Subcellular localization and physiological role of α-methylacyl-CoA racemase

Departments of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
The Journal of Lipid Research (Impact Factor: 4.42). 12/2000; 41(11):1890-6.
Source: PubMed


alpha-Methylacyl-CoA racemase plays an important role in the beta-oxidation of branched-chain fatty acids and fatty acid derivatives because it catalyzes the conversion of several (2R)-methyl-branched-chain fatty acyl-CoAs to their (S)-stereoisomers. Only stereoisomers with the 2-methyl group in the (S)-configuration can be degraded via beta-oxidation. Patients with a deficiency of alpha-methylacyl-CoA racemase accumulate in their plasma pristanic acid and the bile acid intermediates di- and trihydroxycholestanoic acid, which are all substrates of the peroxisomal beta-oxidation system. Subcellular fractionation experiments, however, revealed that both in humans and rats alpha-methylacyl-CoA racemase is bimodally distributed to both the peroxisome and the mitochondrion. Our findings show that the peroxisomal and mitochondrial enzymes are produced from the same gene and that, as a consequence, the bimodal distribution pattern must be the result of differential targeting of the same gene product. In addition, we investigated the physiological role of the enzyme in the mitochondrion. Both in vitro studies with purified heterologously expressed protein and in vivo studies in fibroblasts of patients with an alpha-methylacyl-CoA racemase deficiency revealed that the mitochondrial enzyme plays a crucial role in the mitochondrial beta-oxidation of the breakdown products of pristanic acid byconverting (2R,6)-dimethylheptanoyl-CoA to its (S)-stereoisomer.

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    • "AMACR is a mitochondrial and peroxisomal enzyme that is part of the degradation of branched chained fatty acid derivates. AMACR is essential for the completion of the β-oxidation pathway [15] and has recently been shown to upregulated in colorectal cancer and adenoma [16-18]; 4) BRAF, MLH1 and β-catenin as additional markers involved in the serrated adenocarcinoma carcinogenesis. "
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    ABSTRACT: Hyperplastic polyps (HP) and sessile serrated adenomas (SSA) share morphological similarities. In this immunohistochemical study we chose a panel of potential relevant and promising biomarkers including alpha-methylacyl-coenzyme A racemase (AMACR;p504s) , which is involved in the degradation of branched chained fatty acids derivates, and analysed a cohort of HPs and SSAs in order to identify different immunophenotypes in relation to lesion localisation. 154 specimen were carefully selected and a micro tissue array (TMA) was constructed. Immunohistochemistry of p16Ink4a, Ki67, alpha-methylacyl-coenzyme A racemase (AMACR;p504s), BRAF, CK 20 , MLH1 and beta-catenin was performed and and immunoexpression was compared among proximal and distal HPs as well as SSAs. None of the markers revealed a differential expression among HPs and SSAs. However, the study demonstrates a significant overexpression of AMACR (p = 0.004) and p16Ink4a (p = 0.028) in distal HPs compared to proximal HPs. In addition AMACR overexpression was associated with increased p16 Ink4a immunoexpression (p < 0.001). In this study we describe differential AMACR and p16 Ink4a in HPs in relation to their localisation. Distal HPs were characterized by AMACR and p16Ink4a overexpression in contrast to proximal HPs, although morphological identically. Thus AMACR overexpression points towards a pathobiological relevance of the protein in distal HPs. In context of recently published data this suggest distal HPs as potential precursor lesions of certain adenoma subtypes. However, at this point of time this finding remains speculative and needs to be confirmed by further studies.Virtual slidesThe virtual slide(s) for this article can be found here:
    Full-text · Article · Oct 2013 · Diagnostic Pathology
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    • "Mutations in the AMACR gene have been identified in patients with sensory motor neuropathy (Ferdinandusse et al., 2000), and the association of sequence variants in the coding region of AMACR has been observed in patients with hereditary prostate cancer and colorectal adenoma (Zheng et al., 2002; Daugherty et al., 2007a). "
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    ABSTRACT: The AMACR gene is located in the schizophrenia susceptibility locus on chromosome 5p13, previously identified in a large Puerto Rican pedigree of Spanish origin. The AMACR-encoded protein is an enzyme involved in the metabolism of branched-chain fatty and bile acids. The enzyme deficiency causes structural and functional brain changes, and disturbances in fatty acid and oxidative phosphorylation pathways observed in individuals with schizophrenia. Therefore, AMACR is both a positional and functional candidate gene for susceptibility to schizophrenia. The study had a two-step design: we performed mutation analysis of the coding and flanking regions of AMACR in affected members of the pedigree, and tested the detected sequence variants for association with schizophrenia in a Puerto Rican case-control sample (n=383) of Spanish descent. We identified three missense variants segregating with the disorder in the family, rs2278008, rs2287939 and rs10941112. Two of them, rs2278008 and rs2287939, demonstrated significant differences in genotype (P = 4 × 10-4, P = 4 × 10-4) and allele (P = 1 × 10-4, P = 9.5 × 10-5) frequencies in unrelated male patients compare to controls, with the odds ratios (OR) 2.24 (95% CI: 1.48-3.40) and 2.25 (95% CI: 1.49-3.38), respectively. The G-C-G haplotype of rs2278008-rs2287939-rs10941112 revealed the most significant association with schizophrenia (P = 4.25 × 10-6, OR = 2.96; 95% CI: 1.85-4.76) in male subjects. There were no statistically significant differences in genotype, allele, and haplotype frequencies between female schizophrenia subjects and controls. Our results suggest that AMACR may play a significant role in susceptibility to schizophrenia in male patients.
    Full-text · Article · Sep 2010 · Schizophrenia Research
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    • "Alpha-methylacyl coenzyme A racemase (AMACR) was identified as one of the genes that were highly expressed in prostate cancer tissues through gene expression profiling using a DNA microarray and RT-PCR [6-8]. AMACR is an enzyme that catalyzes the racemization of alpha-methyl carboxylic coenzyme A thioesters in mitochondria and peroxisomes [9,10]. AMACR is expressed abundantly in prostate cancer tissues as well as colorectal cancer and lung cancer tissues, whereas it is barely detected in benign tissues and normal prostate epithelial cells [6-8]. "
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    ABSTRACT: Alpha-methylacyl-CoA racemase (AMACR) is an enzyme playing an important role in the beta-oxidation of branched-chain fatty acids and fatty acid derivatives. High expression levels of AMACR have been described in various cancers, including prostate cancer, colorectal cancer and kidney cancer. Because of its cancer-specific and frequent expression, AMACR could be an attractive target for cytotoxic T-lymphocyte (CTL)-based immunotherapy for cancer. In the present study, we examined the induction of AMACR-specific CTLs from prostate cancer patients' peripheral blood mononuclear cells (PBMCs) and determined HLA-A24-restricted CTL epitopes. RT-PCR and immunohistochemical analysis revealed that AMACR was strongly expressed in prostate cancer cell lines and tissues as compared with benign or normal prostate tissues. Four AMACR-derived peptides carrying the HLA-A24-binding motif were synthesized from the amino acid sequence of this protein and analyzed to determine their binding affinities to HLA-A24. By stimulating patient's PBMCs with the peptides, specific CTLs were successfully induced in 6 of 11 patients. The peptide-specific CTLs exerted significant cytotoxic activity against AMACR-expressing prostate cancer cells in the context of HLA-A24. Our study demonstrates that AMACR could become a target antigen for prostate cancer immunotherapy, and that the AMACR-derived peptides might be good peptide vaccine candidates for HLA-A24-positive AMACR-expressing cancer patients.
    Full-text · Article · Dec 2009 · Journal of Translational Medicine
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