.1016/j.febslet.2013.02.005. 2013FEBSL.587..607C. 23233213.
7. 23879543. 2013. Zhu. X. S.. Knockdown of ECHS1 protein expression inhibits hepatocellular carcinoma cell proliferation via suppression of Akt activity. Critical Reviews in Eukaryotic Gene Expression. 23. 3. 275–82. Dai. Y. C.. Chen. Z. X.. Xie. J. P.. Zeng. W. Lin. Y. Y.. Tan. Q. H. . 10.1615/critreveukaryotgeneexpr.2013007531.
8. 23178449. 2013. Xiao. C. X.. ECHS1 acts as a novel HBs Ag-binding protein enhancing apoptosis through the mitochondrial pathway in HepG2 cells. Cancer Letters. 330. 1. 67–73. Yang. X. N.. Huang. Q. W.. Zhang. Y. Q.. Lin. B. Y.. Liu. J. J.. Liu. Y. P.. Jazag. A. Guleng. B. Ren. J. L.. 10.1016/j.canlet.2012.11.030.