bims-polyam 2022-10-02 papers

Issue of 2022‒10‒02
five papers selected by
Sebastian J. Hofer
University of Graz

Microbiol Res. 2022 Sep 09. pii: S0944-5013(22)00221-X. [Epub ahead of print]265 127181

Mitochondrial Spermidine Synthase is Essential for Blood-stage growth of the Malaria Parasite.

Mohd Kamil, Umit Y Kina, Gozde Deveci, Sevim N Akyuz, Ilknur Yilmaz, Ahmed S I Aly.

Positively-charged polyamines are essential molecules for the replication of eukaryotic cells and are particularly important for the rapid proliferation of parasitic protozoa and cancer cells. Unlike in Trypanosoma brucei, the inhibition of the synthesis of intermediate polyamine Putrescine caused only partial defect in malaria parasite blood-stage growth. In contrast, reducing the intracellular concentrations of Spermidine and Spermine by polyamine analogs caused significant defects in blood-stage growth in Plasmodium yoelii and P. falciparum. However, little is known about the synthesizing enzyme of Spermidine and Spermine in the malaria parasite. Herein, malaria parasite conserved Spermidine Synthase (SpdS) gene was targeted for deletion/complementation analyses by knockout/knock-in constructs in P. yoelii. SpdS was found to be essential for blood-stage growth. Live fluorescence imaging in blood-stages and sporozoites confirmed a specific mitochondrial localization, which is not known for any polyamine-synthesizing enzyme so far. This study identifies SpdS as an excellent drug targeting candidate against the malaria parasite, which is localized to the parasite mitochondrion.

Keywords: Drug target; Mitochondria; Plasmodium yoelii; Polyamine; Spermidine synthase

DOI: https://doi.org/10.1016/j.micres.2022.127181

Front Plant Sci. 2022 ;13 993675

Exogenous Hemin alleviated cadmium stress in maize (Zea mays L.) by enhancing leaf photosynthesis, AsA-GSH cycle and polyamine metabolism.

Lin Piao, Yong Wang, Xiaoming Liu, Guangyan Sun, Shiyu Zhang, Junyao Yan, Yang Chen, Yao Meng, Ming Li, Wanrong Gu.

Cadmium (Cd) stress is one of the principal abiotic stresses that inhibit maize growth. The research was to explore (hemin chloride) Hemin (100 μmol L-1) on photosynthesis, ascorbic acid (AsA)-glutathione (GSH) cycle system, and polyamine metabolism of maize under Cd stress (85 mg L-1) using nutrient solution hydroponics, with Tiannong 9 (Cd tolerant) and Fenghe 6 (Cd sensitive) as experimental materials. The results showed that Hemin can increase leaf photosynthetic pigment content and ameliorate the ratio of Chlorophyll a/chlorophyll b (Chla/Chlb) under Cd stress. The values of ribose 1, 5-diphosphate carboxylase/oxygenase (RuBPcase) and phosphoenolpyruvate carboxylase (PEPCase), and total xanthophyll cycle pool [(violoxanthin (V), antiflavin (A) and zeaxanthin (Z)] increased, which enhancing xanthophyll cycle (DEPS) de-epoxidation, and alleviating stomatal and non-stomatal limitation of leaf photosynthesis. Hemin significantly increased net photosynthetic rate (Pn ), stomatal conductance (gs ), transpiration rate (Tr ), photochemical quenching coefficient (qP), PSII maximum photochemical efficiency (Fv/Fm ), and electron transfer rate (ETR), which contributed to the improvement of the PSII photosynthetic system. Compared with Cd stress, Hemin can reduce thiobartolic acid reactant (TBARS) content, superoxide anion radical (O2 -) production rate, hydrogen peroxide (H2O2) accumulation, and the extent of electrolyte leakage (EL); decreased the level of malondialdehyde (MDA) content and increased the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT); slowed the decrease in dehydroascorbic acid reductase (DHAR) and monodehydroascorbate reductase (MDHAR) activity and the increase in glutathione reductase (GR) and ascorbate peroxidase (APX) activity in leaves; promoted the increase in AsA and GSH content, decreased dehydroascorbic acid (DHA) and oxidized glutathione (GSSG), and increased AsA/DHA and GSH/GSSG ratios under Cd stress. Hemin promoted the increase of conjugated and bound polyamine content, and the conversion process speed of free putrescine (Put) to free spermine (Spm) and spermidine (Spd) in maize; decreased polyamine oxidase (PAO) activity and increased diamine oxidase (DAO), arginine decarboxylase (ADC), ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) enzyme activities in leaves under Cd stress.

Keywords: AsA-GSH cycle; Hemin; cadmium stress; photosynthetic capacity; polyamine metabolism

DOI: https://doi.org/10.3389/fpls.2022.993675

Mol Cancer Res. 2022 Sep 27. pii: MCR-22-0316. [Epub ahead of print]

JAZF1: A Master Metabolic Regulator of Sensitivity to a Polyamine Targeted Therapy.

Spencer R Rosario, Justine J Jacobi, Mark D Long, Hayley C Affronti, Aryn M Rowsam, Dominic J Smiraglia.

Identifying and leveraging unique points of metabolic dysregulation in different disease settings is vital for safe and effective incorporation of metabolism-targeted therapies in the clinic. Additionally, it has been shown identification of master metabolic transcriptional regulators of individual metabolic pathways, and how they relate to the disease in question, may offer the key to understanding therapeutic response. In prostate cancer, we have previously demonstrated polyamine biosynthesis and the methionine cycle were targetable metabolic vulnerabilities. However, the master metabolic transcriptional regulators of these pathways, and how they affect treatment, have yet to be explored. We sought to characterize differential sensitivity of prostate cancer to polyamine and methionine targeted therapies by identifying novel master metabolic transcriptional regulators. We began by developing a gene signature from patient samples, which can predict response to metabolic therapy, and further uncovered a master metabolic transcriptional regulator, JAZF1. We characterized the effects of JAZF1 overexpression on prostate cancer cells, basally and in the context of treatment, by assessing mRNA levels, proliferation, colony formation capability, and key metabolic processes. Lastly, we confirmed the relevance of our findings in large publicly available cohorts of prostate cancer patient samples. We demonstrated differential sensitivity to polyamine and methionine therapies and identified JAZF1 as a master metabolic transcriptional regulator of this response. Implications: We have shown JAZF1 can alter sensitivity of cells and its expression can segregate patient populations into those that do, or do not highly express polyamine genes, leading to better prediction of response to a polyamine targeting therapy.

DOI: https://doi.org/10.1158/1541-7786.MCR-22-0316

J Appl Genet. 2022 Sep 30.

In search of the relationship between the rye polyamine oxidase (PAO) gene and resistance to powdery mildew (PM).

Paweł Milczarski, Magdalena Góralska, Kinga Pałatyńska, Bartłomiej Wysoczański, Ilona Czyczyło-Mysza, Fatemeh Maghuly, Beata Myśków.

Powdery mildew (PM), a common cereal disease in cultivated areas, including Europe and other temperate regions, is caused by the fungus Blumeria graminis. While PM is one of the most important wheat leaf diseases globally, rye is highly tolerant to PM. It has been reported that in barley infected with PM, polyamine oxidase (PAO) activity related to the production of hydrogen peroxide (H2O2) has increased, which may promote defense against biotrophic or hemibiotrophic pathogens. The current study aimed to assess the relationship between the segregation of the polymorphic marker for rye PAO (ScPAO) and the level of PM infection in plants. The genetic mapping in two interline populations shows that ScPAO is located on chromosome 7R. Further analysis comparing ScPAO location to mapped wheat (Triticum aestivum L.) PAO duplicates suggests the ScPAO homology with TaPAO6 or TaPAO7. A possible association of ScPAO from 7R with PM resistance is demonstrated in the recombinant inbred lines (RIL)-L population phenotyped for PM infection. Finally, three novel QTLs for PM resistance on the 7R chromosome of rye are detected.

Keywords: Biotic stress; Erysiphe graminis; Fungus resistance; Genetic mapping; QTL; Secale cereale L

DOI: https://doi.org/10.1007/s13353-022-00723-x

Metabolomics. 2022 Sep 30. 18(10): 76

Glutathione, polyamine, and lysophosphatidylcholine synthesis pathways are associated with circulating pro-inflammatory cytokines.

Ming Liu, Hongwei Zhang, Zikun Xie, Yiheng Huang, Guang Sun, Dake Qi, Andrew Furey, Edward W Randell, Proton Rahman, Guangju Zhai.

INTRODUCTION: Pro-inflammatory cytokines are responsible for initiating an effective defense against exogenous pathogens, and their regulation has a vital role in maintaining physiological homeostasis. The involvement of pro-inflammatory cytokines in pathological conditions have been explored in great detail, however, studies investigating metabolic pathways associated with these cytokines under normal homeostatic conditions are scarce.OBJECTIVES: The aim of the current study was to identify metabolites and metabolic pathways associated with circulating pro-inflammatory cytokines under homeostatic conditions using a metabolomics approach.
METHODS: The study participants (n = 133) were derived from the Newfoundland Osteoarthritis Study (NFOAS) and the Complex Diseases in the Newfoundland population: Environment and Genetics (CODING) study. Plasma concentrations of cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and macrophage migration inhibitory factor (MIF) were assessed by enzyme-linked immunosorbent assay. Targeted metabolomic profiling on fasting plasma samples was performed using Biocrates MxP® Quant 500 kit which measures a total of 630 metabolites. Associations between natural log-transformed metabolite concentrations and metabolite sums/ratios and cytokine levels were assessed using linear regression with adjustment for age, sex, body mass index (BMI), and osteoarthritis status.
RESULTS: Seven metabolites and 11 metabolite sums/ratios were found to be significantly associated with TNF-α, IL-1β, and MIF (all p ≤ 5.13 × 10- 5) after controlling multiple testing with Bonferroni method, indicating the association between glutathione (GSH), polyamine, and lysophosphatidylcholine (lysoPC) synthesis pathways and these pro-inflammatory cytokines.
CONCLUSION: GSH, polyamine, and lysoPC synthesis pathways were positively associated with circulating TNF-α, IL-1β, and MIF levels under homeostatic conditions.

Keywords: Glutathione; Lysophosphatidylcholine; Metabolomics; Polyamine; Pro-inflammatory cytokine

DOI: https://doi.org/10.1007/s11306-022-01932-5