View source for Alpha-methylacyl-CoA racemase

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{cs1 config|name-list-style=vanc}}{{Infobox_gene}}
'''α-Methylacyl-CoA racemase''' ('''AMACR''', {{EnzExplorer|5.1.99.4}}) is an [[enzyme]] that in humans is encoded by the ''AMACR'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: AMACR alpha-methylacyl-CoA racemase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23600}}</ref><ref name="pmid9307041">{{cite journal | vauthors = Schmitz W, Helander HM, Hiltunen JK, Conzelmann E | title = Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases | journal = The Biochemical Journal | volume = 326 | issue =  3| pages = 883–9 | date = Sep 1997 | pmid = 9307041 | pmc = 1218746 | doi =  10.1042/bj3260883| url = http://www.biochemj.org/bj/326/0883/bj3260883.htm | series = 326 }}</ref><ref>{{cite web | title =  P504S, a-methylacyl-CoA racemase, AMACR | url = http://e-immunohistochemistry.info/web/P504S.htm | access-date = 25 April 2012 }}</ref> AMACR [[catalysis|catalyzes]] the following [[chemical reaction]]:

:(2''R'')-2-methylacyl-CoA <math>\rightleftharpoons</math> (2''S'')-2-methylacyl-CoA

In [[mammal]]ian 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.<ref name = "Schmitz_1994"/><ref name = "Lloyd_2008"/>

== Nomenclature ==
{{infobox enzyme
| Name       = alpha-methylacyl-CoA racemase
| EC_number  = 5.1.99.4
| CAS_number = 156681-44-6
| GO_code    = 0008111
| image      =
| width      = 
| caption    =  
}}
This enzyme belongs to the family of [[isomerase]]s, specifically the [[racemase]]s and [[epimerase]]s which act on other compounds.  The [[List of enzymes|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|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 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.<ref name = "Ferdinandusse_2000"/>

The first documented cases of AMACR deficiency in adults were reported in 2000.<ref name = "Ferdinandusse_2000"/> 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's disease|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."<ref name="pmid11861706">{{cite journal | vauthors = McLean BN, Allen J, Ferdinandusse S, Wanders RJ | title = A new defect of peroxisomal function involving pristanic acid: a case report | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 72 | issue = 3 | pages = 396–9 | date = Mar 2002 | pmid = 11861706 | pmc = 1737782 | doi = 10.1136/jnnp.72.3.396 }}</ref>

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.<ref name="urlPeroxisomal Disorders: Overview - eMedicine Neurology">{{cite web | url = http://emedicine.medscape.com/article/1177387-overview | title = Peroxisomal Disorders: Overview - eMedicine Neurology |vauthors=Chedrawi A, Clark GD | date = 2007-03-08 | publisher = medscape.com | access-date = 2009-03-16| archive-url= https://web.archive.org/web/20090302094129/http://emedicine.medscape.com/article/1177387-overview| archive-date= 2 March 2009 | url-status= live}}</ref><ref name="urlRefsum Disease -- GeneReviews -- NCBI Bookshelf">{{cite book | chapter-url = https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=refsum | title = Refsum Disease  |vauthors=Wanders RJ, Waterham HR, Leroy BP | chapter = Adult Refsum Disease | date = 2006-03-20 | journal =  GeneReviews -- NCBI Bookshelf | publisher = University of Washington, Seattle | pmid = 20301527 | access-date = 2009-03-16}}</ref>

=== 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 [[dimer (chemistry)|dimer]]isation. 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 | vauthors = Rubin MA, Bismar TA, Andrén O, Mucci L, Kim R, Shen R, Ghosh D, Wei JT, 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 Epidemiology, Biomarkers & Prevention | volume = 14 | issue = 6 | pages = 1424–32 | date = Jun 2005 | pmid = 15941951 | doi = 10.1158/1055-9965.EPI-04-0801 | doi-access = free }}</ref>

Antibodies to AMACR are used in [[immunohistochemistry]] to demonstrate [[prostate carcinoma]], since the enzyme is greatly overexpressed in this type of tumour.<ref name=Zhou2003>{{cite journal | vauthors = Zhou M, Jiang Z, Epstein JI | title = Expression and diagnostic utility of alpha-methylacyl-CoA-racemase (P504S) in foamy gland and pseudohyperplastic prostate cancer | journal = Am. J. Surg. Pathol. | volume = 27 | issue = 6 | pages = 772–8 | year = 2003 | pmid = 12766580 | doi =10.1097/00000478-200306000-00007| s2cid = 20098833 }}</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)  [[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,<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 | vauthors = Schmitz W, Fingerhut R, Conzelmann E | title = Purification and properties of an alpha-methylacyl-CoA racemase from rat liver | journal = European Journal of Biochemistry | volume = 222 | issue = 2 | pages = 313–23 | date = Jun 1994 | pmid = 8020470 | doi = 10.1111/j.1432-1033.1994.tb18870.x }}</ref>

<ref name = "Lloyd_2008">{{cite journal | vauthors = Lloyd MD, Darley DJ, Wierzbicki AS, Threadgill MD | title = Alpha-methylacyl-CoA racemase--an 'obscure' metabolic enzyme takes centre stage | journal = The FEBS Journal | volume = 275 | issue = 6 | pages = 1089–102 | date = Mar 2008 | pmid = 18279392 | doi = 10.1111/j.1742-4658.2008.06290.x | s2cid = 31870315 | doi-access = free }}</ref>

<ref name = "Woodman_2011">{{cite journal | vauthors = 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 = Chemical Communications | volume = 47 | issue = 26 | pages = 7332–4 | date = Jul 2011 | pmid = 21614403 | doi = 10.1039/c1cc10763a | s2cid = 205776988 | url = http://opus.bath.ac.uk/24764/1/Ibuprofen_AMACR.pdf }}</ref>

<ref name = "Darley_2009">{{cite journal | vauthors = 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 = Organic & Biomolecular Chemistry | volume = 7 | issue = 3 | pages = 543–52 | date = Feb 2009 | pmid = 19156321 | doi = 10.1039/b815396e }}</ref>

<ref name = "Sharma_2007">{{cite journal | vauthors = 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 = The Journal of Physical Chemistry B | volume = 116 | issue = 11 | pages = 3619–29 | date = Mar 2012 | pmid = 22360758 | doi = 10.1021/jp210185m }}</ref>

<ref name = "Ferdinandusse_2000">{{cite journal | vauthors = 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 = Nature Genetics | volume = 24 | issue = 2 | pages = 188–91 | date = Feb 2000 | pmid = 10655068 | doi = 10.1038/72861 | s2cid = 22649743 }}</ref>

<ref name = "Ouyang_2011">{{cite journal | vauthors = 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 = Jan 2011 | pmid = 21195844 | pmc = 3051191 | doi = 10.1016/j.urology.2010.08.005 }}</ref>

}}

==External links==
* {{UCSC gene info|AMACR}}
* [https://www.cbc.ca/news/canada/nova-scotia/halifax-man-genetic-condition-amacr-deficiency-oklahoma-young-boy-1.6340380 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 ==
{{refbegin | 2}}
* {{cite journal | vauthors = 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 = American Journal of Clinical Pathology | volume = 122 | issue = 2 | pages = 275–89 | date = Aug 2004 | pmid = 15323145 | doi = 10.1309/EJUY-UQPE-X1MG-68MK | doi-access = free }}
* {{cite journal | vauthors = Schmitz W, Albers C, Fingerhut R, Conzelmann E | title = Purification and characterization of an alpha-methylacyl-CoA racemase from human liver | journal = European Journal of Biochemistry | volume = 231 | issue = 3 | pages = 815–22 | date = Aug 1995 | pmid = 7649182 | doi = 10.1111/j.1432-1033.1995.tb20766.x | doi-broken-date = 3 December 2024 }}
* {{cite journal | vauthors = 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 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Schmitz W, Helander HM, Hiltunen JK, Conzelmann E | title = Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases | journal = The Biochemical Journal | volume = 326 | issue =  3| pages = 883–9 | date = Sep 1997 | pmid = 9307041 | pmc = 1218746 | doi =  10.1042/bj3260883| series = 326 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | 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 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = 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 = Nature Genetics | volume = 24 | issue = 2 | pages = 188–91 | date = Feb 2000 | pmid = 10655068 | doi = 10.1038/72861 | s2cid = 22649743 }}
* {{cite journal | vauthors = Kotti TJ, Savolainen K, Helander HM, Yagi A, Novikov DK, Kalkkinen N, Conzelmann E, Hiltunen JK, Schmitz W | title = In mouse alpha -methylacyl-CoA racemase, the same gene product is simultaneously located in mitochondria and peroxisomes | journal = The Journal of Biological Chemistry | volume = 275 | issue = 27 | pages = 20887–95 | date = Jul 2000 | pmid = 10770938 | doi = 10.1074/jbc.M002067200 | doi-access = free }}
* {{cite journal | vauthors = Amery L, Fransen M, De Nys K, Mannaerts GP, Van Veldhoven PP | title = Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans | journal = Journal of Lipid Research | volume = 41 | issue = 11 | pages = 1752–9 | date = Nov 2000 | doi = 10.1016/S0022-2275(20)31968-4 | pmid = 11060344 | doi-access = free }}
* {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = Nov 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
* {{cite journal | vauthors = Rubin MA, Zhou M, Dhanasekaran SM, Varambally S, Barrette TR, Sanda MG, Pienta KJ, Ghosh D, Chinnaiyan AM | title = alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer | journal = JAMA | volume = 287 | issue = 13 | pages = 1662–70 | date = Apr 2002 | pmid = 11926890 | doi = 10.1001/jama.287.13.1662 | doi-access = free }}
* {{cite journal | vauthors = Luo J, Zha S, Gage WR, Dunn TA, Hicks JL, Bennett CJ, Ewing CM, Platz EA, Ferdinandusse S, Wanders RJ, Trent JM, Isaacs WB, De Marzo AM | title = Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer | journal = Cancer Research | volume = 62 | issue = 8 | pages = 2220–6 | date = Apr 2002 | pmid = 11956072 }}
* {{cite journal | vauthors = Zhou M, Chinnaiyan AM, Kleer CG, Lucas PC, Rubin MA | title = Alpha-Methylacyl-CoA racemase: a novel tumor marker over-expressed in several human cancers and their precursor lesions | journal = The American Journal of Surgical Pathology | volume = 26 | issue = 7 | pages = 926–31 | date = Jul 2002 | pmid = 12131161 | doi = 10.1097/00000478-200207000-00012 | s2cid = 23042229 }}
* {{cite journal | vauthors = Kuefer R, Varambally S, Zhou M, Lucas PC, Loeffler M, Wolter H, Mattfeldt T, Hautmann RE, Gschwend JE, Barrette TR, Dunn RL, Chinnaiyan AM, Rubin MA | title = alpha-Methylacyl-CoA racemase: expression levels of this novel cancer biomarker depend on tumor differentiation | journal = The American Journal of Pathology | volume = 161 | issue = 3 | pages = 841–8 | date = Sep 2002 | pmid = 12213712 | pmc = 1867250 | doi = 10.1016/S0002-9440(10)64244-7 }}
* {{cite journal | vauthors = Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM | title = The polycomb group protein EZH2 is involved in progression of prostate cancer | journal = Nature | volume = 419 | issue = 6907 | pages = 624–9 | date = Oct 2002 | pmid = 12374981 | doi = 10.1038/nature01075 | bibcode = 2002Natur.419..624V | hdl = 2027.42/62896 | s2cid = 4414767 | url = http://deepblue.lib.umich.edu/bitstream/2027.42/62896/1/nature01075.pdf | hdl-access = free }}
* {{cite journal | vauthors = 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 = Human Pathology | volume = 34 | issue = 3 | pages = 228–33 | date = Mar 2003 | pmid = 12673556 | doi = 10.1053/hupa.2003.42 }}
* {{cite journal | vauthors = Shen-Ong GL, Feng Y, Troyer DA | title = Expression profiling identifies a novel alpha-methylacyl-CoA racemase exon with fumarate hydratase homology | journal = Cancer Research | volume = 63 | issue = 12 | pages = 3296–301 | date = Jun 2003 | pmid = 12810662 }}
* {{cite journal | vauthors = Zha S, Ferdinandusse S, Denis S, Wanders RJ, Ewing CM, Luo J, De Marzo AM, Isaacs WB | title = Alpha-methylacyl-CoA racemase as an androgen-independent growth modifier in prostate cancer | journal = Cancer Research | volume = 63 | issue = 21 | pages = 7365–76 | date = Nov 2003 | pmid = 14612535 }}
{{refend}}

{{Peroxisomal proteins}}
{{Racemases and epimerases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

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