Biology:Alpha-methylacyl-CoA racemase
 Generic protein structure example |
α-Methylacyl-CoA racemase (AMACR, EC 5.1.99.4) is an enzyme that in humans is encoded by the AMACR gene.[1][2][3] AMACR catalyzes the following chemical reaction:
- (2R)-2-methylacyl-CoA [math]\displaystyle{ \rightleftharpoons }[/math] (2S)-2-methylacyl-CoA
In mammalian cells, the enzyme is responsible for converting (2R)-methylacyl-CoA esters to their (2S)-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 (2R)-methylacyl-CoA esters by β-oxidation, which process requires the (2S)-epimer. The enzyme is known to be localised in peroxisomes and mitochondria, both of which are known to β-oxidize 2-methylacyl-CoA esters.[4][5]
Nomenclature
| alpha-methylacyl-CoA racemase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC number | 5.1.99.4 | ||||||||
| CAS number | 156681-44-6 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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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 (2S)- and (2R)-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[6]) followed by non-sterespecific reprotonation.[7] 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.[8]
The first documented cases of AMACR deficiency in adults were reported in 2000.[8] 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, dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA) and to a lesser extent 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."[9]
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.[10][11]
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.[5][12][13]
Antibodies to AMACR are used in immunohistochemistry to demonstrate prostate carcinoma, since the enzyme is greatly overexpressed in this type of tumour.[14]
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,[15] suggesting a common chiral inversion pathway for this class of drugs.
References
- ↑ "Entrez Gene: AMACR alpha-methylacyl-CoA racemase". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23600.
- ↑ "Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases". The Biochemical Journal. 326 326 (3): 883–9. Sep 1997. doi:10.1042/bj3260883. PMID 9307041. PMC 1218746. http://www.biochemj.org/bj/326/0883/bj3260883.htm.
- ↑ "P504S, a-methylacyl-CoA racemase, AMACR". http://e-immunohistochemistry.info/web/P504S.htm.
- ↑ "Purification and properties of an alpha-methylacyl-CoA racemase from rat liver". European Journal of Biochemistry 222 (2): 313–23. Jun 1994. doi:10.1111/j.1432-1033.1994.tb18870.x. PMID 8020470.
- ↑ 5.0 5.1 "Alpha-methylacyl-CoA racemase--an 'obscure' metabolic enzyme takes centre stage". The FEBS Journal 275 (6): 1089–102. Mar 2008. doi:10.1111/j.1742-4658.2008.06290.x. PMID 18279392.
- ↑ "The enolization chemistry of a thioester-dependent racemase: the 1.4 Å crystal structure of a reaction intermediate complex characterized by detailed QM/MM calculations". The Journal of Physical Chemistry B 116 (11): 3619–29. Mar 2012. doi:10.1021/jp210185m. PMID 22360758.
- ↑ "Synthesis and use of isotope-labelled substrates for a mechanistic study on human alpha-methylacyl-CoA racemase 1A (AMACR; P504S)". Organic & Biomolecular Chemistry 7 (3): 543–52. Feb 2009. doi:10.1039/b815396e. PMID 19156321.
- ↑ 8.0 8.1 "Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy". Nature Genetics 24 (2): 188–91. Feb 2000. doi:10.1038/72861. PMID 10655068.
- ↑ "A new defect of peroxisomal function involving pristanic acid: a case report". Journal of Neurology, Neurosurgery, and Psychiatry 72 (3): 396–9. Mar 2002. doi:10.1136/jnnp.72.3.396. PMID 11861706.
- ↑ "Peroxisomal Disorders: Overview - eMedicine Neurology". medscape.com. 2007-03-08. http://emedicine.medscape.com/article/1177387-overview.
- ↑ "Adult Refsum Disease". Refsum Disease. 2006-03-20. https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=refsum. Retrieved 2009-03-16.
- ↑ "α-Methylacyl-CoA racemase spliced variants and their expression in normal and malignant prostate tissues". Urology 77 (1): 249.e1–7. Jan 2011. doi:10.1016/j.urology.2010.08.005. PMID 21195844.
- ↑ "Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death". Cancer Epidemiology, Biomarkers & Prevention 14 (6): 1424–32. Jun 2005. doi:10.1158/1055-9965.EPI-04-0801. PMID 15941951.
- ↑ "Expression and diagnostic utility of alpha-methylacyl-CoA-racemase (P504S) in foamy gland and pseudohyperplastic prostate cancer". Am. J. Surg. Pathol. 27 (6): 772–8. 2003. doi:10.1097/00000478-200306000-00007. PMID 12766580.
- ↑ "Chiral inversion of 2-arylpropionyl-CoA esters by human α-methylacyl-CoA racemase 1A (P504S)--a potential mechanism for the anti-cancer effects of ibuprofen". Chemical Communications 47 (26): 7332–4. Jul 2011. doi:10.1039/c1cc10763a. PMID 21614403. http://opus.bath.ac.uk/24764/1/Ibuprofen_AMACR.pdf.
External links
- Human AMACR genome location and AMACR gene details page in the UCSC Genome Browser.
- N.S. man thought he'd never find anyone else with his condition. Then he got a text from Oklahoma. CBC News. Feb 7, 2022
Further reading
- "Discovery and clinical application of a novel prostate cancer marker: alpha-methylacyl CoA racemase (P504S)". American Journal of Clinical Pathology 122 (2): 275–89. Aug 2004. doi:10.1309/EJUY-UQPE-X1MG-68MK. PMID 15323145.
- "Purification and characterization of an alpha-methylacyl-CoA racemase from human liver". European Journal of Biochemistry 231 (3): 815–22. Aug 1995. doi:10.1111/j.1432-1033.1995.tb20766.x. PMID 7649182.
- "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. Jan 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- "Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases". The Biochemical Journal. 326 326 (3): 883–9. Sep 1997. doi:10.1042/bj3260883. PMID 9307041.
- "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. Oct 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- "Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy". Nature Genetics 24 (2): 188–91. Feb 2000. doi:10.1038/72861. PMID 10655068.
- "In mouse alpha -methylacyl-CoA racemase, the same gene product is simultaneously located in mitochondria and peroxisomes". The Journal of Biological Chemistry 275 (27): 20887–95. Jul 2000. doi:10.1074/jbc.M002067200. PMID 10770938.
- "Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans". Journal of Lipid Research 41 (11): 1752–9. Nov 2000. doi:10.1016/S0022-2275(20)31968-4. PMID 11060344.
- "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. Nov 2000. doi:10.1101/gr.143000. PMID 11076863.
- "alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer". JAMA 287 (13): 1662–70. Apr 2002. doi:10.1001/jama.287.13.1662. PMID 11926890.
- "Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer". Cancer Research 62 (8): 2220–6. Apr 2002. PMID 11956072.
- "Alpha-Methylacyl-CoA racemase: a novel tumor marker over-expressed in several human cancers and their precursor lesions". The American Journal of Surgical Pathology 26 (7): 926–31. Jul 2002. doi:10.1097/00000478-200207000-00012. PMID 12131161.
- "alpha-Methylacyl-CoA racemase: expression levels of this novel cancer biomarker depend on tumor differentiation". The American Journal of Pathology 161 (3): 841–8. Sep 2002. doi:10.1016/S0002-9440(10)64244-7. PMID 12213712.
- "The polycomb group protein EZH2 is involved in progression of prostate cancer". Nature 419 (6907): 624–9. Oct 2002. doi:10.1038/nature01075. PMID 12374981. Bibcode: 2002Natur.419..624V. http://deepblue.lib.umich.edu/bitstream/2027.42/62896/1/nature01075.pdf.
- "Alpha-methylacyl-CoA racemase (P504S) expression in evolving carcinomas within benign prostatic hyperplasia and in cancers of the transition zone". Human Pathology 34 (3): 228–33. Mar 2003. doi:10.1053/hupa.2003.42. PMID 12673556.
- "Expression profiling identifies a novel alpha-methylacyl-CoA racemase exon with fumarate hydratase homology". Cancer Research 63 (12): 3296–301. Jun 2003. PMID 12810662.
- "Alpha-methylacyl-CoA racemase as an androgen-independent growth modifier in prostate cancer". Cancer Research 63 (21): 7365–76. Nov 2003. PMID 14612535.
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