α-Methylacyl-CoA racemase (AMACR, ) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''AMACR''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
AMACR
catalyzes the following
chemical reaction
A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
:
:(2''R'')-2-methylacyl-CoA
(2''S'')-2-methylacyl-CoA
In
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
ian cells, the enzyme is responsible for converting (2''R'')-methylacyl-CoA esters to their (2''S'')-methylacyl-CoA epimers and known substrates, including
coenzyme A
Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
esters of
pristanic acid
Pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) is a terpenoid acid present at micromolar concentrations in the blood plasma of healthy individuals. It is also found in the lipids from many sources such as freshwater sponges, krill, earthw ...
(mostly derived from
phytanic acid
Phytanic acid (or 3,7,11,15-tetramethyl hexadecanoic acid) is a branched chain fatty acid that humans can obtain through the consumption of dairy products, ruminant animal fats, and certain fish. Western diets are estimated to provide 50–100  ...
, 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 (2''R'')-methylacyl-CoA esters by
β-oxidation
In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, ...
, which process requires the (2''S'')-epimer. The enzyme is known to be localised in
peroxisomes
A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...
and
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
, both of which are known to β-oxidize 2-methylacyl-CoA esters.
Nomenclature
This enzyme belongs to the family of
isomerase
Isomerases are a general class of enzymes that convert a molecule from one isomer to another. Isomerases facilitate intramolecular rearrangements in which bonds are broken and formed. The general form of such a reaction is as follows:
A–B ↠...
s, specifically the
racemase Epimerases and racemases are isomerase enzymes that catalyze the inversion of stereochemistry in biological molecules.
Racemases catalyze the stereochemical inversion around the asymmetric carbon atom in a substrate having only one center of asymm ...
s and
epimerase Epimerases and racemases are isomerase enzymes that catalyze the inversion of stereochemistry in biological molecules.
Racemases catalyze the stereochemical inversion around the asymmetric carbon atom in a substrate having only one center of asymme ...
s which act on other compounds. The
systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature.
A semisystematic name or semitrivial ...
of this enzyme class is 2-methylacyl-CoA 2-epimerase. In vitro experiments with the human enzyme AMACR 1A show that both (2''S'')- and (2''R'')-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) followed by non-sterespecific reprotonation.
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
Refsum disease is an autosomal recessive neurological disease that results in the over-accumulation of phytanic acid in cells and tissues. It is one of several disorders named after Norwegian neurologist Sigvald Bernhard Refsum (1907–1991). Ref ...
and usually appear in the late teens or early twenties.
The first documented case of AMACR deficiency was reported in 2006. This deficiency falls within a class of disorders called
peroxisome biogenesis disorders
Peroxisomal disorders represent a class of medical conditions caused by defects in peroxisome functions. This may be due to defects in single enzymes important for peroxisome function or in peroxins, proteins encoded by ''PEX'' genes that are cri ...
(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
Pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) is a terpenoid acid present at micromolar concentrations in the blood plasma of healthy individuals. It is also found in the lipids from many sources such as freshwater sponges, krill, earthw ...
,
DHCA and
EHCA and to a lesser extent
Very long chain fatty acid A very-long-chain fatty acid (VLCFA) is a fatty acid with 22 or more carbons. Their biosynthesis occurs in the endoplasmic reticulum. VLCFA's can represent up to a few percent of the total fatty acid content of a cell.
Unlike most fatty acids, V ...
and
phytanic acid
Phytanic acid (or 3,7,11,15-tetramethyl hexadecanoic acid) is a branched chain fatty acid that humans can obtain through the consumption of dairy products, ruminant animal fats, and certain fish. Western diets are estimated to provide 50–100  ...
. 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."
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.
Cancer
Increased levels of AMACR protein concentration and activity are associated with
prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
, and the enzyme is used widely as a
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
(known in cancer literature as
P504S
α-Methylacyl-CoA racemase (AMACR, ) is an enzyme that in humans is encoded by the ''AMACR'' gene. AMACR catalyzes the following chemical reaction:
:(2''R'')-2-methylacyl-CoA \rightleftharpoons (2''S'')-2-methylacyl-CoA
In mammalian cells, the ...
) 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
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ...
isation. 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.
Antibodies to AMACR are used in
immunohistochemistry
Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to an ...
to demonstrate
prostate carcinoma
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
, since the enzyme is greatly overexpressed in this type of tumour.
Ibuprofen metabolism
The enzyme is also involved in a chiral inversion pathway which converts
ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arte ...
, a member of the 2-arylpropionic acid (2-APA)
non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
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
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arte ...
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
Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prost ...
enzymes and induces an anti-inflammatory effect. Human AMACR 1A has been demonstrated to epimerise other 2-APA-CoA esters,
suggesting a common chiral inversion pathway for this class of drugs.
References
External links
*
N.S. man thought he'd never find anyone else with his condition. Then he got a text from Oklahoma CBC News
CBC News is a division of the Canadian Broadcasting Corporation responsible for the news gathering and production of news programs on the corporation's English-language operations, namely CBC Television, CBC Radio, CBC News Network, and CBC.ca. ...
. Feb 7, 2022
Further reading
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EC 5.1.99
Enzymes of known structure
Genes on human chromosome 5
Tumor markers