Malonyl-CoA decarboxylase (), (which can also be called MCD and malonyl-CoA carboxyl-lyase) is found in bacteria and humans and has important roles in regulating fatty acid metabolism and food intake, and it is an attractive target for drug discovery. It is an enzyme associated with Malonyl-CoA decarboxylase deficiency. In humans, it is encoded by the MLYCD gene.
Its main function is to catalyze the conversion of malonyl-CoA into acetyl-CoA and carbon dioxide. It is involved in fatty acid biosynthesis. To some degree, it reverses the action of Acetyl-CoA carboxylase.
Structure
MCD presents two isoforms which can be transcribed form one gene: a long isoform (54kDa), distributed in mitochondria, and a short isoform (49kDa) that can be found in peroxisomes and cytosol. The long isoform includes a sequence of signaling towards mitochondria in the N-terminus; whereas the short one only contains the typical sequence of peroxisomal signaling PTS1 in the C-terminus, also shared by the long isoform.
MCD is a protein tetramer, an oligomer formed by a dimer of heterodimers related by an axis of binary symmetry with a rotation angle of about 180 degrees. The strong structural asymmetry between the monomers of the heterodimer suggests a half of the sites reactivity, in which only half of the active sites are functional simultaneously. Each monomer contains basically two domains:
The N-terminus one, which is involved in oligomerization and has a helical structure of eight helixes organised as a bundle of four antiparallel helixes with two pairs of inserted helixes. The C-terminus one is where malonyl-CoA catalysis takes place and which is present in GCN5- Histone acetyiltranferase family. It also includes a cluster of seven helixes.
However, the binding site for malonyl-CoA in MCD presents a variation with respect to their homologous: the center of the binding site has a glutamic residue instead of a glycine, acting as a molecular lever in the substrate releasing.
As said before, MCD presents a half of the sites reactivity, due to the fact that each heterodimer has two different structural conformations: B state (bound), in which the substrate is united; and U conformation (unbound), where the substrate union isn't allowed. According to this, the half of the sites mechanism might present a consumption of catalytic energy. Nevertheless, the conformational change produced in a subunit when changing from the B state to the U state (which produces the release of the product) coincides with the formation of a new union site in the active site of the neighbour subunit when changing from the U stat to B state. As a result, the conformational changes synchronised in the pair of subunits facilitates the catalysis despite the reduction of the number of available active sites.
Each monomer of that structure exhibits a large hydrophobic interface with the possibility to form an inter subunit disulfide bridge. Heterodimers are also interconnected by a small C-terminus domain interface, where a pair of cysteines is properly disposed. The disulfide bonds gives to MCD the capability to form a tetrameric enzyme linked by inter subunits covalent bonds in the presence of oxidants such as hydrogen peroxide.
Gene: MLYCD
The malonyl-CoA decarboxylase gene (MLYCD) is located in chromosome 16 (locus: 16q23.3). This gene has 2 transcripts or splice variants, one of which encodes MCD (the other doesn’t encode any protein). It has also 59 orthologues, 1 paralogue and it is associated with 5 phenotypes.
MLYCD is strongly expressed in heart, liver and some other tissues like kidney. This gene is also weakly expressed in many other tissues such as brain, placenta, testis, etc.
Processing and post-translational modifications
Malonyl-CoA decarboxylase is firstly processed as a pro-protein or proenzyme, in which the transit peptide, whose role is to transport the enzyme to a specific organelle (in this case the mitochondria), comprises the first 39 amino acids (beginning with a methionine and ending with an alanine). The polypeptide chain in the mature protein is comprised between amino acid 40 and 493.