bims-polyam 2019-06-23 papers

on Polyamines

Issue of 2019–06–23
eleven papers selected by
Sebastian J. Hofer, University of Graz and Alexander Ivanov, Engelhardt Institute of Molecular Biology

Polyamines in mammalian pathophysiology.
Spermidine Prevents Heart Injury in Neonatal Rats Exposed to Intrauterine Hypoxia by Inhibiting Oxidative Stress and Mitochondrial Fragmentation.
Spermine oxidase: A Promising Therapeutic Target for Neurodegeneration in Diabetic Retinopathy.
Amino acid and polyamine membrane transporters in Trypanosoma cruzi: Biological function and evaluation as drug targets.
A novel hydroxycinnamoyl transferase for synthesis of hydroxycinnamoyl spermine conjugates in plants.
Progress and challenges in development of new therapies for urea cycle disorders.
Biological conversion of methane to putrescine using genome-scale model-guided metabolic engineering of a methanotrophic bacterium Methylomicrobium alcaliphilum 20Z.
Analysis of crystalline and solution states of ligand-free spermidine N-acetyltransferase (SpeG) from Escherichia coli.
INSIGHTS INTO GENE THERAPY FOR UREA CYCLE DEFECTS BY MATHEMATICAL MODELLING.
Nitrogen-Rich Porous Organic Polyamines for Stabilization of Highly Dispersed Metal Nanoparticles and Catalytic Application.
Citrullinemia type I is associated with a novel splicing variant, c.773 + 4A > C, in ASS1: a case report and literature review.

Cell Mol Life Sci. 2019 Jun 21.

Polyamines in mammalian pathophysiology.

Francisca Sánchez-Jiménez, Miguel Ángel Medina, Lorena Villalobos-Rueda, José Luis Urdiales.

  Polyamines (PAs) are essential organic polycations for cell viability along the whole phylogenetic scale. In mammals, they are involved in the most important physiological processes: cell proliferation and viability, nutrition, fertility, as well as nervous and immune systems. Consequently, altered polyamine metabolism is involved in a series of pathologies. Due to their pathophysiological importance, PA metabolism has evolved to be a very robust metabolic module, interconnected with the other essential metabolic modules for gene expression and cell proliferation/differentiation. Two different PA sources exist for animals: PA coming from diet and endogenous synthesis. In the first section of this work, the molecular characteristics of PAs are presented as determinant of their roles in living organisms. In a second section, the metabolic specificities of mammalian PA metabolism are reviewed, as well as some obscure aspects on it. This second section includes information on mammalian cell/tissue-dependent PA-related gene expression and information on crosstalk with the other mammalian metabolic modules. The third section presents a synthesis of the physiological processes described as modulated by PAs in humans and/or experimental animal models, the molecular bases of these regulatory mechanisms known so far, as well as the most important gaps of information, which explain why knowledge around the specific roles of PAs in human physiology is still considered a "mysterious" subject. In spite of its robustness, PA metabolism can be altered under different exogenous and/or endogenous circumstances so leading to the loss of homeostasis and, therefore, to the promotion of a pathology. The available information will be summarized in the fourth section of this review. The different sections of this review also point out the lesser-known aspects of the topic. Finally, future prospects to advance on these still obscure gaps of knowledge on the roles on PAs on human physiopathology are discussed.

Keywords:  Cancer; Cell proliferation; Diet; Diseases; Immune system; Metabolism; Nervous system; Polyamines

DOI:  https://doi.org/10.1007/s00018-019-03196-0
Oxid Med Cell Longev. 2019 ;2019 5406468

Spermidine Prevents Heart Injury in Neonatal Rats Exposed to Intrauterine Hypoxia by Inhibiting Oxidative Stress and Mitochondrial Fragmentation.

Nannan Chai, Hao Zhang, Lingxu Li, Xue Yu, Yan Liu, Yan Lin, Lina Wang, Jiamin Yan, Sazonova Elena Nikolaevna, Yajun Zhao.

Intrauterine hypoxia (IUH) is a common intrauterine dysplasia that can cause programming of the offspring cardiovascular system. In this study, we hypothesized that placental treatment with spermidine (SPD) can prevent heart injury in neonatal offspring exposed to IUH. Pregnant rats were exposed to 21% O2 or 10% O2 (hypoxia) for 7 days prior to term or were exposed to hypoxia and intraperitoneally administered SPD or SPD+difluromethylornithine (DFMO) on gestational days 15-21. Seven-day-old offspring were then sacrificed to assess several parameters. Our results demonstrated that IUH led to decreased myocardial ornithine decarboxylase (ODC) and increased spermidine/spermine N1-acetyltransferase (SSAT) expression in the offspring. IUH also resulted in decreased offspring body weight, heart weight, cardiomyocyte proliferation, and antioxidant capacity and increased cardiomyocyte apoptosis and fibrosis. Furthermore, IUH caused mitochondrial structure abnormality, dysfunction, and decreased biogenesis and led to a fission/fusion imbalance in offspring hearts. In vitro, hypoxia induced mitochondrial ROS accumulation, decreased membrane potential, and increased fragmentation. Notably, all hypoxia-induced changes analyzed in this study were prevented by SPD. Thus, in utero SPD treatment is a potential strategy for preventing IUH-induced neonatal cardiac injury.

DOI: https://doi.org/10.1155/2019/5406468
Pharmacol Res. 2019 Jun 14. pii: S1043-6618(18)32027-9. [Epub ahead of print] 104299

Spermine oxidase: A Promising Therapeutic Target for Neurodegeneration in Diabetic Retinopathy.

S Priya Narayanan, Esraa Shosha, Chithra D Palani.

Diabetic Retinopathy (DR), is a significant public health issue and the leading cause of blindness in working-aged adults worldwide. The vision loss associated with DR affects patients' quality of life and has negative social and psychological effects. In the past, diabetic retinopathy was considered a vascular disease; however, it is now recognized to be a neuro-vascular disease of the retina. Current therapies for DR, such as laser photocoagulation and anti-VEGF therapy, treat advanced stages of the disease, particularly the vasculopathy and have adverse side effects. Unavailability of effective treatments to prevent the incidence or progression of DR is a major clinical problem. There is a great need for therapeutic interventions capable of preventing retinal damage in DR patients. A growing body of evidence shows that neurodegeneration is an early event in DR pathogenesis. Therefore, studies of the underlying mechanisms that lead to neurodegeneration are essential for identifying new therapeutic targets in the early stages of DR. Deregulation of the polyamine metabolism is implicated in various neurodegenerative diseases, cancer, renal failure, and diabetes. Spermine Oxidase (SMOX) is a highly inducible enzyme, and its dysregulation can alter polyamine homeostasis. The oxidative products of polyamine metabolism are capable of inducing cell damage and death. The current review provides insight into the SMOX-regulated molecular mechanisms of cellular damage and dysfunction, and its potential as a therapeutic target for diabetic retinopathy. Structural and functional changes in the diabetic retina and the mechanisms leading to neuronal damage (excitotoxicity, loss of neurotrophic factors, oxidative stress, etc.) are summarized in this review. Furthermore, existing therapies and new approaches to neuroprotection are discussed.

DOI: https://doi.org/10.1016/j.phrs.2019.104299
Curr Med Chem. 2019 Jun 19.

Amino acid and polyamine membrane transporters in Trypanosoma cruzi: Biological function and evaluation as drug targets.

Melisa Sayé, Chantal Reigada, Lucrecia Gauna, Edward A Valera-Vera, Claudio A Pereira, Mariana R Miranda.

  Amino acids and polyamines are involved in relevant processes for the parasite Trypanosoma cruzi, like protein synthesis, stress resistance, life cycle progression, infection establishment and redox balance, among others. In addition to the biosynthetic routes of amino acids, T. cruzi possesses transport systems that allow the active uptake from the extracellular medium; and in the case of polyamines, the uptake is the unique way to obtain these compounds. The TcAAAP protein family is absent in mammals and its members are responsible for amino acid and derivative uptake, thus the TcAAAP permeases are not only interesting and promising therapeutic targets but also could be used to direct the entry of toxic compounds into the parasite. Although there is a treatment available for Chagas disease, its limited efficacy in the chronic stage of the disease, as well as the side effects reported, highlight the urgent need to develop new therapies. Discovery of new drugs is a slow and money-consuming process, and even during clinical trials the drugs can fail. In this context, drug repositioning is an interesting and recommended strategy by the World Health Organization since costs and time are significantly reduced. In this article, amino acids and polyamines transport and its potential as therapeutic targets will be revised, including examples of synthetic drugs and drug repurposing.

Keywords:  Chagas disease.; Trypanosoma cruzi; amino acid transport; drug repositioning; drug discovery; new therapies; polyamine transport; therapeutic target

DOI:  https://doi.org/10.2174/0929867326666190620094710
BMC Plant Biol. 2019 Jun 17. 19(1): 261

A novel hydroxycinnamoyl transferase for synthesis of hydroxycinnamoyl spermine conjugates in plants.

Hui Peng, Rachel S Meyer, Tianbao Yang, Bruce D Whitaker, Frances Trouth, Lingfei Shangguan, Jingbing Huang, Amy Litt, Damon P Little, Hengming Ke, Wayne M Jurick.

   BACKGROUND: Hydroxycinnamoyl-spermine conjugates (HCSpm) are a class of hydroxycinnamic acid amides (HCAAs), which not only are instrumental in plant development and stress response, but also benefit human health. However, HCSpm are not commonly produced in plants, and the mechanism of their biosynthesis remains unclear. In previous investigations of phenolics in Solanum fruits related to eggplant (Solanum melongena L.), we discovered that Solanum richardii, an African wild relative of eggplant, was rich in HCSpms in fruits.
RESULTS: The putative spermine hydroxycinnamoyl transferase (HT) SpmHT was isolated from S. richardii and eggplant. SrSpmHT expression was high in flowers and fruit, and was associated with HCSpm accumulation in S. richardii; however, SpmHT was hardly detected in eggplant cultivars and other wild relatives. Recombinant SpmHT exclusively selected spermine as the acyl acceptor substrate, while showing donor substrate preference in the following order: caffeoyl-CoA, feruloyl-CoA, and p-coumaroyl-CoA. Molecular docking revealed that substrate binding pockets of SpmHT could properly accommodate spermine but not the shorter, more common spermidine.
CONCLUSION: SrSpmHT is a novel spermine hydroxycinnamoyl transferase that uses Spm exclusively as the acyl acceptor substrate to produce HCSpms. Our findings shed light on the HCSpm biosynthetic pathway that may allow an increase of health beneficial metabolites in Solanum crops via methods such as introgression or engineering HCAA metabolism.

Keywords:  Crop improvement; Eggplant; Hydroxycinnamic acid amide; Phytochemicals; Solanum richardii; Spermine hydroxycinnamoyl transferase; Substrate specificity

DOI:  https://doi.org/10.1186/s12870-019-1846-3
Hum Mol Genet. 2019 Jun 22. pii: ddz140. [Epub ahead of print]

Progress and challenges in development of new therapies for urea cycle disorders.

Leandro R Soria, Nicholas Ah Mew, Nicola Brunetti-Pierri.

Urea cycle disorders (UCD) are inborn errors of metabolism caused by deficiency of enzymes required to transfer nitrogen from ammonia into urea. Current paradigms of treatment focus on dietary manipulations, ammonia scavenger drugs, and orthotopic liver transplantation. In the last years, there has been intense preclinical research aiming at developing more effective treatments for UCD and as a result, several novel approaches based on new knowledge of the disease pathogenesis, cell and gene therapies are currently under clinical investigation. We provide an overview of the latest advances for the development of novel therapies for UCD.

DOI: https://doi.org/10.1093/hmg/ddz140
Biotechnol Biofuels. 2019 ;12 147

Biological conversion of methane to putrescine using genome-scale model-guided metabolic engineering of a methanotrophic bacterium Methylomicrobium alcaliphilum 20Z.

Linh Thanh Nguyen, Eun Yeol Lee.

   Background: Methane is the primary component of natural gas and biogas. The huge abundance of methane makes it a promising alternative carbon source for industrial biotechnology. Herein, we report diamine compound, putrescine, production from methane by an industrially promising methanotroph Methylomicrobium alcaliphilum 20Z.
Results: We conducted adaptive evolution to improve putrescine tolerance of M. alcaliphilum 20Z because putrescine highly inhibits the cell growth. The evolved strain 20ZE was able to grow in the presence of 400 mM of putrescine dihydrochloride. The expression of linear pathway ornithine decarboxylase genes from Escherichia coli and Methylosinus trichosporium OB3b allowed the engineered strain to produce putrescine. A higher putrescine titer of 12.44 mg/L was obtained in the strain 20ZE-pACO with ornithine decarboxylase from M. trichosporium OB3b. For elimination of the putrescine utilization pathway, spermidine synthase (MEALZ_3408) was knocked out, resulting in no spermidine formation in the strain 20ZES1-pACO with a putrescine titer of 18.43 mg/L. Next, a genome-scale metabolic model was applied to identify gene knockout strategies. Acetate kinase (MEALZ_2853) and subsequently lactate dehydrogenase (MEALZ_0534) were selected as knockout targets, and the deletion of these genes resulted in an improvement of the putrescine titer to 26.69 mg/L. Furthermore, the putrescine titer was improved to 39.04 mg/L by overexpression of key genes in the ornithine biosynthesis pathway under control of the pTac promoter. Finally, suitable nitrogen sources for growth of M. alcaliphilum 20Z and putrescine production were optimized with the supplement of 2 mM ammonium chloride to nitrate mineral salt medium, and this led to the production of 98.08 mg/L putrescine, almost eightfold higher than that from the initial strain. Transcriptome analysis of the engineered strains showed upregulation of most genes involved in methane assimilation, citric acid cycle, and ammonia assimilation in ammonia nitrate mineral salt medium, compared to nitrate mineral salt medium.
Conclusions: The engineered M. alcaliphilum 20ZE4-pACO strain was able to produce putrescine up to 98.08 mg/L, almost eightfold higher than the initial strain. This study represents the bioconversion of methane to putrescine-a high value-added diamine compound.

Keywords:  Metabolic engineering; Methane; Methanotroph; Methylomicrobium alcaliphilum 20Z; Putrescine

DOI:  https://doi.org/10.1186/s13068-019-1490-z
Acta Crystallogr D Struct Biol. 2019 Jun 01. 75(Pt 6): 545-553

Analysis of crystalline and solution states of ligand-free spermidine N-acetyltransferase (SpeG) from Escherichia coli.

Ekaterina V Filippova, Steven Weigand, Olga Kiryukhina, Alan J Wolfe, Wayne F Anderson.

  Spermidine N-acetyltransferase (SpeG) transfers an acetyl group from acetyl-coenzyme A to an N-terminal amino group of intracellular spermidine. This acetylation inactivates spermidine, reducing the polyamine toxicity that tends to occur under certain chemical and physical stresses. The structure of the SpeG protein from Vibrio cholerae has been characterized: while the monomer possesses a structural fold similar to those of other Gcn5-related N-acetyltransferase superfamily members, its dodecameric structure remains exceptional. In this paper, structural analyses of SpeG isolated from Escherichia coli are described. Like V. cholerae SpeG, E. coli SpeG forms dodecamers, as revealed by two crystal structures of the ligand-free E. coli SpeG dodecamer determined at 1.75 and 2.9 Å resolution. Although both V. cholerae SpeG and E. coli SpeG can adopt an asymmetric open dodecameric state, solution analysis showed that the oligomeric composition of ligand-free E. coli SpeG differs from that of ligand-free V. cholerae SpeG. Based on these data, it is proposed that the equilibrium balance of SpeG oligomers in the absence of ligands differs from one species to another and thus might be important for SpeG function.

Keywords:  Escherichia coli; GNAT family; SpeG; polyamine acetylation; spermidine N-acetyltransferase

DOI:  https://doi.org/10.1107/S2059798319006545
Hum Gene Ther. 2019 Jun 19.

INSIGHTS INTO GENE THERAPY FOR UREA CYCLE DEFECTS BY MATHEMATICAL MODELLING.

Ian Edward Alexander, Cindy Kok, Sharon Carla Cunningham, Philip Kuchel.

Metabolic liver diseases are attractive gene therapy targets that necessitate reconstitution of enzymatic activity in functionally complex biochemical pathways. The levels of enzyme activity required in individual hepatocytes and the proportion of the hepatic cell mass that must be gene-corrected for therapeutic benefit varies in a disease-dependent manner that is difficult to predict. While empirical evaluation is inevitably required, useful insights can nevertheless be gained from knowledge of disease pathophysiology and theoretical approaches such as mathematical modelling. Urea cycle defects provide an excellent example. Building on a previously described one-compartment model of the urea cycle, we have constructed a two-compartment model that can simulate liver-targeted gene therapy interventions using the computational program <i>Mathematica</i>. The model predicts that therapeutically effective reconstitution of ureagenesis will correlate most strongly with the proportion of the hepatic cell mass transduced rather than the level of enzyme-encoding transgene expression achieved in individual hepatocytes. Importantly, these predictions are supported by experimental data in mice and human genotype-phenotype correlations. The most notable example of the latter is ornithine transcarbamylase deficiency (X-linked) where impairment of ureagenesis in male and female patients is closely simulated by the one and two-compartment models, respectively. Collectively these observations support the practical value of mathematical modelling in evaluation of the disease-specific gene transfer challenges posed by complex metabolic phenotypes.

DOI: https://doi.org/10.1089/hum.2019.053
Macromol Rapid Commun. 2019 Jun 17. e1900100

Nitrogen-Rich Porous Organic Polyamines for Stabilization of Highly Dispersed Metal Nanoparticles and Catalytic Application.

Dong Yang, Yinglai Hou, Qiang Zhuang, Pei Liu, Jie Kong.

  Nitrogen-rich triazine-based porous organic polyamines (POPa) synthesized via a one-step polycondensation of melamine and 4,4',4''-(1,3,5-triazine-2,4,6-triyl)tribenzaldehyde is employed to synthesize Au and Pd nanoparticles well-dispersed on POPa. The as-prepared POPa-supported Au NPs and Pd NPs (AuNPs@POPa, PdNPs@POPa) with a narrow size distribution show remarkable catalytic activity for the reduction of nitrobenzene compounds and organic dyes and the Suzuki-Miyaura coupling reaction, respectively. Benefitting from POPa the AuNPs@POPa and PdNPs@POPa catalysts can be readily recovered and reused almost without loss of activity. The nitrogen-rich porous organic polyamines provide great opportunities to prepare functional metal nanocatalysts with potential in the heterogeneous catalysis field.

Keywords:  coupling reaction; nanocatalysts; porous organic polymers; reduction reaction

DOI:  https://doi.org/10.1002/marc.201900100
BMC Med Genet. 2019 Jun 17. 20(1): 110

Citrullinemia type I is associated with a novel splicing variant, c.773 + 4A > C, in ASS1: a case report and literature review.

Yiming Lin, Hongzhi Gao, Bin Lu, Shuang Zhou, Tianwen Zheng, Weihua Lin, Lin Zhu, Mengyi Jiang, Qingliu Fu.

   BACKGROUND: Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder of the urea cycle caused by a deficiency in the argininosuccinate synthetase (ASS1) enzyme due to mutations in the ASS1 gene. Only a few Chinese patients with CTLN1 have been reported, and ASS1 gene mutations have been identified sporadically in China.
CASE PRESENTATION: A Chinese family with one member affected with mild CTLN1 was enrolled. Targeted exome sequencing was performed on the proband, and Sanger sequencing was used to validate the detected mutation. We also reviewed the genetic and clinical characteristics of CTLN1 in Chinese patients that have been published to date. Newborn screening showed remarkably increased concentrations of citrulline with elevated ratios of citrulline/arginine and citrulline/phenylalanine, and the patient presented with a speech delay at age three. The urinary organic acid profiles were normal. A novel homozygous splicing variant c.773 + 4A > C in the ASS1 gene was identified in the proband, and it was predicted to affect splicing by in silico analysis. To date, only nine Chinese patients with CTLN1 have been reported, with a total of 15 ASS1 mutations identified and no high frequency or hot spot mutations found; the mutation spectrum of Chinese patients with CTLN1 was heterogeneous.
CONCLUSIONS: We described a mild Chinese CTLN1 case with a novel homozygous splicing variant c.773 + 4A > C and reviewed previous genotypes and phenotypes in Chinese patients with CTLN1. Thus, our findings contribute to understanding the molecular genetic background and clinical phenotype of CTLN1 in this population.

Keywords:  ASS1; Citrullinemia type I; Mutation spectrum; Novel variant

DOI:  https://doi.org/10.1186/s12881-019-0836-5