bims-polyam Biomed News
on Polyamines
Issue of 2023–09–17
six papers selected by
Sebastian J. Hofer, University of Graz
  1. Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome.
  2. Evidence of polyamines mediated 2-acetyl-1-pyrroline biosynthesis in aromatic rice rhizospheric fungal species Aspergillus niger.
  3. Effects of exogenous spermidine on autophagy and antioxidant capacity in ovaries and granulosa cells of Sichuan white geese.
  4. Rebalancing polyamine levels to treat Snyder-Robinson syndrome.
  5. Polyamine detergents tailored for native mass spectrometry studies of membrane proteins.
  6. Combination of tea catechins and ornithine effectively activates the urea cycle: an in vitro and human pilot study.
  1. EMBO Mol Med. 2023 Sep 13. e17833
    Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome.
    Tracy Murray Stewart, Jackson R Foley, Cassandra E Holbert, Maxim Khomutov, Noushin Rastkari, Xianzun Tao, Alex R Khomutov, R Grace Zhai, Robert A Casero.
      Snyder-Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2-difluoromethylornithine (DFMO), an FDA-approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential.
    Keywords:  S-adenosylmethionine decarboxylase; alpha-methylated polyamine analogue; eflornithine; spermidine; spermine synthase
    DOI:  https://doi.org/10.15252/emmm.202317833
  2. Braz J Microbiol. 2023 Sep 13.
    Evidence of polyamines mediated 2-acetyl-1-pyrroline biosynthesis in aromatic rice rhizospheric fungal species Aspergillus niger.
    Andleeb Zehra, Harshal V Dhondge, Vitthal T Barvkar, Sanjay K Singh, Altafhusain B Nadaf.
      Rhizosphere soil of aromatic rice inhabits different fungal species that produce many bioactive metabolites including 2-acetyl-1-pyrroline (2AP). The mechanism for the biosynthesis of 2AP in the fungal system is still elusive. Hence, the present study investigates the role of possible nitrogen (N) precursors such as some amino acids and polyamines as well as the enzymes involved in 2AP synthesis in the fungal species isolated from the rhizosphere of aromatic rice varieties. Three fungal isolates were found to synthesize 2AP (0.32-1.07 ppm) and maximum 2AP was synthesized by Aspergillus niger (1.07 ppm) isolated from rhizosphere of Dehradun Basmati (DB). To determine the N source for 2AP synthesis, various N sources such as proline, glutamate, ornithine putrescine, spermine, and spermidine were used in place of putrescine in the synthetic medium (Syn18). The results showed that maximum 2AP synthesis was found with putrescine (1.07 ppm) followed by spermidine (0.89 ppm) and spermine (0.84 ppm). Further, LC-QTOF-MS analysis revealed the mobilization of spermine and spermidine into the putrescine, indicating that putrescine is the key N source for 2AP synthesis. Moreover, higher enzyme activity of DAO, PAO, and ODC as well as higher content of methylglyoxal metabolite in the A. niger NFCCI 5060 as compared to A. niger NFCCI 4064 (control) suggests the prominent role of these enzymes in the synthesis of 2AP. In conclusion, this study showed evidence of the polyamines mediated 2AP biosynthesis in A. niger NFCCI 5060.
    Keywords:  2-Acetyl-1-pyrroline; Aromatic rice; Aspergillus niger; Polyamines; Rhizosphere fungi
    DOI:  https://doi.org/10.1007/s42770-023-01124-w
  3. J Anim Sci. 2023 Sep 12. pii: skad301. [Epub ahead of print]
    Effects of exogenous spermidine on autophagy and antioxidant capacity in ovaries and granulosa cells of Sichuan white geese.
    Dongmei Jiang, Qian Sun, Yilong Jiang, Xuemin Zhou, Lijuan Kang, Zelong Wang, Xin Wang, Xiaoguang An, Chengweng Ji, Weikang Ling, Bo Kang.
      Autophagy can inhibit ovarian senescence induced by oxidative stress and regulate follicle development and atresia, but its mechanism is still unclear. Exogenous spermidine can induce autophagy and scavenge reactive oxygen species (ROS). In this experiment, oxidative stress in Sichuan white geese ovaries and follicular granulosa cells (GCs) were caused by 3-nitropropionic acid (3-NPA) and spermidine was added to explore the effect of exogenous spermidine inducing autophagy and inhibiting oxidative stress in vivo and in vitro. Research results showed that putrescine, spermidine and spermine contents in goose ovaries in the group treated with spermidine combined with 3-NPA were 2.70, 1.94 and 1.70 times higher than those in the group treated with 3-NPA, respectively (P < 0.05). The contents of spermidine and spermine in GCs were 1.37 and 0.89 times higher in the spermidine in combination with the 3-NPA group than in the 3-NPA group, respectively (P < 0.05). LC3 and p62 were mainly expressed in the follicular granulosa layer. The LC3-II/I ratio and p62 level in GCs in the spermidine combined with 3-NPA treatment group were 1.37 and 0.77 times higher than that of the 3-NPA treatment group, respectively (P < 0.05). 3-NPA treatment significantly increased ROS level and the apoptosis rate in GCs, while the combined treatment of spermidine and 3-NPA reversed this change (P < 0.05). In conclusion, spermidine alleviated the oxidative damage induced by 3-NPA by improving the antioxidant capacity of ovaries and follicular GCs of Sichuan white geese and may be alleviated by inducing autophagy in GCs.
    Keywords:  autophagy; goose ovaries; granulosa cells; oxidative stress; spermidine
    DOI:  https://doi.org/10.1093/jas/skad301
  4. EMBO Mol Med. 2023 Sep 15. e18506
    Rebalancing polyamine levels to treat Snyder-Robinson syndrome.
    Susan K Gilmour.
      Snyder-Robinson syndrome (SRS) is a rare genetic disorder characterized by intellectual disability and delayed development beginning early in childhood. It was first described in a single family in 1969 as a sex-linked disorder (Snyder & Robinson, 1969) and has since been only identified in less than 100 individuals worldwide. Inherited in an X-linked recessive pattern, SRS has only been identified in males thus far. Snyder-Robinson syndrome primarily affects the nervous system and skeletal tissues and is caused by loss-of-function mutations in the gene encoding spermine synthase (SMS), a polyamine biosynthesis enzyme. Affected males display a collection of clinical features including intellectual disability ranging from mild to profound, speech and vision impairment, osteoporosis, hypotonia, and increasing loss of muscle tissue with age, kyphoscoliosis, seizures, and distinctive facial features including a prominent lower lip and facial asymmetry. Currently, there is no cure or treatment for this debilitating disorder aside from symptom management.
    DOI:  https://doi.org/10.15252/emmm.202318506
  5. Nat Commun. 2023 Sep 14. 14(1): 5676
    Polyamine detergents tailored for native mass spectrometry studies of membrane proteins.
    Yun Zhu, Bo-Ji Peng, Smriti Kumar, Lauren Stover, Jing-Yuan Chang, Jixing Lyu, Tianqi Zhang, Samantha Schrecke, Djavdat Azizov, David H Russell, Lei Fang, Arthur Laganowsky.
      Native mass spectrometry (MS) is a powerful technique for interrogating membrane protein complexes and their interactions with other molecules. A key aspect of the technique is the ability to preserve native-like structures and noncovalent interactions, which can be challenging depending on the choice of detergent. Different strategies have been employed to reduce charge on protein complexes to minimize activation and preserve non-covalent interactions. Here, we report the synthesis of a class of polyamine detergents tailored for native MS studies of membrane proteins. These detergents, a series of spermine covalently attached to various alkyl tails, are exceptional charge-reducing molecules, exhibiting a ten-fold enhanced potency over spermine. Addition of polyamine detergents to proteins solubilized in maltoside detergents results in improved, charge-reduced native mass spectra and reduced dissociation of subunits. Polyamine detergents open new opportunities to investigate membrane proteins in different detergent environments that have thwarted previous native MS studies.
    DOI:  https://doi.org/10.1038/s41467-023-41429-w
  6. Eur J Appl Physiol. 2023 Sep 14.
    Combination of tea catechins and ornithine effectively activates the urea cycle: an in vitro and human pilot study.
    Takahiro Hasumura, Keita Kinoshita, Yoshihiko Minegishi, Noriyasu Ota.
       PURPOSE: Accumulation of ammonia causes central and peripheral fatigue. This study aimed to investigate the synergistic effect of tea catechins and low-dose ornithine in activating the urea cycle to reduce blood ammonia levels during exercise.
    METHODS: We used hepatocyte-like cells derived from human-induced pluripotent stem (iPS) cells to assess the effect of tea catechins combined with ornithine on urea cycle activity. The urea production and expression of key genes involved in the metabolism of urea were investigated. We then examined the synergistic improvement in ammonia metabolism by tea catechins in combination with ornithine in a human pilot study.
    RESULTS: Tea catechins combined with ornithine increased urea cycle activity in hepatocyte-like cells derived from human iPS cells. Intake of 538.6 mg of tea catechins with 1592 mg of ornithine for 2 consecutive days during exercise loading suppressed the exercise-induced increase in the blood ammonia concentration as well as stabilized blood glucose levels.
    CONCLUSION: Controlling the levels of ammonia, a toxic waste produced in the body, is important in a variety of situations, including exercise. The present study suggests that a heterogeneous combination of polyphenols and amino acids efficiently suppresses elevated ammonia during exercise in humans by a mechanism that includes urea cycle activation.
    TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trial Registry (No. UMIN000035484, dated January 8, 2019).
    Keywords:  Ammonia; Exercise; Ornithine; Tea catechins; Urea cycle
    DOI:  https://doi.org/10.1007/s00421-023-05310-4
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