Enoyl CoA Isomerase
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Enoyl-CoA-(∆) isomerase (, also known as dodecenoyl-CoA-(∆) isomerase, 3,2-trans-enoyl-CoA isomerase, ∆3(cis),∆2(trans)-enoyl-CoA isomerase, or acetylene-allene isomerase, is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that
catalyzes Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the conversion of cis- or trans-
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s of coenzyme A (CoA) bound fatty acids at gamma- carbon (position 3) to trans
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s at beta- carbon (position 2) as below: This enzyme has an important role in the metabolism of unsaturated fatty acids in beta oxidation.


Mechanism

Enoyl-CoA isomerase is involved in the beta-oxidation, one of the most frequently used pathways in fatty acid degradation, of unsaturated fatty acids with
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s at odd-numbered carbon positions. It does so by shifting the position of the
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s in the acyl-CoA intermediates and converting 3-cis or trans-enoyl-CoA to 2-trans-enoyl-CoA. Since the key step in the degradation of fatty acids with
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s at even-numbered carbon positions also produces 3-trans-enoyl-CoA in
mammal Mammals () are a group of vertebrate animals constituting the class (biology), class Mammalia (), characterized by the presence of mammary glands which in Female#Mammalian female, females produce milk for feeding (nursing) their young, a ...
s and yeasts, enoyl-CoA isomerase is technically required for their metabolism as well. The
reaction mechanism In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs. A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage of ...
is detailed in figure 1, and the base that initiates the isomerization and NH groups that stabilize the intermediate are located on the active site of enoyl-coA isomerase. As it functions in the step immediately preceding the actual beta-oxidation and forms a
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
extending from the beta- carbon (position 2), enoyl-CoA isomerase is involved in both the
NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
-dependent and
NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
-independent pathways of beta-oxidation. The
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
serves as the target of oxidation and carbon-to- carbon bond cleavage, thereby shortening the fatty acid chain.


Sub-classification

Enoyl-CoA isomerases can be categorized into three classes: *monofunctional
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
*monofunctional peroxisomal *multifunctional The monofunctional
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
and peroxisomal
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s are found in the
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 ...
and
peroxisome 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 ...
s of
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s, respectively. The multifunctional
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s are found in
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
and in the
peroxisome 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 ...
s of some
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s, but they serve two functions: the
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
domain works the same as the other classes of enoyl-CoA isomerases and the
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
domain works as a dehydrogenase, specifically, to 3-hydroxyactyl-CoA. There are two divisions among the
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 ...
l enoyl Co-A isomerase: short-chain and long-chain In an immunoblot, antibodies were run against all enoyl CoA isomerase. However, two of these isomerases had
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
attachment: the short chain isomerase and the peroxisomal multifunctional enzyme. There was one
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
which did not have binding specificity to this
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
: mitochondrial long-chain isomerase. Long-chain isomerase was found when it eluted at a lower potassium phosphate concentration in the gradient. Thus, the discovery of three sub-classes of enoyl CoA isomerase was made. Although all three classes of
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s have the same function, there is little overlap among their
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
sequences. For example, only 40 out of 302
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
sequences (13%) are the same between monofunctional peroxisomal and
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s in
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
s. In fact, in
mammal Mammals () are a group of vertebrate animals constituting the class (biology), class Mammalia (), characterized by the presence of mammary glands which in Female#Mammalian female, females produce milk for feeding (nursing) their young, a ...
s, the peroxisomal
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
has an extra
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
domain that is not present in the
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
counterpart. Also, it has been found to be a
subunit Subunit may refer to: *Subunit HIV vaccine, a class of HIV vaccine *Protein subunit, a protein molecule that assembles with other protein molecules *Monomer, a molecule that may bind chemically to other molecules to form a polymer *Sub-subunit, a ...
of the peroxisomal trifunctional
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
(pTFE) and contributes only to minor cleavages of the fatty acid chain. In that sense, for many higher organisms, the
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
is essential for deriving maximum energy from lipids and fueling
muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
s.
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 short- and long-chain) of rat liver contain more than one enoyl Co-A isomerase. To further support the idea that short- and long-chain isomerases elute at different concentration of potassium phosphate concentration, they do not share similar primary polypeptide structure, hence they must not be evolutionarily related.
Peroxisome 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 ...
s of plants and of rat liver are very different in the way they operate. Despite their
primary structure Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthes ...
similarities, there are differences among the different specimen. To begin with, the
peroxisome 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 ...
s of rat liver are a multifunctional
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
including enoyl-CoA isomerase, enoyl-CoA
hydratase In chemistry, a hydration reaction is a chemical reaction in which a substance combines with water. In organic chemistry, water is added to an unsaturated substrate, which is usually an alkene or an alkyne. This type of reaction is employed industr ...
, and L-(−)-3-hydroxyacyl-CoA dehydrogenase. Three different
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s reside on this entity (multifunctional protein) allowing this
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
to perform isomerization, hydration, and dehydration. Isomerase activity on the multifunctional
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
occurs at the amino-terminal catalytic half of the protein along with the
hydratase In chemistry, a hydration reaction is a chemical reaction in which a substance combines with water. In organic chemistry, water is added to an unsaturated substrate, which is usually an alkene or an alkyne. This type of reaction is employed industr ...
activity. The dehydrogenase activity of enoyl-CoA occurs in the carboxyl-terminal. Upon further investigation of the CoA binding site on the amino-terminal half of the multifunctional
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
, the CoA
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...
is not transferred through the aqueous phase from the isomerization phase to the site of hydration or does not have a bulk phase. This removes the need for a substrate transferring
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
. On the other hand, the
cotyledon A cotyledon (; ; ; , gen. (), ) is a significant part of the embryo within the seed of a plant, and is defined as "the embryonic leaf in seed-bearing plants, one or more of which are the first to appear from a germinating seed." The num ...
s convert long-chain 3-trans-enoyl-CoA, long-chain 3-cis-enoyl-CoA, and short-chain 3-cis-enoyl-CoA species into their 2- trans-enoyl-CoA respective forms. As previously mentioned, plant enoyl-CoA isomerase exclusively forms the 2-trans
isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...
as product. It does not act on 4-cis-enoyl-CoA species or 2-trans- 4-trans-dienoyl-CoA species. In comparing the products of the plant
peroxisome 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 the multifunctional enzyme of rat liver, the plant has no
hydratase In chemistry, a hydration reaction is a chemical reaction in which a substance combines with water. In organic chemistry, water is added to an unsaturated substrate, which is usually an alkene or an alkyne. This type of reaction is employed industr ...
activity. The Plant form did not form a 2-cis-isomer (from enoyl-CoA hydratase) or D- or L- 3 hydroxy derivative (L-(−)-3-hydroxyacyl-CoA dehydrogenase): products of multifunctional enzyme of rat liver. The turnover rates of these the two sub divisions of
peroxisome 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 ...
s are very different. The Kcat/Km ratio in
cotyledon A cotyledon (; ; ; , gen. (), ) is a significant part of the embryo within the seed of a plant, and is defined as "the embryonic leaf in seed-bearing plants, one or more of which are the first to appear from a germinating seed." The num ...
s is 10^6 M-1s-1 which outperforms the ratio .07 * 10^6 M-1s-1. Due to a high turnover rate, the plant
peroxisome 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 ...
s contain a lesser amount of enoyl-CoA isomerase than their counterparts in the rat liver. In rat liver,
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 ...
l enoyl CoA isomerase and peroxisomal enoyl CoA isomerase embedded in the multifunctional enzyme have similarities in the primary structure sequence. When comparing the amino-terminal half of
E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
against the amino-terminal half of rat liver, there were primary and secondary structure similarities towards the middle of the amino-terminal end. This conserved region must be important for structure and function of this specific enzyme since showing equally in both
E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
and rat liver.


Structure

All classes of enoyl-CoA isomerases belong to a family of
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s, the
hydratase In chemistry, a hydration reaction is a chemical reaction in which a substance combines with water. In organic chemistry, water is added to an unsaturated substrate, which is usually an alkene or an alkyne. This type of reaction is employed industr ...
/ isomerase or crotonase superfamily, and when examined with x-ray crystallography, exhibit a common structural feature of the family, the
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
core with a spiral fold composed of four turns, each turn consisting of two beta-sheets and one alpha-helix. In enoyl-CoA isomerase, the two beta-sheets are part of the catalytic site, since the NH groups of
residues Residue may refer to: Chemistry and biology * An amino acid, within a peptide chain * Crop residue, materials left after agricultural processes * Pesticide residue, refers to the pesticides that may remain on or in food after they are appli ...
following the beta-sheets attach to the
carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containin ...
oxygen of the acyl-CoA intermediate. The formation of this oxyanion hole stabilizes the transition state of the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
-catalyzed reaction. Moreover, a
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
residue located next to body cavities filled with water molecules and lined with hydrophobic or apolar side chains has also been identified as a part of the catalytic site. In its deprotonated form, the
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
can act as a base and remove a
proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
from the acyl-CoA intermediate. The body cavities aid in rearranging the
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
side chain to retain the
proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
and later deliver it back to the acyl-CoA, on a different carbon position. The NH-containing
residues Residue may refer to: Chemistry and biology * An amino acid, within a peptide chain * Crop residue, materials left after agricultural processes * Pesticide residue, refers to the pesticides that may remain on or in food after they are appli ...
have been identified as Ala70 and Leu126 and the
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
as Glu158 in peroxisomal
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s in a yeast species, '' Saccharomyces cerevisiae''. Their relative locations on the enzyme can be compared in figure 2. The
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s of the
hydratase In chemistry, a hydration reaction is a chemical reaction in which a substance combines with water. In organic chemistry, water is added to an unsaturated substrate, which is usually an alkene or an alkyne. This type of reaction is employed industr ...
/ isomerase or crotonase superfamily are typically trimeric disks dimerized into hexamers. The wide range of their
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...
-
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
specificity derives from the variations in the distances between the trimeric disks and their orientation. However, the
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
enoyl-CoA isomerase is a trimer and orients the fatty acid tail in a completely different direction from that seen in the
hexamers In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relative ...
. The trimeric disk of peroxisomal
enzymes 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 ...
in '' Saccharomyces cerevisiae'' is displayed in figure 3.


History

Enoyl-CoA isomerase was first identified and purified from
rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...
liver
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 ...
in the 1960s and 1970s via gel filtration and ion exchange chromatography. Since then, all classes of enoyl-CoA isomerase,
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
, peroxisomal and multifunctional, have been identified in different organisms, including more
mammal Mammals () are a group of vertebrate animals constituting the class (biology), class Mammalia (), characterized by the presence of mammary glands which in Female#Mammalian female, females produce milk for feeding (nursing) their young, a ...
s, plants, and unicellular organisms. By 1994, using the
rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...
enoyl-CoA isomerase cDNA as a hybridization probe,
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
enoyl-CoA isomerase cDNA could be sequenced and cloned. In the same year, the protein itself was isolated, not by affinity to
rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
or cDNA probes, but by co purification with a transferase, human glutathione S-transferases. In the attempts to examine the
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
enoyl-CoA isomerase in detail, the
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
in the mammalian liver was identified as a potential biological marker for metabolic diseases due to its elevated levels in defective cells, and linked defects in fatty acid beta-oxidation to
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
diseases, to be specified in the next section.


Clinical significance

In
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
s, defects in the beta-oxidation mechanism result in hypoketotic
hyperglycemia Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200  mg/dL), but symptoms may not start to become noticeable until even ...
, a
symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
of
starvation Starvation is a severe deficiency in caloric energy intake, below the level needed to maintain an organism's life. It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ damage and eventually, dea ...
, due to the inefficient utilization of fatty acids as a primary source of energy. The metabolic disease was found to be on a genetic level:
rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...
s without the
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 b ...
s for enoyl-CoA isomerase also displayed high blood glucose level. Moreover, a biological marker for this condition may have been identified as the urine of these
rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...
s included high concentrations of medium chain unsaturated dicarboxylic acids, a condition called dicarboxylic aciduria. More recent studies link hepatitis C virus (HCV) infection to defects in fatty acid degradation, specifically, to that in enoyl-CoA isomerase. HCV is the leading cause of chronic hepatitis,
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
, and
liver cancer Liver cancer (also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy) is cancer that starts in the liver. Liver cancer can be primary (starts in liver) or secondary (meaning cancer which has spread from elsewhere to th ...
, and more than 180 million people are affected globally. Due to the prolonged latency of the
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
and no existing cures to rid the
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
specifically, HCV is a serious problem that is causing more deaths than HIV/AIDS in the
United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., federal district, five ma ...
, but its threat still do not receive adequate attention. The need for a HCV-specific treatment is essential, and according to John Ward, the director of the CDC Hepatitis Division, it can save up to 120,000 lives. According to
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
profiling in the
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
liver biopsies of HCV patients, a correlation was initially discovered between dysfunctional
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
processes, which include beta-oxidation, and HCV. As a matter of fact, lipids play an important role in the
replication Replication may refer to: Science * Replication (scientific method), one of the main principles of the scientific method, a.k.a. reproducibility ** Replication (statistics), the repetition of a test or complete experiment ** Replication crisi ...
cycle of HCV, and in the " in vivo" samples from HCV patients, many lipids were found in abundance to aid HCV in
virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...
uptake, RNA replication, and secretion from host cells.
Enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s that regulate
fatty acid metabolism Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes ...
, including enoyl-CoA isomerase, were also similarly upregulated. Gene silencing techniques revealed that enoyl-CoA isomerase is essential in HCV RNA replication, and opened ways to stop HCV infection on an intracellular level.


See also

*
Fatty acid metabolism Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes ...
* Isomerase * 2,4-dienoyl-CoA reductase 1


References

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