Alpha-methylacyl-CoA racemase

Alpha-methylacyl-CoA racemase (AMACR) is an enzyme that in humans is encoded by the "AMACR" gene. AMACR catalyzes the following chemical reaction:
In mammalian cells, the enzyme is responsible for converting (2"R")-methylacyl-CoA esters to their (2"S")-methylacyl-CoA epimers and known substrates, including coenzyme A esters of pristanic acid (mostly derived from phytanic acid, a 3-methyl branched-chain fatty acid that is abundant in the diet) and bile acids derived from cholesterol. This transformation is required in order to degrade (2"R")-methylacyl-CoA esters by β-oxidation, which process requires the (2"S")-epimer. The enzyme is known to be localised in peroxisomes and mitochondria, both of which are known to β-oxidize 2-methylacyl-CoA esters.
Nomenclature.
This enzyme belongs to the family of isomerases, specifically the racemases and epimerases which act on other compounds. The systematic name of this enzyme class is 2-methylacyl-CoA 2-epimerase. In vitro experiments with the human enzyme AMACR 1A show that both (2"S")- and (2"R")-methyldecanoyl-CoA esters are substrates and are converted by the enzyme with very similar efficiency. Prolonged incubation of either substrate with the enzyme establishes an equilibrium with both substrates or products present in a near 1:1 ratio. The mechanism of the enzyme requires removal of the α-proton of the 2-methylacyl-CoA to form a deprotonated intermediate (which is probably the enol or enolate) followed by non-sterespecific reprotonation. Thus either epimer is converted into a near 1:1 mixture of both isomers upon full conversion of the substrate.
Clinical significance.
Both decreased and increased levels of the enzyme in humans are linked with diseases.
Neurological diseases.
Reduction of the protein level or activity results in the accumulation of (2R)-methyl fatty acids such as bile acids which causes neurological symptoms. The symptoms are similar to those of adult Refsum disease and usually appear in the late teens or early twenties.
The first documented case of AMACR deficiency was reported in 2006. This deficiency falls within a class of disorders called peroxisome biogenesis disorders (PBDs), although it is quite different from other peroxisomal disorders and does not share classic Refsum disorder symptoms. The deficiency causes an accumulation of pristanic acid, DHCA and EHCA and to a lesser extent Very long chain fatty acid and phytanic acid. This phenomenon was verified in 2002, when researchers reported of a certain case, "His condition would have been missed if they hadn't measured the pristanic acid concentration." 
AMACR deficiency can cause mental impairment, confusion, learning difficulties, and liver damage. It can be treated by dietary elimination of pristanic and phytanic acid through reduced intake of dairy products and meats such as beef, lamb, and chicken. Compliance to the diet is low, however, because of eating habits and loss of weight.
Cancer.
Increased levels of AMACR protein concentration and activity are associated with prostate cancer, and the enzyme is used widely as a biomarker (known in cancer literature as P504S) in biopsy tissues. Around 10 different variants of human AMACR have been identified from prostate cancer tissues, which variants arise from alternative mRNA splicing. Some of these splice variants lack catalytic residues in the active site or have changes in the C-terminus, which is required for dimerisation. Increased levels of AMACR are also associated with some breast, colon, and other cancers, but it is unclear exactly what the role of AMACR is in these cancers.
Antibodies to AMACR are used in immunohistochemistry to demonstrate prostate carcinoma, since the enzyme is greatly overexpressed in this type of tumour.
Ibuprofen metabolism.
The enzyme is also involved in a chiral inversion pathway which converts ibuprofen, a member of the 2-arylpropionic acid (2-APA) non-steroidal anti-inflammatory drug family (NSAIDs), from the "R"-enantiomer to the "S"-enantiomer. The pathway is uni-directional because only "R"-ibuprofen can be converted into ibuprofenoyl-CoA, which is then epimerized by AMACR. Conversion of "S"-ibuprofenoyl-CoA to "S"-ibuprofen is assumed to be performed by one of the many human acyl-CoA thioesterase enzymes (ACOTs). The reaction is of pharmacological importance because ibuprofen is typically used as a racemic mixture, and the drug is converted to the "S"-isomer upon uptake, which inhibits the activity of the cyclo-oxygenase enzymes and induces an anti-inflammatory effect. Human AMACR 1A has been demonstrated to epimerise other 2-APA-CoA esters, suggesting a common chiral inversion pathway for this class of drugs.