Isopentenyl-diphosphate delta isomerase
Encyclopedia
Isopentenyl-diphosphate delta isomerase (or isopentenyl pyrophosphate isomerase) (IPP isomerase) is an isomerase
which catalyzes
the conversion of the relatively un-reactive isopentenyl pyrophosphate
(IPP) to the more-reactive electrophile
dimethylallyl pyrophosphate
(DMAPP). This isomerization is a key step in the biosynthesis
of isoprenoids
through the mevalonate pathway.
. The empirical evidence suggests that this reaction proceeds by a protonation
/deprotonation
mechanism, with the addition of a proton
to the re-face of the inactivated C3-C4 double bond
resulting in a transient carbocation
intermediate
. The removal of the pro-R proton from C2 forms the C2-C3 double bond of DMAPP.
studies have observed that the active form of IPP isomerase is a monomer
with alternating α-helices
and β-sheets
. The active site
of IPP isomerase is deeply buried within the enzyme
and consists of a glutamic acid
residue and a cysteine
residue that interact with opposite sides of the IPP substrate
, consistent with the antarafacial stereochemistry
of isomerization. The origin of the initial protonation step has not been conclusively established. Recent evidence suggests that the glutamic acid residue is involved in the protonating step despite the observation that its carboxylic acid
side chain
is stabilized in its carboxylate form. This discrepancy has been addressed by the discovery of a water
molecule in the active site of human IPP isomerase, suggesting a mechanism where the glutamine residue polarizes
the double bond of IPP and makes it more susceptible to protonation by water.
IPP isomerase also requires a divalent
cation to fold into its active conformation. The enzyme contains several amino acids, including the catalytic glutamate, that are involved in coordinating with Mg2+
or Mn2+
. The coordination of the metal cation to the glutamate residue stabilizes the carbiocation intermediate after protonation.
and mammalian
mitochondria.
in IDI1, the gene
that codes for IPP isomerase 1, have been implicated in decreased viability in a number of organisms, including the yeast Saccharomyces cerevisiae
, the nematode Caenorhabditis elegans
and the plant Arabidopsis thaliana
. While there have been no evidence directly implicating IDI1 mutations in human disease, genomic analysis
has identified a copy-number gain near two IPP isomerase genes in a substantial proportion of patients with sporadic amyotrophic lateral sclerosis
, suggesting that the isomerase may play a role in this disease.
Isomerase
In biochemistry, an isomerase is an enzyme that catalyzes the structural rearrangement of isomers. Isomerases thus catalyze reactions of the formwhere B is an isomer of A.-Nomenclature:...
which catalyzes
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
the conversion of the relatively un-reactive isopentenyl pyrophosphate
Isopentenyl pyrophosphate
Isopentenyl pyrophosphate is an intermediate in the classical, HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes and terpenoids. IPP is formed from acetyl-CoA via mevalonic acid...
(IPP) to the more-reactive electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate is an intermediate product of both mevalonic acid pathway and DOXP/MEP pathway. It is an isomer of isopentenyl pyrophosphate and exists in virtually all life forms...
(DMAPP). This isomerization is a key step in the biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of isoprenoids
Terpenoid
The terpenoids , sometimes called isoprenoids, are a large and diverse class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures that differ from one another not only in...
through the mevalonate pathway.
Enzyme Mechanism
IPP isomerase catalyzes the isomerization of IPP to DMAPP by an antarafacial transposition of hydrogenHydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
. The empirical evidence suggests that this reaction proceeds by a protonation
Protonation
In chemistry, protonation is the addition of a proton to an atom, molecule, or ion. Some classic examples include*the protonation of water by sulfuric acid:*the protonation of isobutene in the formation of a carbocation:2C=CH2 + HBF4 → 3C+ + BF4−*the protonation of ammonia in the...
/deprotonation
Deprotonation
Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...
mechanism, with the addition of a proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
to the re-face of the inactivated C3-C4 double bond
Double bond
A double bond in chemistry is a chemical bond between two chemical elements involving four bonding electrons instead of the usual two. The most common double bond, that between two carbon atoms, can be found in alkenes. Many types of double bonds between two different elements exist, for example in...
resulting in a transient carbocation
Carbocation
A carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...
intermediate
Reaction intermediate
A reaction intermediate or an intermediate is a molecular entity that is formed from the reactants and reacts further to give the directly observed products of a chemical reaction. Most chemical reactions are stepwise, that is they take more than one elementary step to complete...
. The removal of the pro-R proton from C2 forms the C2-C3 double bond of DMAPP.
Enzyme Structure
CrystallographicCrystallography
Crystallography is the experimental science of the arrangement of atoms in solids. The word "crystallography" derives from the Greek words crystallon = cold drop / frozen drop, with its meaning extending to all solids with some degree of transparency, and grapho = write.Before the development of...
studies have observed that the active form of IPP isomerase is a monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
with alternating α-helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and β-sheets
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
. The active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
of IPP isomerase is deeply buried within the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
and consists of a glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
residue and a cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residue that interact with opposite sides of the IPP substrate
Substrate
Substrate may mean:*Substrate , Natural stone, masonry surface, ceramic and porcelain tiles*Substrate , the material used in the bottom of an aquarium*Substrate , the material used in the bottom of a vivarium or terrarium...
, consistent with the antarafacial stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
of isomerization. The origin of the initial protonation step has not been conclusively established. Recent evidence suggests that the glutamic acid residue is involved in the protonating step despite the observation that its carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
is stabilized in its carboxylate form. This discrepancy has been addressed by the discovery of a water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
molecule in the active site of human IPP isomerase, suggesting a mechanism where the glutamine residue polarizes
Intermolecular force
Intermolecular forces are forces of attraction or repulsion which act between neighboring particles: atoms, molecules or ions. They are weak compared to the intramolecular forces, the forces which keep a molecule together...
the double bond of IPP and makes it more susceptible to protonation by water.
IPP isomerase also requires a divalent
Divalent
In chemistry, a divalent ion or molecule has a valence of two and thus can form two bonds with other ions or molecules. An older term for divalent is bivalent....
cation to fold into its active conformation. The enzyme contains several amino acids, including the catalytic glutamate, that are involved in coordinating with Mg2+
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
or Mn2+
Manganese
Manganese is a chemical element, designated by the symbol Mn. It has the atomic number 25. It is found as a free element in nature , and in many minerals...
. The coordination of the metal cation to the glutamate residue stabilizes the carbiocation intermediate after protonation.
Biological Function
The protonation of an inactivated double bond is rarely seen in nature, highlighting the unique catalytic mechanism of IPP isomerase. The isomerization of IPP to DMAPP is a crucial step in the synthesis of isoprenoids and isoprenoid-derivatives, compounds that play vital roles in the biosynthetic pathways of all living organisms. Because of the importance of the melavonate pathway in isoprenoid biosynthesis, IPP isomerase is found in a variety of different cellular compartments, including plastidsPlastid
Plastids are major organelles found in the cells of plants and algae. Plastids are the site of manufacture and storage of important chemical compounds used by the cell...
and mammalian
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
mitochondria.
Disease Relevance
MutationsMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in IDI1, the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that codes for IPP isomerase 1, have been implicated in decreased viability in a number of organisms, including the yeast Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
, the nematode Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
and the plant Arabidopsis thaliana
Arabidopsis thaliana
Arabidopsis thaliana is a small flowering plant native to Europe, Asia, and northwestern Africa. A spring annual with a relatively short life cycle, arabidopsis is popular as a model organism in plant biology and genetics...
. While there have been no evidence directly implicating IDI1 mutations in human disease, genomic analysis
Full genome sequencing
Full genome sequencing , also known as whole genome sequencing , complete genome sequencing, or entire genome sequencing, is a laboratory process that determines the complete DNA sequence of an organism's genome at a single time...
has identified a copy-number gain near two IPP isomerase genes in a substantial proportion of patients with sporadic amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
, suggesting that the isomerase may play a role in this disease.