Function
The first reaction in β-oxidation, or fatty acid metabolism, is the catalyzation of the ester bond (C2 and C3) of the substrate Acyl-CoA. This is accomplished through Acyl-CoA Dehydrogenase (ACDH) and its cofactor FAD. ACDH is classified according to its length of its substrates: short (SCAD), medium (MCAD), very and very long-chain (VLCAD).
Disease
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disorder that affects fatty acid oxidation and can be characterized by a hypoglycemic crisis during times of increased stressed. Expression of MCADD results in a decrease of ketone production and an increase in medium-chain fatty acid concentration. MCADD is a disorder inherited genetically through an autosomal recessive trait, and it is caused by mutations in the medium-chain acyl- CoA dehydrogenase (ACADM) gene. The ACADM gene is located on chromosome 1p31. There are over 90 different ACADM gene mutations known so far, most of which are missense mutations. The disorder can lead to symptoms such as a loss in appetite as well as vomiting and diarrhea. This can result in accumulated concentrations of acylcarnitine, which can be potentially toxic. People who are affected and not diagnosed are at a high risk of dying or experiencing permanent neurological damage during their first metabolic crisis. To prevent such events, immediate care should follow catabolic stress and fasting should be averted. Individuals living with MCADD are asymptomatic up until there is an increased demand for energy followed by a prolonged time of fasting. Newborn screening is now widely implemented through the use of liquid chromatography-tandem mass spectrometry.
Relevance
Structural highlights
Catalytic Residues
Glu255 is responsible for the catalytic activity of mutant Medium Chain Acyl-CoA Dehydrogenase (MCADH). It can be in “active” or “resting” states. It is mostly in the “resting” state, due to its ability to hydrogen bond with Glu99.
Long Chain Acyl-CoA Dehydrogenase (LCADH) and Isovaleryl-CoA Dehydrogenase (IVDH) have a higher catalytic activity than MCADH because they have serine and glycine in their 99 position, respectively. Neither of these amino acids can form hydrogen bonds, so the Glu255 is in the “active state.” The catalytic residue of LCADH is Glu261; the catalytic residue of IVDH is Glu254.
Glu376 is the amino acid responsible for catalytic activity of the wild type.
Significance of the Positions of Glutamate on the Wild Type (Glu376) and Mutant (Glu255)
The distance between the donor proton and the base that attacks the donor proton affect the catalytic activity of the carboxylate base of the glutamates. The distance between the proton and glutamates carboxylates are more than 4.0 A.
Glu376 would conform so that its carboxylate oxygen lies close to the proton (2.4A).
Glu255 has a smaller catalytic activity because is over 4.0 A away from the proton. It is thought that due to MCADH’s flexibility at Gly376, Glu255’s carboxylate oxygen will be closer to the donor proton.
References
