Alpha-methylacyl-CoA racemase

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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 / EGO

In enzymology, an alpha-methylacyl-CoA racemase also known as AMACR is an enzyme that catalyzes this chemical reaction:

(2R)-2-methylacyl-CoA \rightleftharpoons (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 include 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 requires the (2S) epimer. The enzyme is known to be localised in peroxisomes and mitochondria, both of which are known to β-oxidise 2-methylacyl-CoA esters.[1][2]

Nomenclature[edit]

This enzyme belongs to the family of isomerases, to be specific those racemases and epimerases acting 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/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[3]] followed by non-sterespecific reprotonation.[4] Thus either epimer is converted into a near 1:1 mixture of both isomers upon full conversion of substrate.

Gene[edit]

Alpha-methylacyl-CoA racemase
Identifiers
Symbols AMACR ; AMACRD; CBAS4; RACE; RM
External IDs OMIM604489 MGI1098273 HomoloGene7410 GeneCards: AMACR Gene
EC number 5.1.99.4
Orthologs
Species Human Mouse
Entrez 23600 17117
Ensembl ENSG00000242110 ENSMUSG00000022244
UniProt Q9UHK6 O09174
RefSeq (mRNA) NM_001167595 NM_008537
RefSeq (protein) NP_001161067 NP_032563
Location (UCSC) Chr 5:
33.99 – 34.01 Mb
Chr 15:
10.98 – 11 Mb
PubMed search [1] [2]

Alpha-methylacyl-CoA racemase in humans is encoded by the AMACR gene.[5][6][7]

Clinical significance[edit]

Both decreased and increased levels of the enzyme in humans is linked with diseases.

Neurological diseases[edit]

Reduction of protein levels or activity results in the accumulation of (2R)-methyl fatty acids such as bile acids which results in neurological symptoms. The symptoms are similar to adult Refsum disease and usually appear in the late teens or early 20's.[8]

AMACR deficiency has recently been discovered. The first documented case was in 2006. It is in a class of disorders called peroxisome biogenesis disorders (PBD) although it is quite different than other peroxisomal disorders and does not share classic Refsum disorder symptoms. It causes an accumulation of pristanic acid, DHCA and EHCA and to a lesser extent VLCFA and phytanic acid. This was verified in 2002, with researchers reporting of a certain case: "His condition would have been missed if they hadn't measured the pristanic acid concentration." [9]

It can cause mental impairment,confusion, learning difficulties and liver damage. It can be treated by dietary elimination of pristanic and phytanic acid from meats such as beef, lamb, chicken, and dairy products, however compliance to the diet is low due to dietary habits, and loss of weight.[10][11]

Cancer[edit]

Increased levels of AMACR protein and activity are associated with prostate cancer, and the enzyme is used widely as a biomarker (known in the cancer literature as P504S) in biopsy tissues. Around 10 different variants of human AMACR have been identified from prostate cancer tissues, which 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.[2][12][13]

Antibodies to AMACR are used in immunohistochemistry to demonstrate prostate carcinoma, since the enzyme is greatly over-expressed in this type of tumour.[14]

Ibuprofen metabolism[edit]

The enzyme is also involved in a chiral inversion pathway which converts ibuprofen, a member of the 2-arylpropionic acid (2-APA) of the 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 epimerised 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 inhibit the activity of the cyclo-oxygenase enzymes and hence bring about an anti-inflammatory effect. Recently 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[edit]

  1. ^ Schmitz W, Fingerhut R, Conzelmann E (Jun 1994). "Purification and properties of an alpha-methylacyl-CoA racemase from rat liver". European Journal of Biochemistry / FEBS 222 (2): 313–23. doi:10.1111/j.1432-1033.1994.tb18870.x. PMID 8020470. 
  2. ^ a b Lloyd M, Darley D, Wierzbicki A, Threadgill M (Mar 2008). "Alpha-methylacyl-CoA racemase--an 'obscure' metabolic enzyme takes centre stage". The FEBS Journal 275 (6): 1089–102. doi:10.1111/j.1742-4658.2008.06290.x. PMID 18279392. 
  3. ^ Sharma S, Bhaumik P, Schmitz W, Venkatesan R, Hiltunen J, Conzelmann E et al. (Mar 2012). "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. doi:10.1021/jp210185m. PMID 22360758. 
  4. ^ Darley D, Butler D, Prideaux S, Thornton T, Wilson A, Woodman T et al. (Feb 2009). "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. doi:10.1039/b815396e. PMID 19156321. 
  5. ^ "Entrez Gene: AMACR alpha-methylacyl-CoA racemase". 
  6. ^ Schmitz W, Helander H, Hiltunen J, Conzelmann E (Sep 1997). "Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases". The Biochemical Journal. 326. 326 ( Pt 3): 883–9. PMC 1218746. PMID 9307041. 
  7. ^ "P504S, a-methylacyl-CoA racemase, AMACR". Retrieved 25 April 2012. 
  8. ^ Ferdinandusse S, Denis S, Clayton P, Graham A, Rees J, Allen J et al. (Feb 2000). "Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy". Nature Genetics 24 (2): 188–91. doi:10.1038/72861. PMID 10655068. 
  9. ^ McLean B, Allen J, Ferdinandusse S, Wanders R (Mar 2002). "A new defect of peroxisomal function involving pristanic acid: a case report". Journal of Neurology, Neurosurgery, and Psychiatry 72 (3): 396–9. doi:10.1136/jnnp.72.3.396. PMC 1737782. PMID 11861706. [dead link]
  10. ^ Chedrawi A, Clark GD (2007-03-08). "Peroxisomal Disorders: Overview - eMedicine Neurology". medscape.com. Archived from the original on 2 March 2009. Retrieved 2009-03-16. 
  11. ^ Wanders RJA, Waterham HR, Leroy BP (2006-03-20). "Refsum Disease". GeneReviews -- NCBI Bookshelf. Retrieved 2009-03-16. 
  12. ^ Ouyang B, Leung Y, Wang V, Chung E, Levin L, Bracken B et al. (Jan 2011). "α-Methylacyl-CoA racemase spliced variants and their expression in normal and malignant prostate tissues". Urology 77 (1): 249.e1–7. doi:10.1016/j.urology.2010.08.005. PMC 3051191. PMID 21195844. 
  13. ^ Rubin M, Bismar T, Andrén O, Mucci L, Kim R, Shen R et al. (Jun 2005). "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. doi:10.1158/1055-9965.EPI-04-0801. PMID 15941951. 
  14. ^ >Zhou M, Jiang Z, Epstein J (2003). "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. doi:10.1097/00000478-200306000-00007. PMID 12766580. 
  15. ^ Woodman T, Wood P, Thompson A, Hutchings T, Steel G, Jiao P et al. (Jul 2011). "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. doi:10.1039/c1cc10763a. PMID 21614403. 

Further reading[edit]

  • Jiang Z, Woda B, Wu C, Yang X (Aug 2004). "Discovery and clinical application of a novel prostate cancer marker: alpha-methylacyl CoA racemase (P504S)". American Journal of Clinical Pathology 122 (2): 275–89. doi:10.1309/EJUY-UQPE-X1MG-68MK. PMID 15323145. 
  • Bautch S (Aug 1991). "Wisconsin doctor selected as national symbol of physicians' sacrifices". Wisconsin Medical Journal 90 (8): 485–7. PMID 1926890. 
  • Schmitz W, Albers C, Fingerhut R, Conzelmann E (Aug 1995). "Purification and characterization of an alpha-methylacyl-CoA racemase from human liver". European Journal of Biochemistry / FEBS 231 (3): 815–22. doi:10.1111/j.1432-1033.1995.tb20766.x. PMID 7649182. 
  • Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
  • Schmitz W, Helander H, Hiltunen J, Conzelmann E (Sep 1997). "Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases". The Biochemical Journal. 326. 326 ( Pt 3): 883–9. PMC 1218746. PMID 9307041. 
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
  • Ferdinandusse S, Denis S, Clayton P, Graham A, Rees J, Allen J et al. (Feb 2000). "Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy". Nature Genetics 24 (2): 188–91. doi:10.1038/72861. PMID 10655068. 
  • Kotti T, Savolainen K, Helander H, Yagi A, Novikov D, Kalkkinen N et al. (Jul 2000). "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. doi:10.1074/jbc.M002067200. PMID 10770938. 
  • Amery L, Fransen M, De Nys K, Mannaerts G, Van Veldhoven P (Nov 2000). "Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans". Journal of Lipid Research 41 (11): 1752–9. PMID 11060344. 
  • Hartley J, Temple G, Brasch M (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. 
  • Rubin M, Zhou M, Dhanasekaran S, Varambally S, Barrette T, Sanda M et al. (Apr 2002). "alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer". Jama 287 (13): 1662–70. doi:10.1001/jama.287.13.1662. PMID 11926890. 
  • Luo J, Zha S, Gage W, Dunn T, Hicks J, Bennett C et al. (Apr 2002). "Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer". Cancer Research 62 (8): 2220–6. PMID 11956072. 
  • Zhou M, Chinnaiyan A, Kleer C, Lucas P, Rubin M (Jul 2002). "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. doi:10.1097/00000478-200207000-00012. PMID 12131161. 
  • Kuefer R, Varambally S, Zhou M, Lucas P, Loeffler M, Wolter H et al. (Sep 2002). "alpha-Methylacyl-CoA racemase: expression levels of this novel cancer biomarker depend on tumor differentiation". The American Journal of Pathology 161 (3): 841–8. doi:10.1016/S0002-9440(10)64244-7. PMC 1867250. PMID 12213712. 
  • Varambally S, Dhanasekaran S, Zhou M, Barrette T, Kumar-Sinha C, Sanda M et al. (Oct 2002). "The polycomb group protein EZH2 is involved in progression of prostate cancer". Nature 419 (6907): 624–9. doi:10.1038/nature01075. PMID 12374981. 
  • Leav I, McNeal J, Ho S, Jiang Z (Mar 2003). "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. doi:10.1053/hupa.2003.42. PMID 12673556. 
  • Shen-Ong G, Feng Y, Troyer D (Jun 2003). "Expression profiling identifies a novel alpha-methylacyl-CoA racemase exon with fumarate hydratase homology". Cancer Research 63 (12): 3296–301. PMID 12810662. 
  • Zha S, Ferdinandusse S, Denis S, Wanders R, Ewing C, Luo J et al. (Nov 2003). "Alpha-methylacyl-CoA racemase as an androgen-independent growth modifier in prostate cancer". Cancer Research 63 (21): 7365–76. PMID 14612535.