National Cancer Research Institute South of England
Prostate Cancer Collaborative
Research

The molecular role of a -Methylacyl-CoA racemase in prostatic cancer

Author

Dr Matthew Lloyd

University of Bath

a -Methylacyl-CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme involved in the metabolism of 2-methyl fatty acids. In the last two or three years it has been observed that expression of this protein is increased in prostate and certain other cancers, and this has been used as the basis of a new diagnostic method in conjunction with prostate specific antigen (PSA) screening. Further experiments have shown that there are several different forms of AMACR, and some of these forms are over-expressed in cancer. Cell experiments have also shown that reducing AMACR expression prevents cancer proliferation, suggesting that it could be a novel prostate cancer target. Branched-chain fatty acids are found at high levels in types of certain food (Figure 1), and men who ingest large quantities are at increase risk of developing prostate cancer. This suggests that branched fats are somehow involved in the development or maintenance of the cancerous state.

Fig01

Figure 1: Typical branched-chain fatty acids and drugs

Normal cells are only able to metabolise 2-methyl fatty acids with S-stereochemistry. However, 2-methyl fatty acids with 2R-stereochemistry are obtained from the diet either directly or as products of abundant 3-methyl fatty acids. A typical intake of phytanic acid is ~100 mg per day, and in humans this is chain shortened to give the 2-methyl homologue, pristanic acid. The major (non-cancerous) form of the enzyme has also been implicated in the pharmaceutical and toxic effects of ibuprofen (Figure 1) and related drugs. Bile acids, which are produced from cholesterol, are produced in the body solely with R-stereochemistry. The role of AMACR in normal cells is to convert these 2-methyl fatty acids with R-stereochemistry into their equivalents with S-stereochemistry to allow further processing.

Fig02

Funding has been obtained from the NCRI to produce the various forms of AMACR for study. Important long-term questions are: (1) Which fats are processed and can they be converted in both directions or only one?; (2) Are all of the forms active and if so do they all process the same fats/drugs?; (3) If different forms have different activities what are the implications for normal and cancerous cells?; (4) What are the structures of the various forms of AMACR and can drugs be designed specifically to inhibit the cancerous forms?

 

 

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