Alpha-methylacyl-CoA racemase
| AMACR | |||
|---|---|---|---|
| Identifiers | |||
Gene ontology | |||
| Molecular function | |||
| Cellular component | |||
| Biological process | |||
| Sources:Amigo / QuickGO | |||
Ensembl | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| UniProt | |||||||||
| RefSeq (mRNA) |
| ||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 5: 33.99 – 34.01 Mb | Chr 15: 10.98 – 11 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
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
In
Nomenclature
| alpha-methylacyl-CoA racemase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
This enzyme belongs to the family of
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.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
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
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
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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000242110 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022244 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: AMACR alpha-methylacyl-CoA racemase".
- PMID 9307041.
- ^ "P504S, a-methylacyl-CoA racemase, AMACR". Retrieved 25 April 2012.
- PMID 8020470.
- ^ S2CID 31870315.
- PMID 22360758.
- PMID 19156321.
- ^ S2CID 22649743.
- PMID 11861706.
- ^ 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.
- )
- PMID 21195844.
- PMID 15941951.
- S2CID 20098833.
- S2CID 205776988.
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
- Jiang Z, Woda BA, Wu CL, Yang XJ (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. PMID 15323145.
- 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. 231 (3): 815–22. 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. PMID 8125298.
- 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. 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. PMID 9373149.
- 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. S2CID 22649743.
- Kotti TJ, Savolainen K, Helander HM, Yagi A, Novikov DK, Kalkkinen N, Conzelmann E, Hiltunen JK, Schmitz W (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. PMID 10770938.
- Amery L, Fransen M, De Nys K, Mannaerts GP, Van Veldhoven PP (Nov 2000). "Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans". Journal of Lipid Research. 41 (11): 1752–9. PMID 11060344.
- Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. PMID 11076863.
- Rubin MA, Zhou M, Dhanasekaran SM, Varambally S, Barrette TR, Sanda MG, Pienta KJ, Ghosh D, Chinnaiyan AM (Apr 2002). "alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer". JAMA. 287 (13): 1662–70. PMID 11926890.
- 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 (Apr 2002). "Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer". Cancer Research. 62 (8): 2220–6. PMID 11956072.
- Zhou M, Chinnaiyan AM, Kleer CG, Lucas PC, Rubin MA (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. S2CID 23042229.
- 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 (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. PMID 12213712.
- 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 (Oct 2002). "The polycomb group protein EZH2 is involved in progression of prostate cancer" (PDF). Nature. 419 (6907): 624–9. S2CID 4414767.
- Leav I, McNeal JE, Ho SM, 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. PMID 12673556.
- Shen-Ong GL, Feng Y, Troyer DA (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 RJ, Ewing CM, Luo J, De Marzo AM, Isaacs WB (Nov 2003). "Alpha-methylacyl-CoA racemase as an androgen-independent growth modifier in prostate cancer". Cancer Research. 63 (21): 7365–76. PMID 14612535.
