Ornithine decarboxylase

The enzyme ornithine decarboxylase (Template:EnzExplorer, ODC) catalyzes the decarboxylation of ornithine (a product of the urea cycle) to form putrescine. This reaction is the committed step in polyamine synthesis.<ref name="pmid10378276">Template:Cite journal</ref> In humans, this protein has 461 amino acids and forms a homodimer.<ref name="pmid16459331">Template:Cite journal</ref>

In humans, ornithine decarboxylase (ODC) is expressed by the gene ODC1. The protein ODC is sometimes referred to as "ODC1" in research pertaining to humans and mice, but certain species such as Drosophila (dODC2),<ref>Template:Cite journal</ref> species of Solanaceae plant family (ODC2),<ref>Template:Cite journal</ref> and the lactic acid bacteria Paucilactobacillus wasatchensis (odc2)<ref>Template:Cite journal</ref> have been shown to have a second ODC gene.

Reaction mechanism

Lysine 69 on ornithine decarboxylase (ODC) binds the cofactor pyridoxal phosphate to form a Schiff base.<ref>Template:Cite journal</ref> 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.<ref name="pmid9398243">Template:Cite journal</ref> This is the first step and the rate-limiting step in humans for the production of polyamines, compounds required for cell division.

Reaction of ODC with ornithine

Spermidine synthase can then catalyze the conversion of putrescine to spermidine by the attachment of an aminopropyl moiety.<ref>Template:Cite journal</ref> Spermidine is a precursor to other polyamines, such as spermine and its structural isomer thermospermine.

Structure

File:Ornithine Decarboxylase Publication View.png

3D crystal structure of ornithine decarboxylase.<ref name="pmid10623504">Template:PDB; Template:Cite journal; rendered via PyMOL.</ref>

The active form of ornithine decarboxylase is a homodimer. Each monomer 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.<ref name="pmid10378276"/>

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.<ref name="pmid10378276"/>

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.<ref name="pmid11533243">Template:Cite journal</ref>

Proteasomal degradation

ODC is the most well-characterized cellular protein subject to ubiquitin-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.<ref name="pmid12660156">Template:Cite journal</ref>

Until a report by Sheaff et al. (2000),<ref name="pmid10882081">Template:Cite journal</ref> 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.<ref name="pmid10830160">Template:Cite journal</ref>

Clinical significance

ODC is a transcriptional target of the oncogene Myc<ref name="pmid8356088">Template:Cite journal</ref> 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.<ref name="pmid15510159">Template:Cite journal</ref> Ultraviolet light,<ref name="pmid11549581">Template:Cite journal</ref> asbestos<ref name="pmid1846307">Template:Cite journal</ref> and androgens released by the prostate gland<ref name="pmid1537280">Template:Cite journal</ref> 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,<ref name="pmid10353725">Template:Cite journal</ref> 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<ref name="pmid11439099">Template:Cite journal</ref> and downregulate tight junction genes. Gap junction genes are involved in communication between carcinogenic cells and tight junction genes act as tumor suppressors.<ref name="pmid15510159"/>

Mutations of the ODC1 gene have been shown to cause Bachmann-Bupp syndrome (BABS), a rare neurometabolic disorder characterized by global developmental delay, alopecia, macrocephaly, dysmorphic features, and behavioral abnormalities.<ref name="Bupp_1993">Template:Cite book</ref> BABS is typically caused by an autosomal dominant de novo ODC1 variant.<ref name="Bupp_1993" />

ODC gene expression is induced by a large number of biological stimuli including seizure activity in the brain.<ref name="pmid1563337">Template:Cite journal</ref> Inactivation of ODC by difluoromethylornithine (DMFO, 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.<ref name="pmid17610127">Template:Cite journal</ref>

Immunological significance

In antigen-activated T cells, ODC enzymatic activity increases after activation, which corresponds with increase in polyamine synthesis in T cells after activation.<ref>Template:Cite journal</ref> As with ODC and cancer, MYC, also referred to as c-Myc for cellular Myc, is the master regulator of polyamine biosynthesis in T cells.<ref>Template:Cite journal</ref>

A 2020 study by Wu et al. using T-cell specific ODC cKO mice showed that T cells can function and proliferate normally in vivo and other polyamine synthesis pathways can compensate for lack of ODC.<ref name="Wu_2020">Template:Cite journal</ref> However, blocking polyamine synthesis via ODC with DMFO and polyamine uptake with AMXT 1501 depleted the polyamine pool and inhibited T-cell proliferation and suppressed T-cell inflammation.<ref name="Wu_2020" />

Recent studies have shown the importance of ODC and polyamine synthesis in T helper cell fate commitment.<ref>Template:Cite journal</ref> A 2021 study by Puleston et al. showed that T_H1 and T_H2 cells express higher levels of ODC than regulatory T (T_reg) cells and T_H17 cells, which corresponded to higher levels of polyamine biosynthesis in T_H1 and T_H2.<ref>Template:Cite journal</ref> A 2021 study by Wagner et al. showed a promotion of a Treg program in Odc1^-/- mice.<ref name="Wagner_2021">Template:Cite journal</ref> They concluded that polyamine-related enzyme expression was enhanced in pathogenic T_H17 and suppressed in Treg cells.<ref name="Wagner_2021" />

External links

• Ornithine decarboxylase at herkules.oulu.fi
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