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{{enzyme
| Name = alpha-methylacyl-CoA racemase
| EC_number = 5.1.99.4
| CAS_number = 156681-44-6
| IUBMB_EC_number = 5/1/99/4
| GO_code = 0008111
| image = 
| width = 
| caption = 
}}
In [[enzymology]], an '''alpha-methylacyl-CoA racemase''' also known as '''AMACR''' is an [[enzyme]] that [[catalysis|catalyzes]] the [[chemical reaction]]

:(2R)-2-methylacyl-CoA <math>\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 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.<ref name = "Schmitz_1994"/><ref name = "Lloyd_2008"/>

== Nomenclature ==

This enzyme belongs to the family of [[isomerase]]s, to be specific those [[racemase]]s and [[epimerase]]s 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 (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/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<ref name = "Sharma_2007"/> followed by non-sterespecific reprotonation.<ref name = "Darley_2009"/> Thus either epimer is converted into a near 1:1 mixture of both isomers upon full conversion of substrate.

== Gene ==
{{PBB|geneid=23600}}
Alpha-methylacyl-CoA racemase in humans is encoded by the ''AMACR'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: AMACR alpha-methylacyl-CoA racemase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23600| accessdate = }}</ref><ref name="pmid9307041">{{cite journal | author = Schmitz W, Helander HM, Hiltunen JK, Conzelmann E | title = Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases | journal = Biochem. J. | volume = ( Pt 3) | issue = | pages = 883–9 |date=September 1997 | series = 326  | pmid = 9307041 | pmc = 1218746 | doi = | url = http://www.biochemj.org/bj/326/0883/bj3260883.htm }}</ref><ref>{{cite web | last =  | first =  | title =  P504S, a-methylacyl-CoA racemase, AMACR | url = http://e-immunohistochemistry.info/web/P504S.htm | accessdate = 25 April 2012 }}</ref>

== Protein structure ==

As of late 2007, 7 [[tertiary structure|structures]] have been solved for this class of enzymes, with [[Protein Data Bank|PDB]] accession codes {{PDB link|1X74}}, {{PDB link|2G04}}, {{PDB link|2GCE}}, {{PDB link|2GCI}}, {{PDB link|2GD0}}, {{PDB link|2GD2}}, and {{PDB link|2GD6}}. A structure of the proposed deprotonated intermediate has since been published.<ref name = "Sharma_2007"/> These structures are of the ''Mycobacterium tuberculosis'' version of the enzyme, known as MCR.

== Clinical significance ==

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

=== Neurological diseases ===

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.<ref name = "Ferdinandusse_2000"/>

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's disease|Refsum disorder]] symptoms. It causes an accumulation of [[pristanic acid]], [[dihydroxycholestanoic acid|DHCA]] and [[EHCA]] and to a lesser extent [[Very long chain fatty acid|VLCFA]] and [[phytanic acid]]. "His condition would have been missed if they hadn't measured the pristanic acid concentration." <ref name="pmid11861706">{{cite journal | author = McLean BN, Allen J, Ferdinandusse S, Wanders RJ | title = A new defect of peroxisomal function involving pristanic acid: a case report | journal = J. Neurol. Neurosurg. Psychiatr. | volume = 72 | issue = 3 | pages = 396–9 |date=March 2002 | pmid = 11861706 | pmc = 1737782 | doi = 10.1136/jnnp.72.3.396| url = http://www.repository.naturalis.nl/document/33804 | issn =  }}{{dead link|date=May 2010}}</ref>

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.<ref name="urlPeroxisomal Disorders: Overview - eMedicine Neurology">{{cite web | url = http://emedicine.medscape.com/article/1177387-overview | title = Peroxisomal Disorders: Overview - eMedicine Neurology | author = Chedrawi A, Clark  GD | authorlink = | coauthors = | date = 2007-03-08 | format = | work = | publisher = medscape.com | pages = | language = | quote = | accessdate = 2009-03-16| archiveurl= http://web.archive.org/web/20090302094129/http://emedicine.medscape.com/article/1177387-overview| archivedate= 2 March 2009 <!--DASHBot-->| deadurl= no}}</ref><ref name="urlRefsum Disease -- GeneReviews -- NCBI Bookshelf">{{cite web | url = http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=refsum | title = Refsum Disease  | author = Wanders RJA, Waterham HR, Leroy BP | authorlink = | coauthors = | date = 2006-03-20 | format = | work =  GeneReviews -- NCBI Bookshelf | publisher = | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2009-03-16}}</ref>

=== Cancer ===

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.<ref name = "Lloyd_2008"/><ref name = "Ouyang_2011"/><ref name="pmid15941951">{{cite journal | author = Rubin MA, Bismar TA, Andrén O, Mucci L, Kim R, Shen R, Ghosh D, Wei JT,  [[Arul Chinnaiyan|Chinnaiyan AM]], Adami HO, Kantoff PW, Johansson JE | title = Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death | journal = Cancer Epidemiol. Biomarkers Prev. | volume = 14 | issue = 6 | pages = 1424–32 |date=June 2005 | pmid = 15941951 | doi = 10.1158/1055-9965.EPI-04-0801 | url = | issn = }}</ref>

Antibodies to AMACR are used in [[immunohistochemistry]] to demonstrate [[prostate carcinoma]], since the enzyme is greatly over-expressed in this type of tumour.<ref name=Zhou2003>{{cite journal | author = Zhou, M. ''et al.'' | year = 2003 | title = Expression and diagnostic utility of alpha-methylacyl-CoA-racemase (P504S) in foamy gland and pseudohyperplastic prostate cancer | journal = American Journal of Surgical Pathology | volume = 27 | issue = 6 | url=http://journals.lww.com/ajsp/Abstract/2003/06000/Expression_and_Diagnostic_Utility_of.7.aspx | pages = 772–778}}</ref>

=== Ibuprofen metabolism ===

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,<ref name = "Woodman_2011"/> suggesting a common chiral inversion pathway for this class of drugs.  

==References==
{{reflist|35em|refs=

<ref name = "Schmitz_1994">{{cite journal | author = Schmitz W, Fingerhut R, Conzelmann E | title = Purification and properties of an alpha-methylacyl-CoA racemase from rat liver | journal = Eur. J. Biochem. | volume = 222 | issue = 2 | pages = 313–23 |date=June 1994 | pmid = 8020470 | doi = 10.1111/j.1432-1033.1994.tb18870.x }}</ref>

<ref name = "Lloyd_2008">{{cite journal | author = Lloyd MD, Darley DJ, Wierzbicki AS, Threadgill MD | title = Alpha-methylacyl-CoA racemase--an 'obscure' metabolic enzyme takes centre stage | journal = FEBS J. | volume = 275 | issue = 6 | pages = 1089–102 |date=March 2008 | pmid = 18279392 | doi = 10.1111/j.1742-4658.2008.06290.x }}</ref>

<ref name = "Woodman_2011">{{cite journal | author = Woodman TJ, Wood PJ, Thompson AS, Hutchings TJ, Steel GR, Jiao P, Threadgill MD, Lloyd MD | title = 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 | journal = Chem. Commun. (Camb.) | volume = 47 | issue = 26 | pages = 7332–4 |date=July 2011 | pmid = 21614403 | doi = 10.1039/c1cc10763a }}</ref>

<ref name = "Darley_2009">{{cite journal | author = Darley DJ, Butler DS, Prideaux SJ, Thornton TW, Wilson AD, Woodman TJ, Threadgill MD, Lloyd MD | title = Synthesis and use of isotope-labelled substrates for a mechanistic study on human alpha-methylacyl-CoA racemase 1A (AMACR; P504S) | journal = Org. Biomol. Chem. | volume = 7 | issue = 3 | pages = 543–52 |date=February 2009 | pmid = 19156321 | doi = 10.1039/b815396e }}</ref>

<ref name = "Sharma_2007">{{cite journal | author = Sharma S, Bhaumik P, Schmitz W, Venkatesan R, Hiltunen JK, Conzelmann E, Juffer AH, Wierenga RK | title = 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 | journal = J Phys Chem B | volume = 116 | issue = 11 | pages = 3619–29 |date=March 2012 | pmid = 22360758 | doi = 10.1021/jp210185m }}</ref>

<ref name = "Ferdinandusse_2000">{{cite journal | author = Ferdinandusse S, Denis S, Clayton PT, Graham A, Rees JE, Allen JT, McLean BN, Brown AY, Vreken P, Waterham HR, Wanders RJ | title = Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy | journal = Nat. Genet. | volume = 24 | issue = 2 | pages = 188–91 |date=February 2000 | pmid = 10655068 | doi = 10.1038/72861 }}</ref>

<ref name = "Ouyang_2011">{{cite journal | author = Ouyang B, Leung YK, Wang V, Chung E, Levin L, Bracken B, Cheng L, Ho SM | title = α-Methylacyl-CoA racemase spliced variants and their expression in normal and malignant prostate tissues | journal = Urology | volume = 77 | issue = 1 | pages = 249.e1–7 |date=January 2011 | pmid = 21195844 | pmc = 3051191 | doi = 10.1016/j.urology.2010.08.005 }}</ref>

}}

==Further reading==
{{refbegin | 2}}
* {{cite journal  | author=Jiang Z, Woda BA, Wu CL, Yang XJ |title=Discovery and clinical application of a novel prostate cancer marker: alpha-methylacyl CoA racemase (P504S). |journal=Am. J. Clin. Pathol. |volume=122 |issue= 2 |pages= 275–89 |year= 2004 |pmid= 15323145 |doi= 10.1309/EJUY-UQPE-X1MG-68MK }}
* {{cite journal  | author=Bautch S |title=Wisconsin doctor selected as national symbol of physicians' sacrifices. |journal=Wis. Med. J. |volume=90 |issue= 8 |pages= 485–7 |year= 1991 |pmid= 1926890 |doi=  }}
* {{cite journal  | author=Schmitz W, Albers C, Fingerhut R, Conzelmann E |title=Purification and characterization of an alpha-methylacyl-CoA racemase from human liver. |journal=Eur. J. Biochem. |volume=231 |issue= 3 |pages= 815–22 |year= 1995 |pmid= 7649182 |doi=10.1111/j.1432-1033.1995.tb20766.x  }}
* {{cite journal  | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=10.1016/0378-1119(94)90802-8  }}
* {{cite journal  | author=Schmitz W, Helander HM, Hiltunen JK, Conzelmann E |title=Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases.  | series=326 |journal=Biochem. J. |volume=( Pt 3) |issue=  |pages= 883–9 |year= 1997 |pmid= 9307041 |doi=  | pmc=1218746  }}
* {{cite journal  | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=10.1016/S0378-1119(97)00411-3  }}
* {{cite journal  | author=Ferdinandusse S, Denis S, Clayton PT, ''et al.'' |title=Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. |journal=Nat. Genet. |volume=24 |issue= 2 |pages= 188–91 |year= 2000 |pmid= 10655068 |doi= 10.1038/72861 }}
* {{cite journal  | author=Kotti TJ, Savolainen K, Helander HM, ''et al.'' |title=In mouse alpha -methylacyl-CoA racemase, the same gene product is simultaneously located in mitochondria and peroxisomes. |journal=J. Biol. Chem. |volume=275 |issue= 27 |pages= 20887–95 |year= 2000 |pmid= 10770938 |doi= 10.1074/jbc.M002067200 }}
* {{cite journal  | author=Amery L, Fransen M, De Nys K, ''et al.'' |title=Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans. |journal=J. Lipid Res. |volume=41 |issue= 11 |pages= 1752–9 |year= 2001 |pmid= 11060344 |doi=  }}
* {{cite journal  | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788–95 |year= 2001 |pmid= 11076863 |doi=10.1101/gr.143000  | pmc=310948  }}
* {{cite journal  | author=Rubin MA, Zhou M, Dhanasekaran SM, ''et al.'' |title=alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer. |journal=JAMA |volume=287 |issue= 13 |pages= 1662–70 |year= 2002 |pmid= 11926890 |doi=10.1001/jama.287.13.1662  }}
* {{cite journal  | author=Luo J, Zha S, Gage WR, ''et al.'' |title=Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer. |journal=Cancer Res. |volume=62 |issue= 8 |pages= 2220–6 |year= 2002 |pmid= 11956072 |doi=  }}
* {{cite journal  | author=Zhou M, Chinnaiyan AM, Kleer CG, ''et al.'' |title=Alpha-Methylacyl-CoA racemase: a novel tumor marker over-expressed in several human cancers and their precursor lesions. |journal=Am. J. Surg. Pathol. |volume=26 |issue= 7 |pages= 926–31 |year= 2002 |pmid= 12131161 |doi=10.1097/00000478-200207000-00012  }}
* {{cite journal  | author=Kuefer R, Varambally S, Zhou M, ''et al.'' |title=alpha-Methylacyl-CoA racemase: expression levels of this novel cancer biomarker depend on tumor differentiation. |journal=Am. J. Pathol. |volume=161 |issue= 3 |pages= 841–8 |year= 2002 |pmid= 12213712 |doi=  10.1016/S0002-9440(10)64244-7| pmc=1867250  }}
* {{cite journal  | author=Varambally S, Dhanasekaran SM, Zhou M, ''et al.'' |title=The polycomb group protein EZH2 is involved in progression of prostate cancer. |journal=Nature |volume=419 |issue= 6907 |pages= 624–9 |year= 2002 |pmid= 12374981 |doi= 10.1038/nature01075 }}
* {{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 }}
* {{cite journal  | author=Leav I, McNeal JE, Ho SM, Jiang Z |title=Alpha-methylacyl-CoA racemase (P504S) expression in evolving carcinomas within benign prostatic hyperplasia and in cancers of the transition zone. |journal=Hum. Pathol. |volume=34 |issue= 3 |pages= 228–33 |year= 2003 |pmid= 12673556 |doi= 10.1053/hupa.2003.42 }}
* {{cite journal  | author=Shen-Ong GL, Feng Y, Troyer DA |title=Expression profiling identifies a novel alpha-methylacyl-CoA racemase exon with fumarate hydratase homology. |journal=Cancer Res. |volume=63 |issue= 12 |pages= 3296–301 |year= 2003 |pmid= 12810662 |doi=  }}
* {{cite journal  | author=Zha S, Ferdinandusse S, Denis S, ''et al.'' |title=Alpha-methylacyl-CoA racemase as an androgen-independent growth modifier in prostate cancer. |journal=Cancer Res. |volume=63 |issue= 21 |pages= 7365–76 |year= 2004 |pmid= 14612535 |doi=  }}
* {{cite journal  | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
{{refend}}

{{Peroxisomal proteins}}

[[Category:EC 5.1.99]]
[[Category:Enzymes of known structure]]
[[Category:Genes on chromosome 5]]
[[Category:Tumor markers]]