Biomolecules

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5 pages, 189 KiB

Open AccessEditorial

Biogenic Polyamines and Related Metabolites

by Alexander V. Ivanov and Alex R. Khomutov

Biomolecules 2022, 12(1), 14; https://doi.org/10.3390/biom12010014 - 22 Dec 2021

Cited by 3 | Viewed by 2079

Abstract

The specific regulation of cell metabolism is one of cornerstones of biochemistry [...] Full article

(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)

Research

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11 pages, 2791 KiB

Open AccessCommunication

Polyamines Counteract Carbonate-Driven Proteasome Stalling in Alkaline Conditions

by Anna A. Kudriaeva, George A. Saratov, Alena N. Kaminskaya, Vasiliy I. Vladimirov, Petro Yu Barzilovich and Alexey A. Belogurov, Jr.

Biomolecules 2020, 10(12), 1597; https://doi.org/10.3390/biom10121597 - 24 Nov 2020

Cited by 3 | Viewed by 2374

Abstract

Cancer cells tend to increase intracellular pH and, at the same time, are known to intensively produce and uptake polyamines such as spermine. Here, we show that various amines, including biogenic polyamines, boost the activity of proteasomes in a dose-dependent manner. Proteasome activity [...] Read more.

Cancer cells tend to increase intracellular pH and, at the same time, are known to intensively produce and uptake polyamines such as spermine. Here, we show that various amines, including biogenic polyamines, boost the activity of proteasomes in a dose-dependent manner. Proteasome activity in the classical amine-containing buffers, such as 2-(N-morpholino)ethanesulfonic acid (MES), Tris, (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), glycylglycine, bis-Tris propane, and bicine, has a skewed distribution with a maximum at pH of 7.0–8.0. The activity of proteasomes in buffers containing imidazole and bis-Tris is maintained almost on the same level, in the pH range of 6.5–8.5. The third type of activation is observed in buffers based on the amino acids arginine and ornithine, as well as the natural polyamines spermine and spermidine. Proteasome activity in these buffers is dramatically increased at pH values greater than 7.5. Anionic buffers such as phosphate or carbonate, in contrast, inhibit proteasome activity during alkalization. Importantly, supplementation of a carbonate–phosphate buffer with spermine counteracts carbonate-driven proteasome stalling in alkaline conditions, predicting an additional physiological role of polyamines in maintaining the metabolism and survival of cancer cells. Full article

(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)

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17 pages, 3383 KiB

Open AccessArticle

Half Way to Hypusine—Structural Basis for Substrate Recognition by Human Deoxyhypusine Synthase

by Elżbieta Wątor, Piotr Wilk and Przemysław Grudnik

Biomolecules 2020, 10(4), 522; https://doi.org/10.3390/biom10040522 - 30 Mar 2020

Cited by 15 | Viewed by 5639

Abstract

Deoxyhypusine synthase (DHS) is a transferase enabling the formation of deoxyhypusine, which is the first, rate-limiting step of a unique post-translational modification: hypusination. DHS catalyses the transfer of a 4-aminobutyl moiety of polyamine spermidine to a specific lysine of eukaryotic translation factor 5A [...] Read more.

Deoxyhypusine synthase (DHS) is a transferase enabling the formation of deoxyhypusine, which is the first, rate-limiting step of a unique post-translational modification: hypusination. DHS catalyses the transfer of a 4-aminobutyl moiety of polyamine spermidine to a specific lysine of eukaryotic translation factor 5A (eIF5A) precursor in a nicotinamide adenine dinucleotide (NAD)-dependent manner. This modification occurs exclusively on one protein, eIF5A, and it is essential for cell proliferation. Malfunctions of the hypusination pathway, including those caused by mutations within the DHS encoding gene, are associated with conditions such as cancer or neurodegeneration. Here, we present a series of high-resolution crystal structures of human DHS. Structures were determined as the apoprotein, as well as ligand-bound states at high-resolutions ranging from 1.41 to 1.69 Å. By solving DHS in complex with its natural substrate spermidine (SPD), we identified the mode of substrate recognition. We also observed that other polyamines, namely spermine (SPM) and putrescine, bind DHS in a similar manner as SPD. Moreover, we performed activity assays showing that SPM could to some extent serve as an alternative DHS substrate. In contrast to previous studies, we demonstrate that no conformational changes occur in the DHS structure upon spermidine-binding. By combining mutagenesis and a light-scattering approach, we show that a conserved “ball-and-chain” motif is indispensable to assembling a functional DHS tetramer. Our study substantially advances our knowledge of the substrate recognition mechanism by DHS and may aid the design of pharmacological compounds for potential applications in cancer therapy. Full article

(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)

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10 pages, 1736 KiB

Open AccessArticle

Upregulation of Polyamine Transport in Human Colorectal Cancer Cells

by Misael Corral and Heather M. Wallace

Biomolecules 2020, 10(4), 499; https://doi.org/10.3390/biom10040499 - 25 Mar 2020

Cited by 21 | Viewed by 4421

Abstract

Polyamines are essential growth factors that have a positive role in cancer cell growth. Their metabolic pathway and the diverse enzymes involved have been studied in depth in multiple organisms and cells. Polyamine transport also contributes to the intracellular polyamine content but this [...] Read more.

Polyamines are essential growth factors that have a positive role in cancer cell growth. Their metabolic pathway and the diverse enzymes involved have been studied in depth in multiple organisms and cells. Polyamine transport also contributes to the intracellular polyamine content but this is less well-studied in mammalian cells. As the polyamine transporters could provide a means of selective drug delivery to cancer cells, a greater understanding of polyamine transport and its regulation is needed. In this study, transport of polyamines and polyamine content was measured and the effect of modulating each was determined in human colorectal cancer cells. The results provide evidence that upregulation of polyamine transport depends on polyamine depletion and on the rate of cell growth. Polyamine transport occurred in all colorectal cancer cell lines tested but to varying extents. The cell lines with the lowest basal uptake showed the greatest increase in response to polyamine depletion. Kinetic parameters for putrescine and spermidine suggest the existence of two separate transporters. Transport was shown to be a saturable but non-polarised process that can be regulated both positively and negatively. Using the polyamine transporter to deliver anticancer drugs more selectively is now a reality, and the ability to manipulate the polyamine transport process increases the possibility of using these transporters therapeutically. Full article

(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)

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16 pages, 2073 KiB

Open AccessArticle

Hydroxylamine Analogue of Agmatine: Magic Bullet for Arginine Decarboxylase

by Mervi T. Hyvönen, Tuomo A. Keinänen, Gulgina K. Nuraeva, Dmitry V. Yanvarev, Maxim Khomutov, Elena N. Khurs, Sergey N. Kochetkov, Jouko Vepsäläinen, Alexander A. Zhgun and Alex R. Khomutov

Biomolecules 2020, 10(3), 406; https://doi.org/10.3390/biom10030406 - 06 Mar 2020

Cited by 17 | Viewed by 3645

Abstract

The biogenic polyamines, spermine, spermidine (Spd) and putrescine (Put) are present at micro-millimolar concentrations in eukaryotic and prokaryotic cells (many prokaryotes have no spermine), participating in the regulation of cellular proliferation and differentiation. In mammalian cells Put is formed exclusively from L-ornithine [...] Read more.

The biogenic polyamines, spermine, spermidine (Spd) and putrescine (Put) are present at micro-millimolar concentrations in eukaryotic and prokaryotic cells (many prokaryotes have no spermine), participating in the regulation of cellular proliferation and differentiation. In mammalian cells Put is formed exclusively from L-ornithine by ornithine decarboxylase (ODC) and many potent ODC inhibitors are known. In bacteria, plants, and fungi Put is synthesized also from agmatine, which is formed from L-arginine by arginine decarboxylase (ADC). Here we demonstrate that the isosteric hydroxylamine analogue of agmatine (AO-Agm) is a new and very potent (IC₅₀ 3•10⁻⁸ M) inhibitor of E. coli ADC. It was almost two orders of magnitude less potent towards E. coli ODC. AO-Agm decreased polyamine pools and inhibited the growth of DU145 prostate cancer cells only at high concentration (1 mM). Growth inhibitory analysis of the Acremonium chrysogenum demonstrated that the wild type (WT) strain synthesized Put only from L-ornithine, while the cephalosporin C high-yielding strain, in which the polyamine pool is increased, could use both ODC and ADC to produce Put. Thus, AO-Agm is an important addition to the set of existing inhibitors of the enzymes of polyamine biosynthesis, and an important instrument for investigating polyamine biochemistry. Full article

(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)

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16 pages, 2963 KiB

Open AccessArticle

Functional Analysis of DNMT3A DNA Methyltransferase Mutations Reported in Patients with Acute Myeloid Leukemia

by Daria A. Khrabrova, Andrei G. Loiko, Anastasia A. Tolkacheva, Natalia A. Cherepanova, Maria I. Zvereva, Olga V. Kirsanova and Elizaveta S. Gromova

Biomolecules 2020, 10(1), 8; https://doi.org/10.3390/biom10010008 - 18 Dec 2019

Cited by 10 | Viewed by 3844

Abstract

In mammals, DNA methylation is necessary for the maintenance of genomic stability, gene expression regulation, and other processes. During malignant diseases progression, changes in both DNA methylation patterns and DNA methyltransferase (MTase) genes are observed. Human de novo MTase DNMT3A is most frequently [...] Read more.

In mammals, DNA methylation is necessary for the maintenance of genomic stability, gene expression regulation, and other processes. During malignant diseases progression, changes in both DNA methylation patterns and DNA methyltransferase (MTase) genes are observed. Human de novo MTase DNMT3A is most frequently mutated in acute myeloid leukemia (AML) with a striking prevalence of R882H mutation, which has been extensively studied. Here, we investigate the functional role of the missense mutations (S714C, R635W, R736H, R771L, P777R, and F752V) found in the catalytic domain of DNMT3A in AML patients. These were accordingly mutated in the murine Dnmt3a catalytic domain (S124C, R45W, R146H, R181L, P187R, and F162V) and in addition, one-site CpG-containing DNA substrates were used as a model system. The 3–15-fold decrease (S124C and P187R) or complete loss (F162V, R45W, and R146H) of Dnmt3a-CD methylation activity was observed. Remarkably, Pro 187 and Arg 146 are not located at or near the Dnmt3a functional motives. Regulatory protein Dnmt3L did not enhance the methylation activity of R45W, R146H, P187R, and F162V mutants. The key steps of the Dnmt3a-mediated methylation mechanism, including DNA binding and transient covalent intermediate formation, were examined. There was a complete loss of DNA-binding affinity for R45W located in the AdoMet binding region and for R146H. Dnmt3a mutants studied in vitro suggest functional impairment of DNMT3A during pathogenesis. Full article

(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)

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18 pages, 1281 KiB

Open AccessArticle

by Iris Samarra, Bruno Ramos-Molina, M Isabel Queipo-Ortuño, Francisco J Tinahones, Lluís Arola, Antoni Delpino-Rius, Pol Herrero and Núria Canela

Biomolecules 2019, 9(12), 779; https://doi.org/10.3390/biom9120779 - 26 Nov 2019

Cited by 9 | Viewed by 4165

Abstract

Polyamines are involved in the regulation of many cellular functions and are promising biomarkers of numerous physiological conditions. Since the concentrations of these compounds in biological fluids are low, sample extraction is one of the most critical steps of their analysis. Here, we [...] Read more.

Polyamines are involved in the regulation of many cellular functions and are promising biomarkers of numerous physiological conditions. Since the concentrations of these compounds in biological fluids are low, sample extraction is one of the most critical steps of their analysis. Here, we developed a comprehensive, sensitive, robust, and high-throughput LC-MS/MS stable-isotope dilution method for the simultaneous determination of 19 metabolites related to polyamine metabolism, including polyamines, acetylated and diacetylated polyamines, precursors, and catabolites from liquid biopsies. The sample extraction was optimized to remove interfering compounds and to reduce matrix effects, thus being useful for large clinical studies. The method consists of two-step liquid-liquid extraction with a Folch extraction and ethyl acetate partitioning combined with dansyl chloride derivatization. The developed method was applied to a small gender-related trial concerning human serum and urine samples from 40 obese subjects. Sex differences were found for cadaverine, putrescine, 1,3-diaminopropane, γ-aminobutyric acid, N8-acetylspermidine, and N-acetylcadaverine in urine; N1-acetylspermine in serum; and spermine in both serum and urine. The results demonstrate that the developed method can be used to analyze biological samples for the study of polyamine metabolism and its association with human diseases. Full article

(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)

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Review

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25 pages, 1635 KiB

Open AccessReview

Nanotechnology-Based Strategies to Develop New Anticancer Therapies

by Massimiliano Magro, Andrea Venerando, Alberto Macone, Gianluca Canettieri, Enzo Agostinelli and Fabio Vianello

Biomolecules 2020, 10(5), 735; https://doi.org/10.3390/biom10050735 - 08 May 2020

Cited by 31 | Viewed by 4848

Abstract

The blooming of nanotechnology has made available a limitless landscape of solutions responding to crucial issues in many fields and, nowadays, a wide choice of nanotechnology-based strategies can be adopted to circumvent the limitations of conventional therapies for cancer. Herein, the current stage [...] Read more.

The blooming of nanotechnology has made available a limitless landscape of solutions responding to crucial issues in many fields and, nowadays, a wide choice of nanotechnology-based strategies can be adopted to circumvent the limitations of conventional therapies for cancer. Herein, the current stage of nanotechnological applications for cancer management is summarized encompassing the core nanomaterials as well as the available chemical–physical approaches for their surface functionalization and drug ligands as possible therapeutic agents. The use of nanomaterials as vehicles to delivery various therapeutic substances is reported emphasizing advantages, such as the high drug loading, the enhancement of the pay-load half-life and bioavailability. Particular attention was dedicated to highlight the importance of nanomaterial intrinsic features. Indeed, the ability of combining the properties of the transported drug with the ones of the nano-sized carrier can lead to multifunctional theranostic tools. In this view, fluorescence of carbon quantum dots, optical properties of gold nanoparticle and superparamagnetism of iron oxide nanoparticles, are fundamental examples. Furthermore, smart anticancer devices can be developed by conjugating enzymes to nanoparticles, as in the case of bovine serum amine oxidase (BSAO) and gold nanoparticles. The present review is aimed at providing an overall vision on nanotechnological strategies to face the threat of human cancer, comprising opportunities and challenges. Full article

(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)

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13 pages, 1758 KiB

Open AccessFeature PaperReview

Diverse Functions of Polyamines in Virus Infection

by Mason R. Firpo and Bryan C. Mounce

Biomolecules 2020, 10(4), 628; https://doi.org/10.3390/biom10040628 - 18 Apr 2020

Cited by 50 | Viewed by 6049

Abstract

As obligate intracellular parasites, viruses rely on host cells for the building blocks of progeny viruses. Metabolites such as amino acids, nucleotides, and lipids are central to viral proteins, genomes, and envelopes, and the availability of these molecules can restrict or promote infection. [...] Read more.

As obligate intracellular parasites, viruses rely on host cells for the building blocks of progeny viruses. Metabolites such as amino acids, nucleotides, and lipids are central to viral proteins, genomes, and envelopes, and the availability of these molecules can restrict or promote infection. Polyamines, comprised of putrescine, spermidine, and spermine in mammalian cells, are also critical for virus infection. Polyamines are small, positively charged molecules that function in transcription, translation, and cell cycling. Initial work on the function of polyamines in bacteriophage infection illuminated these molecules as critical to virus infection. In the decades since early virus-polyamine descriptions, work on diverse viruses continues to highlight a role for polyamines in viral processes, including genome packaging and viral enzymatic activity. On the host side, polyamines function in the response to virus infection. Thus, viruses and hosts compete for polyamines, which are a critical resource for both. Pharmacologically targeting polyamines, tipping the balance to favor the host and restrict virus replication, holds significant promise as a broad-spectrum antiviral strategy. Full article

(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)

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