Medium-chain acyl-CoA dehydrogenase

 

Medium-chain specific acyl-CoA dehydrogenases (MCADs) are mitochondrial beta-oxidation enzymes, which catalyze the alpha,beta dehydrogenation of the corresponding medium chain acyl-CoA by FAD, which becomes reduced. The reduced form of MCAD is reoxidized in the oxidative half-reaction by electron-transferring flavoprotein (ETF), from which the electrons are transferred to the mitochondrial respiratory chain coupled with ATP synthesis.

The enzyme from pig liver can accept substrates with acyl chain lengths of 4 to 16 carbon atoms, but is most active with C8 to C12 compounds [PMID:13295224]. The human enzyme also accepts substrates with chain lengths of between 4 and 16 [PMID:25416781]. The enzyme from rat does not accept C16 at all and is most active with C6-C8 compounds [PMID:3968063].

 

Reference Protein and Structure

Sequence
P41367 UniProt (1.3.8.7) IPR034180 (Sequence Homologues) (PDB Homologues)
Biological species
Sus scrofa (pig) Uniprot
PDB
3mdd - CRYSTAL STRUCTURES OF MEDIUM CHAIN ACYL-COA DEHYDROGENASE FROM PIG LIVER MITOCHONDRIA WITH AND WITHOUT SUBSTRATE (2.4 Å) PDBe PDBsum 3mdd
Catalytic CATH Domains
1.20.140.10 CATHdb (see all for 3mdd)
Cofactors
Fadh2(2-) (1)
Click To Show Structure

Enzyme Reaction (EC:1.3.8.7)

medium-chain 3-substituted propanoyl-CoA(4-)
CHEBI:83723ChEBI
+
hydron
CHEBI:15378ChEBI
+
FAD(3-)
CHEBI:57692ChEBI
→
medium-chain 2,3-trans-enoyl CoA(4-)
CHEBI:83726ChEBI
+
FADH2(2-)
CHEBI:58307ChEBI
Alternative enzyme names: Fatty acyl coenzyme A dehydrogenase, Acyl coenzyme A dehydrogenase, Acyl dehydrogenase, Fatty-acyl-CoA dehydrogenase, Acyl CoA dehydrogenase, General acyl CoA dehydrogenase, Medium-chain acyl-coenzyme A dehydrogenase, Acyl-CoA:(acceptor) 2,3-oxidoreductase, ACADM (gene name),

Enzyme Mechanism

Introduction

Glu376 abstracts a proton from the substrate, which in turn eliminates a hydride to the FAD cofactor. The FAD cofactor is regenerated by the electron-transfer flavoprotein.

Catalytic Residues Roles

UniProt PDB* (3mdd)
Glu401 Glu376(366)A Acts as a general acid/base. The C alpha--C beta of the fatty acyl moiety lies between the flavin and the gamma-carboxylate of this glutamate residue. proton shuttle (general acid/base)
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

References

  1. Ghisla S et al. (2004), Eur J Biochem, 271, 494-508. Acyl-CoA dehydrogenases. A mechanistic overview. DOI:10.1046/j.1432-1033.2003.03946.x. PMID:14728676.
  2. Małecki J et al. (2015), J Biol Chem, 290, 423-434. Human METTL20 is a mitochondrial lysine methyltransferase that targets the β subunit of electron transfer flavoprotein (ETFβ) and modulates its activity. DOI:10.1074/jbc.M114.614115. PMID:25416781.
  3. Nishina Y et al. (2009), J Biochem, 146, 351-357. FT-IR spectroscopic studies on the molecular mechanism for substrate specificity/activation of medium-chain acyl-CoA dehydrogenase. DOI:10.1093/jb/mvp077. PMID:19470521.
  4. Gradinaru R et al. (2007), Biochemistry, 46, 2497-2509. Solvent isotope effects in reactions of human medium-chain acyl-CoA dehydrogenase active site mutants. DOI:10.1021/bi0614582. PMID:17286388.
  5. Bhattacharyya S et al. (2005), Biochemistry, 44, 16549-16562. Potential of mean force calculation for the proton and hydride transfer reactions catalyzed by medium-chain acyl-CoA dehydrogenase: effect of mutations on enzyme catalysis. DOI:10.1021/bi051630m. PMID:16342946.
  6. Toogood HS et al. (2005), J Biol Chem, 280, 30361-30366. Stabilization of non-productive conformations underpins rapid electron transfer to electron-transferring flavoprotein. DOI:10.1074/jbc.M505562200. PMID:15975918.
  7. Toogood HS et al. (2004), J Biol Chem, 279, 32904-32912. Extensive domain motion and electron transfer in the human electron transferring flavoprotein.medium chain Acyl-CoA dehydrogenase complex. DOI:10.1074/jbc.M404884200. PMID:15159392.
  8. Kim JJ et al. (2004), Eur J Biochem, 271, 483-493. Acyl-CoA dehydrogenases and acyl-CoA oxidases. Structural basis for mechanistic similarities and differences. PMID:14728675.
  9. Satoh A et al. (2003), J Biochem, 134, 297-304. Structure of the transition state analog of medium-chain acyl-CoA dehydrogenase. Crystallographic and molecular orbital studies on the charge-transfer complex of medium-chain acyl-CoA dehydrogenase with 3-thiaoctanoyl-CoA. PMID:12966080.
  10. Wu J et al. (2003), Biochemistry, 42, 11846-11856. Probing hydrogen-bonding interactions in the active site of medium-chain acyl-CoA dehydrogenase using Raman spectroscopy. DOI:10.1021/bi0344578. PMID:14529297.
  11. Gopalan KV et al. (2002), Biochemistry, 41, 4638-4648. Beyond the Proton Abstracting Role of Glu-376 in Medium-Chain Acyl-CoA Dehydrogenase:  Influence of Glu-376→Gln Substitution on Ligand Binding and Catalysis†. DOI:10.1021/bi011676p.
  12. Rudik I et al. (1998), Biochemistry, 37, 8437-8445. Protonic equilibria in the reductive half-reaction of the medium-chain acyl-CoA dehydrogenase. DOI:10.1021/bi980388z. PMID:9622495.
  13. Lee HJ et al. (1996), Biochemistry, 35, 12412-12420. Crystal structures of the wild type and the Glu376Gly/Thr255Glu mutant of human medium-chain acyl-CoA dehydrogenase: influence of the location of the catalytic base on substrate specificity. DOI:10.1021/bi9607867. PMID:8823176.
  14. Thorpe C et al. (1995), FASEB J, 9, 718-725. Structure and mechanism of action of the acyl-CoA dehydrogenases. PMID:7601336.
  15. Kim JJ et al. (1993), Proc Natl Acad Sci U S A, 90, 7523-7527. Crystal structures of medium-chain acyl-CoA dehydrogenase from pig liver mitochondria with and without substrate. DOI:10.1073/pnas.90.16.7523. PMID:8356049.
  16. Ikeda Y et al. (1985), J Biol Chem, 260, 1311-1325. Purification and characterization of short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases from rat liver mitochondria. Isolation of the holo- and apoenzymes and conversion of the apoenzyme to the holoenzyme. PMID:3968063.
  17. CRANE FL et al. (1956), J Biol Chem, 218, 701-706. On the mechanism of dehydrogenation of fatty acyl derivatives of coenzyme A. I. The general fatty acyl coenzyme A dehydrogenase. PMID:13295224.

Step 1.

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Catalytic Residues Roles

Residue Roles
Glu376(366)A proton shuttle (general acid/base)

Chemical Components

Step 1.

Contributors

Craig Porter, Gemma L. Holliday