bims-polyam 2021-10-31 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2021–10–31
eight papers selected by
Sebastian J. Hofer, University of Graz

Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment and cognitive functions in mice.
Structural basis of polyamine transport by human ATP13A2 (PARK9).
The Correlation Between PINK-1/Parkin Mediated Mitophagy, Endoplasmic Reticulum Stress and Total Polyamines in Pediatric Bronchial Asthma: An Integrated Network of Pathways.
Genomic analysis of the polyamine biosynthesis pathway in duckweed Spirodela polyrhiza L.: presence of the arginine decarboxylase pathway, absence of the ornithine decarboxylase pathway, and response to abiotic stresses.
A Screening Method to Identify Essential Yeast Genes for Responses Towards Spermine.
Development of a Redox-Sensitive Spermine Prodrug for the Potential Treatment of Snyder Robinson Syndrome.
Structural mechanisms for gating and ion selectivity of the human polyamine transporter ATP13A2.
Polyamine-Responsive Morphological Transformation of a Supramolecular Peptide for Specific Drug Accumulation and Retention in Cancer Cells.

J Biol Chem. 2021 Oct 21. pii: S0021-9258(21)01139-X. [Epub ahead of print] 101333

Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment and cognitive functions in mice.

Rajesh Kumar Kar, Ashleigh S Hanner, Matthew F Starost, Danielle Springer, Teresa L Mastracci, Raghavendra G Mirmira, Myung Hee Park.

  Eukaryotic initiation factor 5A (eIF5A) is an essential protein that requires a unique amino acid, hypusine, for its activity. Hypusine is formed exclusively in eIF5A post-translationally via two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Each of the genes encoding these proteins, Eif5a, Dhps, and Dohh, is required for mouse embryonic development. Variants in EIF5A or DHPS were recently identified as the genetic basis underlying certain rare neurodevelopmental disorders in humans. To investigate the roles of eIF5A and DHPS in brain development, we generated four conditional knockout mouse strains using the Emx1-Cre or Camk2a-Cre strains and examined the effects of temporal- and region-specific deletion of Eif5a or Dhps. The conditional deletion of Dhps or Eif5a by Emx1 promotor-driven Cre expression (E9.5, in the cortex and hippocampus) led to gross defects in forebrain development, reduced growth, and premature death. On the other hand, the conditional deletion of Dhps or Eif5a by Camk2a promoter-driven Cre expression (postnatal, mainly in the CA1 region of the hippocampus) did not lead to global developmental defects; rather, these knockout animals exhibited severe impairment in spatial learning, contextual learning, and memory when subjected to the Morris Water Maze and a contextual learning test. In both models, the Dhps knockout mice displayed more severe impairment than their Eif5a knockout counterparts. The observed defects in the brain, global development, or cognitive functions most likely result from translation errors due to a deficiency in active, hypusinated eIF5A. Our study underscores the important roles of eIF5A and DHPS in neurodevelopment.

Keywords:  cognitive function; deoxyhypusine synthase; eIF5A; hypusine; mouse genetics; neurodevelopment; neurodevelopmental disorder; post-translational modification; translation

DOI:  https://doi.org/10.1016/j.jbc.2021.101333
Mol Cell. 2021 Oct 21. pii: S1097-2765(21)00684-5. [Epub ahead of print]

Structural basis of polyamine transport by human ATP13A2 (PARK9).

Sue Im Sim, Sören von Bülow, Gerhard Hummer, Eunyong Park.

  Polyamines are small, organic polycations that are ubiquitous and essential to all forms of life. Currently, how polyamines are transported across membranes is not understood. Recent studies have suggested that ATP13A2 and its close homologs, collectively known as P5B-ATPases, are polyamine transporters at endo-/lysosomes. Loss-of-function mutations of ATP13A2 in humans cause hereditary early-onset Parkinson's disease. To understand the polyamine transport mechanism of ATP13A2, we determined high-resolution cryoelectron microscopy (cryo-EM) structures of human ATP13A2 in five distinct conformational intermediates, which together, represent a near-complete transport cycle of ATP13A2. The structural basis of the polyamine specificity was revealed by an endogenous polyamine molecule bound to a narrow, elongated cavity within the transmembrane domain. The structures show an atypical transport path for a water-soluble substrate, in which polyamines may exit within the cytosolic leaflet of the membrane. Our study provides important mechanistic insights into polyamine transport and a framework to understand the functions and mechanisms of P5B-ATPases.

Keywords:  P-type ATPase; P5B-ATPase; Parkinson's disease; cryo-EM; lysosome; membrane protein; polyamine; spermine; transporter

DOI:  https://doi.org/10.1016/j.molcel.2021.08.017
Mol Biol Rep. 2021 Oct 29.

The Correlation Between PINK-1/Parkin Mediated Mitophagy, Endoplasmic Reticulum Stress and Total Polyamines in Pediatric Bronchial Asthma: An Integrated Network of Pathways.

Amira Kamel Eltokhy, Osama Toema, Omnia Safwat El-Deeb.

   BACKGROUND: Pediatric bronchial asthma signifies a frequent chronic inflammatory airway disorder influencing many children. Despite its irrefutable importance, its exact pathogenesis is not completely elucidated.
AIM OF THE STUDY: The study aimed to investigate the correlation between mitophagy machinery proteins, ER stress biomarkers and total polyamine and their role in disease progression via targeting NF-κB mechanisms.
METHODS: Sixty children with atopic bronchial asthma were enrolled in the study, they were allocated into 2 equal groups (mild/moderate and severe atopic asthmatic groups). Thirty age-matched healthy control subjects were also included in the study to represent the control group. Phosphatase and tensin homolog (PTEN)-induced kinase-1 (PINK-1) and Parkin messenger RNA (mRNA) expressions were assessed by (RT-PCR) technique. Levels of inositol requiring enzyme 1α (IRE1α), total polyamines, interleukin 6 & 8 (IL-6, IL-8) and nuclear factor kappa B (NF-κB) were assessed by enzyme-linked immunosorbent assay. Oxidative stress (OS) biomarkers were also measured.
RESULTS: PINK-1 and PARK mRNA expressions were significantly upregulated in asthmatic patients. Likewise, the level of IRE1α, total polyamines, inflammatory cytokines, and OS biomarkers were significantly elevated in asthmatic groups comparing to control group with the highest levels noticed in severe atopic asthmatic group.
CONCLUSION: the study documented a correlation between mitophagy machinery proteins, ER stress biomarkers and total polyamines that may pave a new platform to understand pediatric asthma pathogenesis and could be used as reliable biomarkers to evaluate disease progression.

Keywords:  AOPP; Bronchial asthma; IRE1α; NF-κB; Pink/Parkin; Total polyamines

DOI:  https://doi.org/10.1007/s11033-021-06861-5
Planta. 2021 Oct 25. 254(5): 108

Genomic analysis of the polyamine biosynthesis pathway in duckweed Spirodela polyrhiza L.: presence of the arginine decarboxylase pathway, absence of the ornithine decarboxylase pathway, and response to abiotic stresses.

Rakesh K Upadhyay, Jonathan Shao, Autar K Mattoo.

   MAIN CONCLUSION: Identification of the polyamine biosynthetic pathway genes in duckweed S. polyrhiza reveals presence of prokaryotic as well as land plant-type ADC pathway but absence of ODC encoding genes. Their differential gene expression and transcript abundance is shown modulated by exogenous methyl jasmonate, salinity, and acidic pH. Genetic components encoding for polyamine (PA) biosynthetic pathway are known in several land plant species; however, little is known about them in aquatic plants. We utilized recently sequenced three duckweed (Spirodela polyrhiza) genome assemblies to map PA biosynthetic pathway genes in S. polyrhiza. PA biosynthesis in most higher plants except for Arabidopsis involves two pathways, via arginine decarboxylase (ADC) and ornithine decarboxylase (ODC). ADC-mediated PA biosynthetic pathway genes, namely, one arginase (SpARG1), two arginine decarboxylases (SpADC1, SpADC2), one agmatine iminohydrolase/deiminase (SpAIH), one N-carbamoyl putrescine amidase (SpCPA), three S-adenosylmethionine decarboxylases (SpSAMDc1, 2, 3), one spermidine synthase (SpSPDS1) and one spermine synthase (SpSPMS1) in S. polyrhiza genome were identified here. However, no locus was found for ODC pathway genes in this duckweed. Hidden Markov Model protein domain analysis established that SpADC1 is a prokaryotic/biodegradative type ADC and its molecular phylogenic classification fell in a separate prokaryotic origin ADC clade with SpADC2 as a biosynthetic type of arginine decarboxylase. However, thermospermine synthase (t-SPMS)/Aculis5 genes were not found present. Instead, one of the annotated SPDS may also function as SPMS, since it was found associated with the SPMS phylogenetic clade along with known SPMS genes. Moreover, we demonstrate that S. polyrhiza PA biosynthetic gene transcripts are differentially expressed in response to unfavorable conditions, such as exogenously added salt, methyl jasmonate, or acidic pH environment as well as in extreme temperature regimes. Thus, S. polyrhiza genome encodes for complete polyamine biosynthesis pathway and the genes are transcriptionally active in response to changing environmental conditions suggesting an important role of polyamines in this aquatic plant.

Keywords:  Duckweed; Methyl Jasmonate; Polyamines; Putrescine; Salinity; Spermidine; Spermine; Spirodela polyrhiza

DOI:  https://doi.org/10.1007/s00425-021-03755-5
Methods Mol Biol. 2022 ;2377 363-369

A Screening Method to Identify Essential Yeast Genes for Responses Towards Spermine.

Mustapha Aouida, Dindial Ramotar.

  We exploited the yeast DAmP mutant collection to identify essential genes that play a role in polyamine resistance. Herein, we described in details the methodology to obtain these genes. This approach is applicable for screening many nontoxic and toxic drugs.

Keywords:  Essential gene; Polyamine resistance; Spermine; Yeast

DOI:  https://doi.org/10.1007/978-1-0716-1720-5_20
J Med Chem. 2021 Oct 25.

Development of a Redox-Sensitive Spermine Prodrug for the Potential Treatment of Snyder Robinson Syndrome.

Mukund P Tantak, Vandana Sekhar, Xianzun Tao, R Grace Zhai, Otto Phanstiel.

Snyder Robinson Syndrome (SRS) is a rare disease associated with a defective spermine synthase gene and low intracellular spermine levels. In this study, a spermine replacement therapy was developed using a spermine prodrug that enters cells via the polyamine transport system. The prodrug was comprised of three components: a redox-sensitive quinone "trigger", a "trimethyl lock (TML)" aryl "release mechanism", and spermine. The presence of spermine in the design facilitated uptake by the polyamine transport system. The quinone-TML motifs provided a redox-sensitive agent, which upon intracellular reduction generated a hydroquinone, which underwent intramolecular cyclization to release free spermine and a lactone byproduct. Rewardingly, most SRS fibroblasts treated with the prodrug revealed a significant increase in intracellular spermine. Administering the spermine prodrug through feeding in a Drosophila model of SRS showed significant beneficial effects. In summary, a spermine prodrug is developed and provides a lead compound for future spermine replacement therapy experiments.

DOI: https://doi.org/10.1021/acs.jmedchem.1c00419
Mol Cell. 2021 Oct 19. pii: S1097-2765(21)00831-5. [Epub ahead of print]

Structural mechanisms for gating and ion selectivity of the human polyamine transporter ATP13A2.

Jordan Tillinghast, Sydney Drury, Darren Bowser, Alana Benn, Kenneth Pak Kin Lee.

  Mutations in ATP13A2, also known as PARK9, cause a rare monogenic form of juvenile-onset Parkinson's disease named Kufor-Rakeb syndrome and other neurodegenerative diseases. ATP13A2 encodes a neuroprotective P5B P-type ATPase highly enriched in the brain that mediates selective import of spermine ions from lysosomes into the cytosol via an unknown mechanism. Here we present three structures of human ATP13A2 bound to an ATP analog or to spermine in the presence of phosphomimetics determined by cryoelectron microscopy. ATP13A2 autophosphorylation opens a lysosome luminal gate to reveal a narrow lumen access channel that holds a spermine ion in its entrance. ATP13A2's architecture suggests physical principles underlying selective polyamine transport and anticipates a "pump-channel" intermediate that could function as a counter-cation conduit to facilitate lysosome acidification. Our findings establish a firm foundation to understand ATP13A2 mutations associated with disease and bring us closer to realizing ATP13A2's potential in neuroprotective therapy.

Keywords:  ATP13A2; P-type ATPase; PARK9; Parkinson’s disease; cryo-EM; gating mechanism; ion channel; ion selectivity; ion transport; polyamine

DOI:  https://doi.org/10.1016/j.molcel.2021.10.002
Small. 2021 10;17(43): e2101139

Polyamine-Responsive Morphological Transformation of a Supramolecular Peptide for Specific Drug Accumulation and Retention in Cancer Cells.

Chen Sun, Ziyi Wang, Kuikun Yang, Ludan Yue, Qian Cheng, Yan-Long Ma, Siyu Lu, Guosong Chen, Ruibing Wang.

  The precise accumulation and extended retention of nanomedicines in the tumor tissue has been highly desired for cancer therapy. Here a novel supramolecular-peptide derived nanodrug (SPN) that can be transformed to microfibers in response to intracellular polyamine in cancer cells for significantly enhanced tumor specific accumulation and retention is developed. The supramolecular-peptide is constructed via the non-covalent interactions between cucurbit[7]uril (CB[7]) and Phe on Phe-Phe-Val-Leu-Lys-camptothecin conjugates (FFVLK-CPT, PC). The resultant amphiphilic supramolecular complex subsequently self-assembles into nanoparticles with a hydrodynamic diameter of 164.2 ± 3.7 nm. Upon internalization into spermine-overexpressed cancer cells, the CB[7]-Phe host-guest pairs can be competitively dissociated by spermine and can release free PC, which immediately form β-sheet structures and subsequently reorganize into microfibers, leading to dramatically improved accumulation, retention, and sustained release of CPT in tumor cells for highly effective cancer therapy. Accordingly, this SPN exhibit rather low toxicity against non-cancerous cells due to the morphological stability and fast exocytosis of the nanodrugs in those cells without abundant spermine. This study reports the first supramolecular peptide capable of polyamine-responsive "nanoparticle-to-microfiber" transformation for specific tumor therapy with minimal side effects. This work also offers novel insights to the design and development of stimuli-responsive nanomaterials as precision medicine.

Keywords:  cucurbituril; morphology transformation; polyamine-responsive; self-assembly; supramolecular-peptide

DOI:  https://doi.org/10.1002/smll.202101139