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Peroxiomal multifunctional enzyme type 2 (MFE-2) is a three part enzyme used in beta oxidation of very-long-chain fatty acids. The enzyme works the second and third steps in the peroxisomal beta oxidation. The three parts of the enzyme include (3R)-hydroxyacyl-CoA dehydrogenase ((3R)-dehydrogenase), sterol carrier protein 2-like units (SCP-2L), and 2-enoyl-CoA hydratase (hydratase 2). MFE-2 is a two-domain structure with a C-domain complete hot-dog fold around the active site, and a N-domain fold housing the cavity for the aliphatic acyl part of the substrate molecule. MFE-2 is essential in the breakdown of very-long-chain fatty acids, as well as bile acid synthesis.

Function

The (3R)-dehydrogenase unit belongs to the short-chain alcohol dehydrogenase/reductase (SDR) with a typical Rossman fold. Unlike most other enzymes in the SDR, the (3R)-dehydrogenase has an extra C-terminal which helps to form the active site cavity. The hydratase 2 enzyme is used by the enzyme to catalyze the (R)-specific hydration of 2-enoyl-CoA thioesters, and are part of the hydratase/isomerase family. This family of enzyme molecules is used to hydrate the straight-chain fatty-enoyl-CoAs from C8 to C12 with high efficiency. The catalytic activity of this molecule is housed by the active site residues of Ala613-Lys614-Thr615

Disease

One of the main mutations of this disease is that of changing Asn457 into a Tyrosine which leads to reduced numbers of the full length MFE-2 enzyme. This mutation more specifically affects the folding of the Hydratase 2. This portion is very vital to the interaction of Asn457 and the Gly378 portion that helps to stabilize the Beta strands, and when the Tyrosine replaces the Asparagine its bulky and Hydrophobic nature cause a disruption in the fold pushing away the Beta sheet.

Relevance

Structural highlights

The Rossman fold found in the (3R)-dehydrogenase has a G-X-X-X-G-X-G amino acid motif, this allows for the co-factor binding with the Ser-Tyr-Lys. The SCP-2L unit consists of a five-stranded beta sheet covered on one side by five alpha helices. When the substrate binds in the SCP-2L, it structurally changes the C-terminal alpha helices. This causes the peroxisomal targeting signal Ala-Lys-Leu, to become solvent-exposed to strengthen the idea of ligand assisted targeting. The hydratase 2 unit is a homodimer with a two-domain subunit structure whit a hot dog fold. The size of the hydratase 2 portion of the enzyme was found to be 31.5 kDa upon SDS-Page analysis of rat liver peroxisomes.

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