Ornithine Decarboxylase Research Articles

Oleic acid regulates CD4+ T cells differentiation by targeting ODC1-mediated STAT5A phosphorylation in Vogt-Koyanagi-Harada disease.

Oleic acid regulates CD4+ T cells differentiation by targeting ODC1-mediated STAT5A phosphorylation in Vogt-Koyanagi-Harada disease.

Manipulation of artificial light environment improves tropane alkaloids content in Atropa belladonna L.

Manipulation of artificial light environment improves tropane alkaloids content in Atropa belladonna L.

Native nucleosomes intrinsically encode genome organization principles.

The eukaryotic genome is packed into nucleosomes of 147 base pairs around a histone core and is organized into euchromatin and heterochromatin, corresponding to the A and B compartments, respectively1,2. Here we investigated whether individual nucleosomes contain sufficient information for 3D genomic organization into compartments, for example, in their biophysical properties. We purified native mononucleosomes to high monodispersity and used physiological concentrations of polyamines to determine their condensability. The chromosomal regions known to partition into A compartments have low condensability and those for B compartments have high condensability. Chromatin polymer simulations using condensability as the only input, without any trans factors, reproduced the A/B compartments. Condensability is also strongly anticorrelated with gene expression, particularly near the promoters and in a cell type-dependent manner. Therefore, mononucleosomes have biophysical properties associated with genes being on or off. Comparisons with genetic and epigenetic features indicate that nucleosome condensability is an emergent property, providing a natural axis on which to project the high-dimensional cellular chromatin state. Analysis using various condensing agents or histone modifications and mutations indicates that the genome organization principle encoded into nucleosomes is mostly electrostatic in nature. Polyamine depletion in mouse T cells, resulting from either knocking out or inhibiting ornithine decarboxylase, results in hyperpolarized condensability, indicating that when cells cannot rely on polyamines to translate the biophysical properties of nucleosomes to 3D genome organization, they accentuate condensability contrast, which may explain the dysfunction observed with polyamine deficiency3-5.

Exploring the genetic information of Lactobacillus helveticus strains hydrolyzing soy protein using genome-wide association analysis.

Exploring the genetic information of Lactobacillus helveticus strains hydrolyzing soy protein using genome-wide association analysis.

Silicon alleviates aluminum-induced inhibition of photosynthetic and growth attributes in rice by modulating competitive pathways between ethylene and polyamines and activating antioxidant defense.

Silicon alleviates aluminum-induced inhibition of photosynthetic and growth attributes in rice by modulating competitive pathways between ethylene and polyamines and activating antioxidant defense.

Abstract 1515: GCN2 eIF2 kinase promotes polyamine metabolism and progression of prostate cancer

The Integrated Stress Response (ISR) features multiple protein kinases that each sense distinct cellular stresses, phosphorylating eIF2 to direct gene expression that serves to mitigate cell damage and restore homeostasis. Previously, we reported that the eIF2 kinase GCN2 and the ISR are constitutively active in prostate cancer (PCa) and required to maintain amino acid (AA) homeostasis to sustain tumor growth (Cordova et al., 2022, eLife, 11:e81083). GCN2 is induced by nutrient limitation, and basal GCN2 activation in PCa enhances the expression of transporters that ensure sufficient AAs are available for PCa proliferation. However, while genetic or pharmacological inhibition of GCN2 sharply reduces AAs and growth of PCa cells in culture and mouse models, there is minimal cell death. We hypothesized that signaling pathways function to support cell survival in GCN2-deficient PCa cells and can be targeted to promote cell death in combination therapies. Indeed, we discovered that loss of GCN2 leads to compensatory activation of p53 signaling that blocks cell growth and lowers nutrient expenditure (Cordova & Sommers et al., 2024, Science Signaling, 10.1126/scisignal.adp1375). In this recent report, we also carried out a targeted CRISPR-interference screen in castration-resistant 22Rv1 PCa cells with functional wild type (WT) GCN2 or in cells deleted for GCN2 (GCN2 KO). We discovered that reduced expression of ornithine decarboxylase, the rate-limiting enzyme for polyamine (PA) biosynthesis, was synthetically lethal with loss of GCN2. PAs are polycationic metabolites derived from AAs that are ubiquitous among tissues, but especially abundant in prostate tissue. Given that PA biosynthesis requires AAs and GCN2 maintains AA homeostasis in PCa, we propose that GCN2 regulates PA levels in PCa. Indeed, intracellular levels of both AAs and PAs were decreased in GCN2-inhibited LNCaP cells compared to cells treated with vehicle alone. We sought to determine whether defects in PA metabolism also contribute to the growth defect of GCN2-deficient cells. One of the best characterized functions of PAs involves PA-derived hypusination of the translation factor eIF5A, a post-translational modification of eIF5A that is required for efficient translation of mRNAs encoding polyproline tracts. Interestingly, we found that GCN2 promoted eIF5A hypusination and enhanced the expression of several genes associated with PA metabolism in 22Rv1 cells. To investigate whether GCN2-deficient cells are sensitive to defects in eIF5A hypusination, we cultured WT or GCN2 KO 22Rv1 organoids and treated them with a small molecule inhibitor of eIF5A hypusination. While inhibition of eIF5A hypusination resulted in minimal death of WT cells, there was induced death in GCN2 KO cells. Our study suggests that GCN2 maintains PAs in PCa cells and combined therapies targeting GCN2 and PA processes are an effective strategy for the treatment of PCa. Citation Format: Noah R. Sommers, Ricardo A. Cordova, Ronald C. Wek, Kirk A. Staschke. GCN2 eIF2 kinase promotes polyamine metabolism and progression of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1515.

Abstract 4838: Epigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in lung cancer

T cell exhaustion, a dysfunctional state caused by prolonged antigen exposure, presents a major challenge in cancer immunotherapy. While immune checkpoint inhibitors show therapeutic promise, they fail to rejuvenate T cells in a terminally exhaustion state, potentially due to epigenetic barriers. We hypothesized that targeting epigenetic regulators may provide novel therapeutic strategies to overcome these barriers, thereby rescuing terminally exhausted T cells. In this project, we used malignant pleural effusions from advanced lung cancer patients as a source of primary exhausted T cells. Through high-throughput screening of an epigenetic compound library, we identified several bromodomain inhibitors (BETis) as potent enhancers of T cell polyfunctionality in primary human T cells. Treatment with BETis, like JQ1, reduces inhibitory receptor expression and increases effector cytokine production. Transcriptomic and ATAC-seq profiling revealed that JQ1 modulates key metabolic pathways and induces chromatin accessibility changes in primary effusion-infiltrative T cells. Untargeted metabolomics showed that JQ1 expands the polyamine spermidine pool in T cells. Inhibition of ornithine decarboxylase (ODC1), a key enzyme in polyamine biosynthesis, diminishes JQ1’s reinvigorating effects on these T cells. scRNA-seq analysis revealed that JQ1 reduces terminally exhausted T cells and promotes the expansion of progenitor exhausted T cells, which are more responsive to checkpoint inhibitors, by upregulating ODC1 and its upstream regulator, MYC. Notably, adoptive transfer of JQ1-treated T cells significantly reduced tumor-associated MPE in a syngeneic mouse model. Our study demonstrates that BET inhibitors enhance T cell polyfunctionality and modulate terminally exhausted T cells through metabolic reprogramming, notably by upregulating the polyamine biosynthesis pathway. These findings highlight the potential of epigenetic-based cancer immunotherapy for novel therapeutic strategies. Citation Format: Hsing-Chen Tsai, Yi-Chieh Wu, Yu-Ting Lee, Meng-Wei Chou, Shu-Yung Lin, Sheng-Yao Su, Chia-Lang Hsu, Nai-Wen Chang, Yi-Jhen Huang, Yi-Hsiu Juan, Hsuan-Hsuan Lu, Pei-Shan Wu, Miao-Hsia Lin, Li-Chung Hsu, Yen-Ling Chiu, Shih-Yu Chen, Chong-Jen Yu. Epigenetic modulation of polyamine biosynthetic pathways rectifies T cell dysfunction to enhance anti-tumor immunity in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4838.

Astrocytic Ornithine Decarboxylase 1 in Alzheimer's Disease.

Recent research has shed light on the metabolic changes in reactive astrocytes associated with Alzheimer's disease, contributing to disease pathology. In this article, we summarize key findings related to reactive astrogliosis and how the discovery of the role of the enzyme ornithine decarboxylase 1 can set us on the path to finding more effective therapeutic strategies against neurodegenerative diseases.

Approach to the Patient: Hirsutism.

Hirsutism affects approximately 10% of women globally, with significant economic and quality of life impact. Facial and body terminal hair growth in a male-like pattern is determined by a number of factors, including circulating androgens, and tissue androgen receptor, 5α-reductase, 3α- and 17β-hydroxysteroid dehydrogenase, and ornithine decarboxylase content. The presence of hirsutism is usually determined by the modified Ferriman Gallwey (mFG) visual scale, assessing the amount of terminal hair at nine body sites (upper lip, chin, chest, upper and lower back, upper and lower abdomen, upper arms and thighs). Specific diagnostic cut-offs vary somewhat by ethnicity, although hirsutism is usually defined by an mFG score of >4-6. Hirsutism is a sign of polycystic ovary syndrome in 80-90% of affected women, idiopathic hirsutism in 5-10%, and, depending on ethnicity, 21-hydroxylase deficient non-classic adrenal hyperplasia in 1-10%. Rarer causes include androgen-secreting neoplasms, iatrogenic/drug-induced, acromegaly, Cushing's syndrome, syndromes of severe insulin resistance/lipodystrophy, ovarian hyperthecosis, and chronic skin irritation. The choice of treatment for hirsutism depends on the severity of symptoms, the patient's reproductive goals, and the underlying cause. Clinicians should not underestimate the degree of patient distress caused by hirsutism. Further, women who complain of excess unwanted hair growth should be evaluated for underlying causes, regardless of the degree to which hirsutism is observable on examination. Management options include medical therapies, such as combined oral contraceptive pills and anti-androgens, and mechanical methods of hair removal. The most effective therapeutic strategy will involve a combination of these modalities, with shared decision-making a key driver.

Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.

Rare diseases impact approximately 1 in 10 people worldwide, and yet, less than 5% of all rare diseases currently have an approved treatment option available. This is due to many challenges unique to rare diseases, including small, diverse patient populations, the cost of drug development that is not proportionate to the number of patients who could potentially benefit from treatment, and difficulty with clinical trial design to validate new therapeutics. As a result, drug repurposing has become an increasingly promising option for finding treatment options for rare diseases. First described in 2018, Bachmann-Bupp Syndrome (BABS) is a rare neurodevelopmental disorder that is caused by gain-of-function variants in the ornithine decarboxylase (ODC1) gene and is characterized by developmental delay, hypotonia, and alopecia. Through collaboration and the use of a unique drug repurposing strategy, the first patient identified with BABS was treated with the repurposed drug eflornithine, also known as α-difluoromethylornithine (DFMO), in just 16 months. Currently, five additional patients with BABS are being treated with DFMO. This model of drug repurposing of an FDA-approved drug for use in another indication can serve as an example of what is possible in the scope of other rare diseases, specifically in other polyaminopathies.

Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.

Polyamine metabolism is dysregulated in COXFA4-related mitochondrial disease.

In silico discovery of new ornithine decarboxylase inhibitor with potential for human African trypanosomiasis treatment

Human African trypanosomiasis (HAT), a neglected tropical disease endemic to sub-Saharan Africa, faces treatment challenges due to drug-resistant Trypanosoma brucei strains and the need for safer and more effective therapeutic options. This study employed computational approaches, including 3D-similarity search, ADMET predictions, molecular docking simulation, and molecular dynamics (MD) simulation, to identify potential ornithine decarboxylase (ODC) inhibitors. Screening ChEMBL, DrugBank, and ZINC databases yielded seven eflornithine analogues as initial hit candidates. Structural optimization of these hit candidates led to the discovery of a novel compound with improved binding affinity, ADMET properties, safety profiles, and medicinal chemistry friendliness. MD simulation confirmed the stability of the protein–ligand complex involving ODC and the new compound. This study identifies the new compound as a promising candidate for the development of alternative ODC inhibitors for HAT treatment.

Design, Synthesis, and Biological Activity of Novel Ornithine Decarboxylase (ODC) Inhibitors.

We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency in vitro than α-difluoromethylornithine (DFMO), a U.S. Food and Drug Administration (FDA) approved drug. We report two X-ray structures of ODC complexed with new ODC inhibitors, computational docking, molecular dynamics, and binding free energy calculations to validate the experimental models. The X-ray structures reveal that covalent adducts with pyridoxal phosphate (PLP) are formed in the active site of the human ODC enzyme, as verified by their preparation and enzymatic testing. Finally, we verified that the cellular activity of endogenous ODC was inhibited, and polyamine levels were reduced. Given that ODC is a clinically validated target, combined with the fact that DFMO is currently the only ODC inhibitor in clinical use for several indications, the further development of more potent ODC inhibitors with superior activity and physical properties is warranted.

Ornithine decarboxylase antizyme 2 (OAZ2) in human colon adenocarcinoma: a potent prognostic factor associated with immunity

Despite few studies focusing on the OAZ2 gene in colorectal cancer, its potential role in colon adenocarcinoma (COAD) prognosis and immune modulation remains underexplored. This study examines the expression and mechanistic involvement of OAZ2 in COAD using data from The Cancer Genome Atlas (TCGA) and additional laboratory experiments. We employed uni- and multivariate Cox hazard regression analyses to evaluate its prognostic significance and gene set enrichment analysis (GSEA) to identify related signaling pathways. Our findings demonstrate significantly lower OAZ2 expression in COAD tissues compared to normal counterparts (P < 0.05) and establish its value as an independent prognostic indicator (P < 0.05). Laboratory experiments further revealed that the protein and mRNA levels of OAZ2 are significantly diminished in COAD compared to adjacent normal tissues, while its antagonist AZIN2 shows elevated expression, suggesting a competitive interaction that may regulate tumor behavior. Overexpression of OAZ2 in RKO colorectal cancer cells significantly reduced their proliferation rate and impaired migration, confirming the functional impact of OAZ2 dysregulation in COAD. Gene Set Enrichment Analysis (GSEA) highlighted the involvement of OAZ2 in cardiac muscle contraction and oxidative phosphorylation pathways. Additionally, OAZ2’s association with immune features such as tumor mutational burden (TMB), microsatellite instability (MSI), and immune infiltration underscores its integral role in the tumor microenvironment. These comprehensive findings position OAZ2 as a promising biomarker for COAD prognosis and a potential target for therapeutic intervention, with evidence supporting its regulatory effects on cell dynamics and tumor aggressiveness.

Ornithine decarboxylase and its role in cancer.

Ornithine decarboxylase and its role in cancer.

1304 Ornithine Decarboxylase 1 (ODC1) is Associated with Relapse and Prognosis in B-cell Acute Lymphoblastic Leukemia

1304 Ornithine Decarboxylase 1 (ODC1) is Associated with Relapse and Prognosis in B-cell Acute Lymphoblastic Leukemia

Construction of a CRISPR-Cas9-Based Genetic Editing Tool for Serratia marcescens Using a Stationary Phase Promoter and Its Application in Putrescine Production.

Putrescine plays a significant role in green food production and agriculture by promoting plant growth and enhancing crop quality. Its application reduces the reliance on chemical fertilizers and pesticides, thereby supporting the advancement of sustainable agricultural practices. This study achieved efficient production of putrescine in Serratia marcescens. S. marcescens has been extensively used to synthesize antimicrobial substances and express proteins, but its application has been limited by the lack of efficient genome-editing tools. This study presents a CRISPR-Cas9-based tool for gene editing in S. marcescens. A dual-plasmid system was constructed, incorporating an editing template into the plasmid pEdit with target-specific sgRNA. A stationary phase promoter was used to express Cas9 from Streptococcus pyogenes protein, avoiding the need for additional inducers and ensuring efficient one-step gene knockout and integration. The tool demonstrated over 80% editing efficiency across various S. marcescens strains and enabled successful single-base mutations. Using this tool, we enhanced putrescine production in S. marcescens HBQA7, optimizing the expression of ornithine decarboxylase from Clostridium aceticum DSM1496 with the P2 promoter and identifying the optimal integration site. Putrescine production reached 8.46 g/L within 48 h. This study significantly advances S. marcescens gene editing and metabolic engineering.

Putrescine Depletion in Leishmania donovani Parasites Causes Immediate Proliferation Arrest Followed by an Apoptosis-like Cell Death.

The polyamine pathway in Leishmania parasites has emerged as a promising target for therapeutic intervention, yet the functions of polyamines in parasites remain largely unexplored. Ornithine decarboxylase (ODC) and spermidine synthase (SPDSYN) catalyze the sequential conversion of ornithine to putrescine and spermidine. We previously found that Leishmania donovani Δodc and Δspdsyn mutants exhibit markedly reduced growth in vitro and diminished infectivity in mice, with the effect being most pronounced in putrescine-depleted Δodc mutants. Here, we report that, in polyamine-free media, ∆odc mutants arrested proliferation and replication, while ∆spdsyn mutants showed a slow growth and replication phenotype. Starved ∆odc parasites also exhibited a marked reduction in metabolism, which was not observed in the starved ∆spdsyn cells. In contrast, both mutants displayed mitochondrial membrane hyperpolarization. Hallmarks of apoptosis, specifically DNA fragmentation and membrane modifications, were observed in Δodc mutants incubated in polyamine-free media. These results show that putrescine depletion had an immediate detrimental effect on cell growth, replication, and mitochondrial metabolism and caused an apoptosis-like death phenotype. Our findings establish ODC as the most promising therapeutic target within the polyamine biosynthetic pathway for treating leishmaniasis.

Polyamine biosynthesis dysregulation in Alzheimer's disease and Down syndrome cellular models.

Individuals with Down Syndrome (DS) frequently develop early onset Alzheimer's disease (AD) with pathological hallmarks closely resembling AD due to several triplicated genes on chromosome 21. Polyamines are small, organic molecules that play a pivotal role for growth and differentiation, and a dysregulation of polyamine pathways is implicated in AD pathology. However, their role in DS-associated AD is unclear. We analyzed polyamines and their metabolite levels in mouse hippocampal cells and human DS-AD and AD hippocampal tissue and assessed the effects of the ODC inhibitor difluoromethylornithine (DFMO) on Aβ42 aggregation and protein expression in DS fibroblasts. Amyloid-β42 increased polyamine levels via ornithine decarboxylase (ODC) activation in a dose-dependent manner. DFMO reduced Aβ42 aggregation, decreased amyloid precursor protein (APP) levels, and normalized proteins linked to AD pathology in DS fibroblasts. Polyamine levels were elevated in DS-AD hippocampal tissue, with colocalization of ODC and Aβ42 aggregates. These findings suggest that polyamine biosynthesis may exacerbate Aβ42 toxicity and APP expression, contributing to AD progression in DS. The ability of DFMO to reduce Aβ42 aggregation and restore protein homeostasis presents the polyamine pathway as a therapeutic target for DS-AD management.

Identification of CβS and ODC antimony resistance markers in anthroponotic cutaneous leishmaniasis field isolates by gene expression profiling.

Identification of CβS and ODC antimony resistance markers in anthroponotic cutaneous leishmaniasis field isolates by gene expression profiling.