Ornithine decarboxylase
Encyclopedia
The enzyme ornithine decarboxylase (ODC) catalyzes the decarboxylation
of ornithine
(a product of the urea cycle
) to form putrescine
. This reaction is the committed step
in polyamine
synthesis. In humans, this protein has 461 amino acid
s and forms a homodimer.
69 on ornithine decarboxylase binds the cofactor
pyridoxal phosphate to form a Schiff base
. Ornithine displaces the lysine to form a Schiff base attached to ornithine, which decarboxylates to form a quinoid intermediate. This intermediate rearranges to form a Schiff base attached to putrescine
, which is attacked by lysine
to release putrescine product and reform PLP-bound ornithine decarboxylase.
This is the first step and the rate-limiting step in humans for the production of polyamine
s, compounds required for cell division
.
contains a barrel domain, consisting of an alpha-beta barrel, and a sheet domain, composed of two beta-sheets. The domains are connected by loops. The monomers connect to each other via interactions between the barrel of one monomer and the sheet of the other. Binding between monomers is relatively weak, and ODC interconverts rapidly between monomeric and dimeric forms in the cell.
The pyridoxal phosphate cofactor binds lysine 69 at the C-terminus end of the barrel domain. The active site
is at the interface of the two domains, in a cavity formed by loops from both monomers.
in the synthesis of polyamine
s, particularly putrescine
, spermidine
and spermine
. Polyamines are important for stabilizing DNA
structure, the DNA double strand-break repair pathway and as antioxidant
s. Therefore ornithine decarboxylase is an essential enzyme for cell growth, producing the polyamines necessary to stabilize newly synthesized DNA. Lack of ODC causes cell apoptosis
in embryonic mice, induced by DNA damage.
-independent proteasomal
degradation. Although most proteins must first be tagged with multiple ubiquitin
molecules before they are bound and degraded by the proteasome
, ODC degradation is instead mediated by several recognition sites on the protein and its accessory factor antizyme
. The ODC degradation process is regulated in a negative feedback loop by its reaction products.
Until a report by Sheaff et al. (2000), which demonstrated that the cyclin-dependent kinase (Cdk) inhibitor p21Cip1 is also degraded by the proteasome in a ubiquitin-independent manner, ODC was the only clear example of ubiquitin-independent proteasomal degradation.
Myc
and is upregulated in a wide variety of cancers. The polyamine products of the pathway initialized by ODC are associated with increased cell growth and reduced apoptosis
. Ultraviolet light, asbestos
and androgens released by the prostate gland are all known to induce increased ODC activity associated with cancer. Inhibitors of ODC such as eflornithine
have been shown to effectively reduce cancers in animal models, and drugs targeting ODC are being tested for potential clinical use.
The mechanism by which ODC promotes carcinogenesis
is complex and not entirely known. Along with their direct effect on DNA stability, polyamines also upregulate gap junction
genes and downregulate tight junction
genes. Gap junction genes are involved in communication between carcinogenic cells and tight junction genes act as tumor suppressors.
ODC gene expression is induced by a large number of biological stimuli including seizure
activity in the brain. Inactivation of ODC by difluoromethylornithine (eflornithine
) is used to treat cancer
and facial hair growth in postmenopausal females.
ODC is also an enzyme indispensable to parasites
like trypanosoma
, giardia
, and plasmodium
, a fact exploited by the drug eflornithine
.
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
of ornithine
Ornithine
Ornithine is an amino acid that plays a role in the urea cycle.-Role in urea cycle:L-Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. Therefore, ornithine is a central part of the urea cycle, which allows for the disposal of excess nitrogen....
(a product of the urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
) to form putrescine
Putrescine
Putrescine is a foul-smelling organic chemical compound NH24NH2 that is related to cadaverine; both are produced by the breakdown of amino acids in living and dead organisms and both are toxic in large doses...
. This reaction is the committed step
Committed step
In enzymology, the committed step is an effectively irreversible enzymatic reaction that occurs at a branch point during the biosynthesis of some molecules.-What it means:...
in polyamine
Polyamine
A polyamine is an organic compound having two or more primary amino groups .This class of compounds includes several synthetic substances that are important feedstocks for the chemical industry, such as ethylene diamine , 1,3-diaminopropane , and hexamethylenediamine...
synthesis. In humans, this protein has 461 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s and forms a homodimer.
Reaction mechanism
LysineLysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
69 on ornithine decarboxylase binds the cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
pyridoxal phosphate to form a Schiff base
Schiff base
A Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen....
. Ornithine displaces the lysine to form a Schiff base attached to ornithine, which decarboxylates to form a quinoid intermediate. This intermediate rearranges to form a Schiff base attached to putrescine
Putrescine
Putrescine is a foul-smelling organic chemical compound NH24NH2 that is related to cadaverine; both are produced by the breakdown of amino acids in living and dead organisms and both are toxic in large doses...
, which is attacked by lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
to release putrescine product and reform PLP-bound ornithine decarboxylase.
This is the first step and the rate-limiting step in humans for the production of polyamine
Polyamine
A polyamine is an organic compound having two or more primary amino groups .This class of compounds includes several synthetic substances that are important feedstocks for the chemical industry, such as ethylene diamine , 1,3-diaminopropane , and hexamethylenediamine...
s, compounds required for cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
.
Structure
The active form of ornithine decarboyxlase is a homodimer. Each monomerMonomer
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...
contains a barrel domain, consisting of an alpha-beta barrel, and a sheet domain, composed of two beta-sheets. The domains are connected by loops. The monomers connect to each other via interactions between the barrel of one monomer and the sheet of the other. Binding between monomers is relatively weak, and ODC interconverts rapidly between monomeric and dimeric forms in the cell.
The pyridoxal phosphate cofactor binds lysine 69 at the C-terminus end of the barrel domain. 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...
is at the interface of the two domains, in a cavity formed by loops from both monomers.
Function
The ornithine decarboxylation reaction catalyzed by ornithine decarboxylase is the first and committed stepCommitted step
In enzymology, the committed step is an effectively irreversible enzymatic reaction that occurs at a branch point during the biosynthesis of some molecules.-What it means:...
in the synthesis of polyamine
Polyamine
A polyamine is an organic compound having two or more primary amino groups .This class of compounds includes several synthetic substances that are important feedstocks for the chemical industry, such as ethylene diamine , 1,3-diaminopropane , and hexamethylenediamine...
s, particularly putrescine
Putrescine
Putrescine is a foul-smelling organic chemical compound NH24NH2 that is related to cadaverine; both are produced by the breakdown of amino acids in living and dead organisms and both are toxic in large doses...
, spermidine
Spermidine
Spermidine is a polyamine involved in cellular metabolism. Its known actions include:#Inhibition of neuronal nitric oxide synthase, nNOS#Assisting the in vitro process of transcribing RNA via stimulation of T4 polynucleotide kinase and T7 RNA polymerase activity; it binds to and precipitates DNA...
and spermine
Spermine
Spermine is a polyamine involved in cellular metabolism found in all eukaryotic cells. Formed from spermidine, it is found in a wide variety of organisms and tissues and is an essential growth factor in some bacteria. It is found as a polycation at physiological pH...
. Polyamines are important for stabilizing DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
structure, the DNA double strand-break repair pathway and as antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
s. Therefore ornithine decarboxylase is an essential enzyme for cell growth, producing the polyamines necessary to stabilize newly synthesized DNA. Lack of ODC causes cell apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in embryonic mice, induced by DNA damage.
Proteasomal degradation
ODC is the most well-characterized cellular protein subject to ubiquitinUbiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
-independent proteasomal
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
degradation. Although most proteins must first be tagged with multiple ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
molecules before they are bound and degraded by the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
, ODC degradation is instead mediated by several recognition sites on the protein and its accessory factor antizyme
Ornithine decarboxylase antizyme
Ornithine decarboxylase antizyme is a ornithine decarboxylase inhibitor.It was first characterized in 1981.The genes include , , and .-External links:...
. The ODC degradation process is regulated in a negative feedback loop by its reaction products.
Until a report by Sheaff et al. (2000), which demonstrated that the cyclin-dependent kinase (Cdk) inhibitor p21Cip1 is also degraded by the proteasome in a ubiquitin-independent manner, ODC was the only clear example of ubiquitin-independent proteasomal degradation.
Clinical significance
ODC is a transcriptional target of the oncogeneOncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
Myc
Myc
Myc is a regulator gene that codes for a transcription factor. In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases...
and is upregulated in a wide variety of cancers. The polyamine products of the pathway initialized by ODC are associated with increased cell growth and reduced apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Ultraviolet light, asbestos
Asbestos
Asbestos is a set of six naturally occurring silicate minerals used commercially for their desirable physical properties. They all have in common their eponymous, asbestiform habit: long, thin fibrous crystals...
and androgens released by the prostate gland are all known to induce increased ODC activity associated with cancer. Inhibitors of ODC such as eflornithine
Eflornithine
Eflornithine is a drug found to be effective in the treatment of facial hirsutism as well as in African trypanosomiasis...
have been shown to effectively reduce cancers in animal models, and drugs targeting ODC are being tested for potential clinical use.
The mechanism by which ODC promotes carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
is complex and not entirely known. Along with their direct effect on DNA stability, polyamines also upregulate gap junction
Gap junction
A gap junction or nexus is a specialized intercellular connection between a multitude of animal cell-types. It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells....
genes and downregulate tight junction
Tight junction
Tight junctions, or zonula occludens, are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. It is a type of junctional complex present only in vertebrates...
genes. Gap junction genes are involved in communication between carcinogenic cells and tight junction genes act as tumor suppressors.
ODC gene expression is induced by a large number of biological stimuli including seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
activity in the brain. Inactivation of ODC by difluoromethylornithine (eflornithine
Eflornithine
Eflornithine is a drug found to be effective in the treatment of facial hirsutism as well as in African trypanosomiasis...
) is used to treat cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
and facial hair growth in postmenopausal females.
ODC is also an enzyme indispensable to parasites
Parasitism
Parasitism is a type of symbiotic relationship between organisms of different species where one organism, the parasite, benefits at the expense of the other, the host. Traditionally parasite referred to organisms with lifestages that needed more than one host . These are now called macroparasites...
like trypanosoma
Trypanosoma
Trypanosoma is a genus of kinetoplastids , a monophyletic group of unicellular parasitic flagellate protozoa. The name is derived from the Greek trypano and soma because of their corkscrew-like motion. All trypanosomes are heteroxenous and are transmitted via a vector...
, giardia
Giardia
Giardia is a genus of anaerobic flagellated protozoan parasites of the phylum Metamonada in the supergroup "Excavata" that colonise and reproduce in the small intestines of several vertebrates, causing giardiasis, commonly known as Beaver fever...
, and plasmodium
Plasmodium
Plasmodium is a genus of parasitic protists. Infection by these organisms is known as malaria. The genus Plasmodium was described in 1885 by Ettore Marchiafava and Angelo Celli. Currently over 200 species of this genus are recognized and new species continue to be described.Of the over 200 known...
, a fact exploited by the drug eflornithine
Eflornithine
Eflornithine is a drug found to be effective in the treatment of facial hirsutism as well as in African trypanosomiasis...
.