bims-polyam 2024-07-28 papers

Issue of 2024–07–28
five papers selected by
Sebastian J. Hofer, University of Graz

PLoS One. 2024 ;19(7): e0304658

Polyamines (PAs) but not small peptides with closely spaced positively charged groups interact with DNA and RNA, but they do not represent a relevant buffer system at physiological pH values.

Julian Rieck, Christian Derst, Rüdiger W Veh.

Polyamines (PAs) including putrescine (PUT), spermidine (SPD) and spermine (SPM) are small, versatile molecules with two or more positively charged amino groups. Despite their importance for almost all forms of life, their specific roles in molecular and cellular biology remain partly unknown. The molecular structures of PAs suggest two presumable biological functions: (i) as potential buffer systems and (ii) as interactants with poly-negatively charged molecules like nucleic acids. The present report focuses on the question, whether the molecular structures of PAs are essential for such functions, or whether other simple molecules like small peptides with closely spaced positively charged side chains might be suitable as well. Consequently, we created titration curves for PUT, SPD, and SPM, as well as for oligolysines like tri-, tetra-, and penta-lysine. None of the molecules provided substantial buffering capacity at physiological intracellular pH values. Apparently, the most important mechanism for intracellular pH homeostasis in neurons is not a buffer system but is provided by the actions of the sodium-hydrogen and the bicarbonate-chloride antiporters. In a similar approach we investigated the interaction with DNA by following the extinction at 260 nm when titrating DNA with the above molecules. Again, PUT and tri-lysine were not able to interact with herring sperm DNA, while SPD and SPM were. Obviously, the presence of several positively charged groups on its own is not sufficient for the interaction with nucleic acids. Instead, the precise spacing of these groups is necessary for biological activity.

DOI: https://doi.org/10.1371/journal.pone.0304658

Clin Res Hepatol Gastroenterol. 2024 Jul 24. pii: S2210-7401(24)00150-5. [Epub ahead of print] 102429

Targeting SMOX for the treatment of hepatocellular carcinoma?

Yulei Tao, Chunming Cheng.

Dysregulation of the polyamine metabolism is common in different cancer types. SMOX is upregulated in hepatocellular carcinoma (HCC) but the relationship between SMOX and liver inflammation and fibrosis, remain unclear. In this issue of Clin Res Hepatol Gastroenterol, Hu and colleagues find targeting SMOX can alleviate liver cancer progression.

Keywords: Fibrosis; HCC; Hepatocellular Carcinoma; Liver Inflammation; Polyamine Metabolism; SMOX; Treatment

DOI: https://doi.org/10.1016/j.clinre.2024.102429

Eur J Pharmacol. 2024 Jul 18. pii: S0014-2999(24)00512-0. [Epub ahead of print]979 176823

Spermidine as an epigenetic regulator of autophagy in neurodegenerative disorders.

Sairaj Satarker, Joel Wilson, Kiran Kumar Kolathur, Jayesh Mudgal, Shaila A Lewis, Devinder Arora, Madhavan Nampoothiri.

Autophagy is an abnormal protein degradation and recycling process that is impaired in various neurological diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease. Spermidine is a natural polyamine found in various plant- and meat-based diets that can induce autophagy, and is decreased in various neurodegenerative diseases. It acts on epigenetic enzymes like E1A-binding protein p300, HAT enzymes like Iki3p and Sas3p, and α-tubulin acetyltransferase 1 that modulate autophagy. Histone modifications like acetylation, phosphorylation, and methylation could influence autophagy. Autophagy is epigenetically regulated in various neurodegenerative disorders with many epigenetic enzymes and miRNAs. Polyamine regulation plays an essential role in the disease pathogenesis of AD and PD. Therefore, in this review, we discuss various enzymes and miRNAs involved in the epigenetic regulation of autophagy in neurodegenerative disorders and the role of spermidine as an autophagy enhancer. The alterations in spermidine-mediated regulation of Beclin-1, LC3-II, and p62 genes in AD and other PD-associated enzymes could impact the process of autophagy in these neurodegenerative diseases. With the ever-growing data and such promising effects of spermidine in autophagy, we feel it could be a promising target in this area and worth further detailed studies.

Keywords: Alzheimer's disease; Autophagy; Epigenetics; Neurodegenerative disorders; Parkinson's disease; Spermidine; miRNA

DOI: https://doi.org/10.1016/j.ejphar.2024.176823

Biochimie. 2024 Jul 20. pii: S0300-9084(24)00170-6. [Epub ahead of print]

Polyamines putrescine and spermidine as modulators of protein aggregation rate: The effect on DTT-induced aggregation of α-lactalbumin.

Dmitriy A Kara, Vera A Borzova, Svetlana G Roman, Sergey Yu Kleymenov, Natalia A Chebotareva.

Protein aggregation is undesirable for cells due to its possible toxicity, and is also undesirable in biotechnology and pharmaceuticals. Polyamines are known to be capable of both suppressing and stimulating protein aggregation. In the present work polyamines (spermidine, putrescine) have been shown to alter the pathway of α-lactalbumin aggregation induced by dithiothreitol, leading to the formation of larger protein particles during the initial stages of aggregation and promoting the later stage of sticking of aggregates. According to the aggregation kinetics data, polyamines accelerate protein aggregation in a concentration-dependent manner, with a maximum at 50 mM spermidine and 100 mM putrescine. With a further increase in polyamines concentration the effect of aggregation acceleration decreased, thus, the modulation of the aggregation rate by polyamines was shown. A comparison of the aggregation kinetics and hydrodynamic radii growth data registered by dynamic light scattering with the data obtained by asymmetric flow field-flow fractionation and analytical ultracentrifugation allowed us to describe the early stages of aggregation and formation of initial α-lactalbumin clusters. Our results provide a deeper insight into the mechanism of amorphous aggregation of α-lactalbumin and polyamines action on protein aggregation and protein-protein interaction in general.

Keywords: Polyamines; Protein aggregation; Putrescine; Spermidine; α-lactalbumin

DOI: https://doi.org/10.1016/j.biochi.2024.07.011

Cancer Rep (Hoboken). 2024 Jul;7(7): e2130

Identifying Oncogenic Missense Single Nucleotide Polymorphisms in Human SAT1 Gene Using Computational Algorithms and Molecular Dynamics Tools.

Md Mozibullah, Marina Khatun, Md Asaduzzaman Sikder, Mohammod Johirul Islam, Mehbuba Sharmin.

BACKGROUND: The human SAT1 gene encodes spermidine/spermine N1-acetyltransferase 1 (SSAT1), a regulatory biological catalyst of polyamine catabolism. Numerous essential biological processes, such as cellular proliferation, differentiation, and survival, depend on polyamines like spermidine and spermine. Thus, SSAT1 is involved in key cellular activities such as proliferation and survival of cells and mediates various diseases including cancer. A plethora of studies established the involvement of missense single nucleotide polymorphisms (SNPs) in numerous pathological conditions due to their ability to adversely affect the structure and subsequent function of the protein.
AIMS: To date, an in silico study to identify the pathogenic missense SNPs of the human SAT1 gene has not been accomplished yet. This study aimed to filter the missense SNPs that were functionally detrimental and pathogenic.
METHODS AND RESULTS: The rs757435207 (I21N) was ascertained to be the most deleterious and pathogenic by all algorithmic tools. Stability and evolutionary conservation analysis tools also stated that I21N variant decreased the stability and was located in the highly conserved residue. Molecular dynamics simulation revealed that I21N caused substantial alterations in the conformational stability and dynamics of the SSAT1 protein. Consequently, the I21N variant could disrupt the native functional roles of the SSAT1 enzyme.
CONCLUSION: Therefore, the I21N variant was identified and concluded to be an oncogenic missense variant of the human SAT1 gene. Overall, the findings of this study would be a great directory of future experimental research to develop personalized medicine.

Keywords: SAT1 gene; in silico; missense SNPs; molecular dynamics simulations

DOI: https://doi.org/10.1002/cnr2.2130