bims-polyam 2023-04-16 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023–04–16
six papers selected by
Sebastian J. Hofer, University of Graz

Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome: mechanism of action and therapeutic potential.
Restoring polyamine levels by supplementation of spermidine modulates hepatic immune landscape in murine model of NASH.
Phase IIa Clinical Biomarker Trial of Dietary Arginine Restriction and Aspirin in Colorectal Cancer Patients.
Conformational cycle of human polyamine transporter ATP13A2.
Comparison of Human Eukaryotic Translation Initiation Factors 5A1 and 5AL1: Identification of Amino Acid Residues Important for EIF5A1 Lysine 50 Hypusination and Its Protein Stability.
Inflammation-targeting polyamine nanomedicines for the treatment of ulcerative colitis.

bioRxiv. 2023 Apr 10. pii: 2023.03.30.534977. [Epub ahead of print]

Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome: mechanism of action and therapeutic potential.

Tracy R Murray Stewart, Jackson R Foley, Cassandra E Holbert, Maxim A Khomutov, Noushin Rastkari, Xianzun Tao, Alex R Khomutov, Rong Grace Zhai, Robert A Casero.

Snyder-Robinson Syndrome (SRS) is caused by mutations in the spermine synthase (SMS) gene, the enzyme product of which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonic musculature, and seizures, along with other more variable symptoms. Currently, medical management focuses on treating these symptoms without addressing the underlying molecular cause of the disease. Reduced SMS catalytic activity in cells of SRS patients causes the accumulation of spermidine, while spermine levels are reduced. The resulting exaggeration in spermidine-to-spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity in the patient. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this polyamine imbalance and investigate the potential of this approach as a therapeutic strategy for affected individuals. Here we report the use of difluoromethylornithine (DFMO; eflornithine), an FDA-approved inhibitor of polyamine biosynthesis, in re-establishing normal spermidine-to-spermine ratios in SRS patient cells. Through mechanistic studies, we demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of existing spermidine into spermine in cell lines with hypomorphic variants of SMS. Further, DFMO treatment induces a compensatory uptake of exogenous polyamines, including spermine and spermine mimetics, cooperatively reducing spermidine and increasing spermine levels. In a Drosophila SRS model characterized by reduced lifespan, adding DFMO to the feed extended lifespan. As nearly all known SRS patient mutations are hypomorphic, these studies form a foundation for future translational studies with significant therapeutic potential.

DOI: https://doi.org/10.1101/2023.03.30.534977
Biochim Biophys Acta Mol Basis Dis. 2023 Apr 11. pii: S0925-4439(23)00063-7. [Epub ahead of print] 166697

Restoring polyamine levels by supplementation of spermidine modulates hepatic immune landscape in murine model of NASH.

Marta Szydlowska, Ginger Lasky, Stephanie Oldham, Cristian Rivera, Michael Ford, Bret R Sellman, Christopher J Rhodes, Taylor S Cohen.

   AIMS: To determine if changes in polyamines metabolism occur during non-alcoholic steatohepatitis (NASH) in human patients and mice, as well as to assess systemic and liver-specific effects of spermidine administration into mice suffering from advanced NASH.
MATERIALS AND METHODS: Human fecal samples were collected from 50 healthy and 50 NASH patients. For the preclinical studies C57Bl6/N male mice fed GAN or NIH-31 diet for 6 months were ordered from Taconic and liver biopsy was performed. Based on severity of liver fibrosis, body composition and body weight, the mice from both dietary groups were randomized into another two groups: half receiving 3 mM spermidine in drinking water, half normal water for subsequent 12 weeks. Body weight was measured weekly and glucose tolerance and body composition were assessed at the end. Blood and organs were collected during necropsy, and intrahepatic immune cells were isolated for flow cytometry analysis.
RESULTS: Metabolomic analysis of human and murine feces confirmed that levels of polyamines decreased along NASH progression. Administration of exogenous spermidine to the mice from both dietary groups did not affect body weight, body composition or adiposity. Moreover, incidence of macroscopic hepatic lesions was higher in NASH mice receiving spermidine. On the other hand, spermidine normalized numbers of Kupffer cells in the livers of mice suffering from NASH, although these beneficial effects did not translate into improved liver steatosis or fibrosis severity.
CONCLUSION: Levels of polyamines decrease during NASH in mice and human patients but spermidine administration does not improve advanced NASH.

Keywords:  Hepatitis; Liver; NAFLD; NASH; Polyamines; Spermidine

DOI:  https://doi.org/10.1016/j.bbadis.2023.166697
Cancers (Basel). 2023 Mar 31. pii: 2103. [Epub ahead of print]15(7):

Phase IIa Clinical Biomarker Trial of Dietary Arginine Restriction and Aspirin in Colorectal Cancer Patients.

Jason A Zell, Thomas H Taylor, C Gregory Albers, Joseph C Carmichael, Christine E McLaren, Lari Wenzel, Michael J Stamos.

  After potentially curative treatment, colorectal cancer (CRC) patients remain at high risk for recurrence, second primary CRC, and high-risk adenomas. In combination with existing data, our previous findings provide a rationale for reducing tissue polyamines as tertiary prevention in non-metastatic CRC patients. The goal of this study was to demonstrate rectal tissue polyamine reduction in optimally treated stage I-III CRC patients after intervention with daily oral aspirin + dietary arginine restriction. A single-institution phase IIa clinical trial was conducted. Patients were treated with aspirin 325 mg/day and an individualized dietary regimen designed to reduce arginine intake by ≥30% over a 12-week study period. Dietary intake, endoscopy with rectal biopsies, and phlebotomy were performed pre- and post-intervention. The primary endpoint was to demonstrate ≥50% decrease in rectal tissue putrescine levels from baseline as a measure of polyamine reduction in the target tissue. Twenty eligible patients completed the study. After study intervention, mean dietary arginine intake decreased from 3.7 g/day ± 1.3 SD to 2.6 g/day ± 1.2 SD (29.7% decrease, p < 0.02 by Sign test). Mean plasma arginine levels decreased from 46.0 ng/mL ± 31.5 SD at baseline to 35 ng/mL ± 21.7 SD (p < 0.001). Rectal tissue putrescine levels were 0.90 nMol/mg-protein pre-intervention and 0.99 nMol/mg-protein post-intervention (p < 0.64, NS). No significant differences were observed for the other tissue polyamines investigated: spermidine (p < 0.13), spermine (p < 0.21), spermidine:spermine ratio (p < 0.71). Among CRC survivors, treatment with daily oral aspirin and an individualized dietary arginine restriction intervention resulted in lower calculated dietary arginine intake and plasma arginine levels but did not affect rectal tissue polyamine levels.

Keywords:  arginine restriction; aspirin; cancer prevention; clinical trial; colorectal cancer; dietary intervention; polyamines

DOI:  https://doi.org/10.3390/cancers15072103
Nat Commun. 2023 Apr 08. 14(1): 1978

Conformational cycle of human polyamine transporter ATP13A2.

Jianqiang Mu, Chenyang Xue, Lei Fu, Zongjun Yu, Minhan Nie, Mengqi Wu, Xinmeng Chen, Kun Liu, Ruiqian Bu, Ying Huang, Baisheng Yang, Jianming Han, Qianru Jiang, Kevin C Chan, Ruhong Zhou, Huilin Li, Ancheng Huang, Yong Wang, Zhongmin Liu.

Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway. Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations allows us to obtain a better understanding of the structural basis of how hATP13A2 transports polyamines, providing a mechanistic framework for ATP13A2-related diseases.

DOI: https://doi.org/10.1038/s41467-023-37741-0
Int J Mol Sci. 2023 Mar 23. pii: 6067. [Epub ahead of print]24(7):

Comparison of Human Eukaryotic Translation Initiation Factors 5A1 and 5AL1: Identification of Amino Acid Residues Important for EIF5A1 Lysine 50 Hypusination and Its Protein Stability.

Yu-Yao Wu, Gao-Qi Wu, Na-Li Cai, Yan-Ming Xu, Andy T Y Lau.

  The human eukaryotic translation initiation factor 5A (EIF5A) family consists of three members, namely EIF5A1, EIF5A2, and EIF5AL1. Recent studies have shown that the expression of EIF5As is related to many human diseases, such as diabetes, viral infection, central nervous system injury, and cancer. Among them, EIF5A1 plays different functions in various cancers, possibly as a tumor-suppressor or oncogene, while EIF5A2 promotes the occurrence and development of cancer. Yet, the biological function of EIF5AL1 is not being studied so far. Interestingly, although there are only three amino acid (at residues 36, 45, and 109) differences between EIF5A1 and EIF5AL1, we demonstrate that only EIF5A1 can be hypusinated while EIF5AL1 cannot, and EIF5AL1 has a tumor-suppressor-like function by inhibiting cell proliferation and migration. We also show that EIF5AL1 protein turnover is mediated through the proteasomal pathway, and EIF5AL1 protein turnover is much faster than that of EIF5A1, which may explain their differential protein expression level in cells. By engineering single and double mutations on these three amino acids, we pinpoint which of these amino acids are critical for hypusination and protein stability. The data of this work should fill in the gaps in EIF5As research and pave the way for future studies on EIF5AL1.

Keywords:  EIF5A1; EIF5AL1; hypusine; migration; proliferation; protein stability

DOI:  https://doi.org/10.3390/ijms24076067
J Mater Chem B. 2023 Apr 11.

Inflammation-targeting polyamine nanomedicines for the treatment of ulcerative colitis.

Akihiro Nishiguchi, Tetsushi Taguchi.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by immune system dysfunction. Despite the availability of various anti-inflammatory drugs, they exhibit low therapeutic efficacy with systemic side effects. In this study, we developed oral anti-inflammatory polyamine-based nanomedicines for the treatment of ulcerative colitis. Polyamine-bearing nanoparticles were prepared by the self-assembly of hyaluronic acid in organic solvents and crosslinking with branched oligoethyleneimine. Polyamine nanoparticles were found to suppress excessive inflammatory responses by scavenging the reactive oxygen species (ROS). Moreover, these nanoparticles inhibited enzymatic degradation and targeting of inflamed intestinal tissues. Additionally, they suppressed the inflammatory responses and recovered the pathological disorders in the colon of an ulcerative colitis mouse model. Therefore, polyamine-based nanomedicines exhibit great potential as biocompatible ROS-scavenging drugs for the treatment of IBD.

DOI: https://doi.org/10.1039/d3tb00424d