Alpha-methylacyl-CoA racemase

α-Methylacyl-CoA racemase (AMACR, EC 5.1.99.4) is an enzyme that in humans is encoded by the AMACR gene.[5][6][7] AMACR catalyzes the following chemical reaction:

(2R)-2-methylacyl-CoA (2S)-2-methylacyl-CoA
AMACR
Identifiers
AliasesAMACR, AMACRD, CBAS4, RACE, RM, alpha-methylacyl-CoA racemase, P504S
External IDsOMIM: 604489 MGI: 1098273 HomoloGene: 7410 GeneCards: AMACR
EC number5.1.99.4
Orthologs
SpeciesHumanMouse
Entrez

23600

17117

Ensembl

ENSG00000242110

ENSMUSG00000022244

UniProt

Q9UHK6

O09174

RefSeq (mRNA)

NM_008537

RefSeq (protein)

NP_001161067
NP_055139
NP_976316

NP_032563

Location (UCSC)Chr 5: 33.99 – 34.01 MbChr 15: 10.98 – 11 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[8][9]

Nomenclature
alpha-methylacyl-CoA racemase
Identifiers
EC no.5.1.99.4
CAS no.156681-44-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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[10]) followed by non-sterespecific reprotonation.[11] 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.[12]

The first documented cases of AMACR deficiency in adults were reported in 2000.[12] 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."[13]

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.[14][15]

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.[9][16][17]

Antibodies to AMACR are used in immunohistochemistry to demonstrate prostate carcinoma, since the enzyme is greatly overexpressed in this type of tumour.[18]

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,[19] suggesting a common chiral inversion pathway for this class of drugs.

References
  1. GRCh38: Ensembl release 89: ENSG00000242110 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000022244 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: AMACR alpha-methylacyl-CoA racemase".
  6. Schmitz W, Helander HM, Hiltunen JK, Conzelmann E (Sep 1997). "Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases". The Biochemical Journal. 326. 326 (3): 883–9. doi:10.1042/bj3260883. PMC 1218746. PMID 9307041.
  7. "P504S, a-methylacyl-CoA racemase, AMACR". Retrieved 25 April 2012.
  8. Schmitz W, Fingerhut R, Conzelmann E (Jun 1994). "Purification and properties of an alpha-methylacyl-CoA racemase from rat liver". European Journal of Biochemistry. 222 (2): 313–23. doi:10.1111/j.1432-1033.1994.tb18870.x. PMID 8020470.
  9. Lloyd MD, Darley DJ, Wierzbicki AS, Threadgill MD (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. S2CID 31870315.
  10. Sharma S, Bhaumik P, Schmitz W, Venkatesan R, Hiltunen JK, Conzelmann E, Juffer AH, Wierenga RK (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.
  11. Darley DJ, Butler DS, Prideaux SJ, Thornton TW, Wilson AD, Woodman TJ, Threadgill MD, Lloyd MD (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.
  12. Ferdinandusse S, Denis S, Clayton PT, Graham A, Rees JE, Allen JT, McLean BN, Brown AY, Vreken P, Waterham HR, Wanders RJ (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. S2CID 22649743.
  13. McLean BN, Allen J, Ferdinandusse S, Wanders RJ (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.
  14. 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.
  15. Wanders RJ, Waterham HR, Leroy BP (2006-03-20). "Adult Refsum Disease". Refsum Disease. PMID 20301527. Retrieved 2009-03-16. {{cite book}}: |journal= ignored (help)
  16. Ouyang B, Leung YK, Wang V, Chung E, Levin L, Bracken B, Cheng L, Ho SM (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.
  17. Rubin MA, Bismar TA, Andrén O, Mucci L, Kim R, Shen R, Ghosh D, Wei JT, Chinnaiyan AM, Adami HO, Kantoff PW, Johansson JE (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.
  18. Zhou M, Jiang Z, Epstein JI (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. S2CID 20098833.
  19. Woodman TJ, Wood PJ, Thompson AS, Hutchings TJ, Steel GR, Jiao P, Threadgill MD, Lloyd MD (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" (PDF). Chemical Communications. 47 (26): 7332–4. doi:10.1039/c1cc10763a. PMID 21614403.

Further reading
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