The enzyme ornithine decarboxylase (, ODC) catalyzes the
decarboxylation of
ornithine
Ornithine is a non-proteinogenic amino acid that plays a role in the urea cycle. Ornithine is abnormally accumulated in the body in ornithine transcarbamylase deficiency. The radical is ornithyl.
Role in urea cycle
L-Ornithine is one of the produ ...
(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 acids and forms a
homodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
.
Reaction mechanism
Lysine 69 on ornithine decarboxylase (ODC) binds the
cofactor pyridoxal phosphate to form a
Schiff base
In organic chemistry, a Schiff base (named after Hugo Schiff) is a compound with the general structure ( = alkyl or aryl, but not hydrogen). They can be considered a sub-class of imines, being either secondary ketimines or secondary aldimine ...
.
Ornithine displaces the lysine to form a Schiff base attached to orthonine, 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 ODC.
This is the first step and the rate-limiting step in humans for the production of
polyamines, compounds required for
cell division.
Structure
image:Ornithine Decarboxylase Publication View.png, 270px, 3D crystal structure of ornithine decarboxylase.
[; ; rendered vi]
PyMOL
The active form of ornithine decarboxylase is a
homodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
. Each
monomer contains a barrel domain, consisting of an
alpha-beta barrel, and a sheet domain, composed of two
beta-sheet
The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a ge ...
s. 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.
Function
The ornithine decarboxylation reaction catalyzed by ornithine decarboxylase is the first and
committed step in the synthesis of
polyamines, particularly
putrescine,
spermidine and
spermine. Polyamines are important for stabilizing
DNA structure, the DNA
double strand-break repair pathway and as
antioxidants. 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.
Proteasomal degradation
ODC is the most well-characterized cellular protein subject to
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
-independent
proteasomal degradation. Although most proteins must first be tagged with multiple
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
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.
Clinical significance
ODC is a transcriptional target of the
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. Myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' ( MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refe ...
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
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
released by the
prostate gland are all known to induce increased ODC activity associated with cancer. Inhibitors of ODC such as
eflornithine
Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women. Specifically it is used for the 2nd stage of sleeping sickness ...
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
Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...
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
Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women. Specifically it is used for the 2nd stage of sleeping sickness ...
) is used to treat
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
and facial hair growth in postmenopausal females.
ODC is also an enzyme indispensable to
parasites
Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson ha ...
like ''
Trypanosoma'', ''
Giardia'', and ''
Plasmodium'', a fact exploited by the drug
eflornithine
Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women. Specifically it is used for the 2nd stage of sleeping sickness ...
.
References
External links
Ornithine decarboxylase at herkules.oulu.fi*
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