bims-polyam 2024-05-26 papers

Issue of 2024‒05‒26
five papers selected by
Sebastian J. Hofer, University of Graz

Chemphyschem. 2024 May 21. e202400412

Atomic Insight into the Enzymatic Selectivity of Acetyltransferase for Endogenous Polyamines.

Baolin Guo, Qian Xue, Zhiyang Zhang, Jihang Zhai, Chaojie Wang, Yuan Zhao, Jie Zhang.

The N1-Spermidine/spermine acetyltransferase (SSAT) serves as the rate-limiting enzyme in the polyamine metabolism pathway, specifically catalyzing the acetylation of spermidine, spermine, and other specific polyamines. The source of its enzymatic selectivity remains elusive. Here, we used quantum mechanics and molecular mechanics simulations combined with various technologies to explore the enzymatic mechanism of SSAT for endogenous polyamines from an atomic perspective. The static binding and chemical transformation were considered. The binding affinity was identified to be dependent on the protonated state of polyamine. The order of the binding affinity for Spm, Spd, and Put is consistent with the experimental results, which is also verified by the dynamic separation of polyamine and SSAT. Hydrogen bond interactions and salt bridges contribute most, and the common hot residues were identified. In addition, the transfer of acetyl and proton between polyamine and AcCoA was discovered to follow a concerted mechanism, and thermodynamic properties are responsible for the catalytic efficiency of SSAT. This work may be helpful for the development of polyamine derivatives based on catalysis to regulate polyamine metabolism.

Keywords: Acetyltransferase, enzymatic mechanism, selectivity, substrate delivery, polyamine

DOI: https://doi.org/10.1002/cphc.202400412

Discov Oncol. 2024 May 18. 15(1): 173

Polyamines: the pivotal amines in influencing the tumor microenvironment.

Cassandra E Holbert, Robert A Casero, Tracy Murray Stewart.

Cellular proliferation, function and survival is reliant upon maintaining appropriate intracellular polyamine levels. Due to increased metabolic needs, cancer cells elevate their polyamine pools through coordinated metabolism and uptake. High levels of polyamines have been linked to more immunosuppressive tumor microenvironments (TME) as polyamines support the growth and function of many immunosuppressive cell types such as MDSCs, macrophages and regulatory T-cells. As cancer cells and other pro-tumorigenic cell types are highly dependent on polyamines for survival, pharmacological modulation of polyamine metabolism is a promising cancer therapeutic strategy. This review covers the roles of polyamines in various cell types of the TME including both immune and stromal cells, as well as how competition for nutrients, namely polyamine precursors, influences the cellular landscape of the TME. It also details the use of polyamines as biomarkers and the ways in which polyamine depletion can increase the immunogenicity of the TME and reprogram tumors to become more responsive to immunotherapy.

Keywords: Amino acid metabolism; Immunotherapy; Polyamine; Tumor microenvironment

DOI: https://doi.org/10.1007/s12672-024-01034-9

Adv Sci (Weinh). 2024 May 22. e2306912

The Spermine Oxidase/Spermine Axis Coordinates ATG5-Mediated Autophagy to Orchestrate Renal Senescence and Fibrosis.

Dan Luo, Xiaohui Lu, Hongyu Li, Yi Li, Yating Wang, Simin Jiang, Guanglan Li, Yiping Xu, Kefei Wu, Xianrui Dou, Qinghua Liu, Wei Chen, Yi Zhou, Haiping Mao.

Decreased plasma spermine levels are associated with kidney dysfunction. However, the role of spermine in kidney disease remains largely unknown. Herein, it is demonstrated that spermine oxidase (SMOX), a key enzyme governing polyamine metabolism, is predominantly induced in tubular epithelium of human and mouse fibrotic kidneys, alongside a reduction in renal spermine content in mice. Moreover, renal SMOX expression is positively correlated with kidney fibrosis and function decline in patients with chronic kidney disease. Importantly, supplementation with exogenous spermine or genetically deficient SMOX markedly improves autophagy, reduces senescence, and attenuates fibrosis in mouse kidneys. Further, downregulation of ATG5, a critical component of autophagy, in tubular epithelial cells enhances SMOX expression and reduces spermine in TGF-β1-induced fibrogenesis in vitro and kidney fibrosis in vivo. Mechanically, ATG5 readily interacts with SMOX under physiological conditions and in TGF-β1-induced fibrogenic responses to preserve cellular spermine levels. Collectively, the findings suggest SMOX/spermine axis is a potential novel therapy to antagonize renal fibrosis, possibly by coordinating autophagy and suppressing senescence.

Keywords: SMOX; autophagy; cell senescence; renal fibrosis; spermine

DOI: https://doi.org/10.1002/advs.202306912

Rare. 2024 ;pii: 100017. [Epub ahead of print]2

Snyder-Robinson syndrome presenting with learning disability, epilepsy, and osteoporosis: a novel SMS gene variant.

Megumi Leung, Meredith Sanchez-Castillo, Newell Belnap, Marcus Naymik, Anna Bonfitto, Jennifer Sloan, Katie Hassett, Wayne M Jepsen, Aravind Sankaramoorthy, Tracy Murray Stewart, Jackson R Foley, Sampathkumar Rangasamy, Matthew J Huentelman, Vinodh Narayanan, Keri Ramsey.

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder characterized by a collection of clinical features including mild to severe intellectual disability, hypertonia, marfanoid habitus, facial asymmetry, osteoporosis, developmental delay and seizures. Whole genome sequencing (WGS) identified a mutation in the spermine synthase (SMS) gene (c.746 A>G, p.Tyr249Cys) in a male with kyphosis, seizures, and osteoporosis. His phenotype is unique in that he does not have intellectual disability (ID) but does have a mild learning disability. This case demonstrates a milder presentation of SRS and expands the phenotype beyond the reported literature.

Keywords: Snyder-Robinson syndrome; osteoporosis; seizures; spermidine; spermine; spermine synthase

DOI: https://doi.org/10.1016/j.rare.2023.100017

Open Med (Wars). 2024 ;19(1): 20240962

Prognostic value of EIF5A2 in solid tumors: A meta-analysis and bioinformatics analysis.

Jianwen Fang, Tianze Yu, Xiaocong Jiang, Yuexin Lu, Xi Shang, Haixing Shen, Yue Lu, Jingyan Zheng, Peifen Fu.

Aims: In cancer biology, the aberrant overexpression of eukaryotic translation initiation factor 5A2 (EIF5A2) has been correlative with an ominous prognosis, thereby underscoring its pivotal role in fostering metastatic progression. Consequently, EIF5A2 has garnered significant attention as a compelling prognostic biomarker for various malignancies. Our research endeavors were thus aimed at elucidating the utility and significance of EIF5A2 as a robust indicator of cancer outcome prediction.Method: An exhaustive search of the PubMed, EMBASE, and Web of Science databases found relevant studies. The link between EIF5A2 and survival prognosis was examined using hazard ratios and 95% confidence intervals. Subsequently, The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases were employed to validate EIF5A2 expression across various cancer types.
Results: Through pooled analysis, we found that increased EIF5A2 expression was significantly associated with decreased overall survival (OS) and disease-free survival/progression-free survival/relapse-free survival (DFS/PFS/RFS). Moreover, TCGA analysis revealed that EIF5A2 was significantly upregulated in 27 types of cancer, with overexpression being linked to shorter OS in three, worse DFS in two, and worse PFS in six types of cancer. GEPIA showed that patients with EIF5A2 overexpression had reduced OS and DFS.
Conclusions: In solid tumors, EIF5A2 emerges as a reliable prognostic marker. Our meta-analysis comprehensively analyzed the prognostic value of EIF5A2 in solid tumors and assessed its efficacy as a predictive marker.

Keywords: EIF5A2; EMT; cancer; meta-analysis; prognosis

DOI: https://doi.org/10.1515/med-2024-0962