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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.
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.
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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