Ornithine decarboxylase

The enzyme ornithine decarboxylase (

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),^[3] species of Solanaceae plant family (ODC2),^[4] and the lactic acid bacteria Paucilactobacillus wasatchensis (odc2)^[5] 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.^[6] 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.^[7] This is the first step and the rate-limiting step in humans for the production of polyamines, compounds required for cell division.

Spermidine synthase can then catalyze the conversion of putrescine to spermidine by the attachment of an aminopropyl moiety.^[8] Spermidine is a precursor to other polyamines, such as spermine and its structural isomer thermospermine.

Structure

The active form of ornithine decarboxylase is a

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.^[1]

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.^[10]

Proteasomal degradation

ODC is the most well-characterized cellular protein subject to

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.^[21] BABS is typically caused by an autosomal dominant de novo ODC1 variant.^[21]

ODC gene expression is induced by a large number of biological stimuli including seizure activity in the brain.^[22] 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.^[23]

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.^[24] 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.^[25]

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.^[26] 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.^[26]

Recent studies have shown the importance of ODC and polyamine synthesis in