bims-polyam Biomed News
on Polyamines
Issue of 2020‒02‒16
four papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology

  1. Biochim Biophys Acta Gen Subj. 2020 Feb 08. pii: S0304-4165(20)30047-7. [Epub ahead of print] 129557
    Kabir A, Jash C, Payghan PV, Ghoshal N, Kumar GS.
      BACKGROUND: Polyamines can induce protein aggregation that can be related to the physiology of the cellular function. Polyamines have been implicated in protein aggregation which may lead to neuropathic and non neuropathic amyloidosis.SCOPE OF REVIEW: Change in the level of polyamine concentration has been associated with ageing and neurodegeneration such as Parkinson's disease, Alzheimer's disease. Lysozyme aggregation in the presence of polyamines leads to non neuropathic amyloidosis. Polyamine analogues can suppress or inhibit protein aggregation suggesting their efficacy against amyloidogenic protein aggregates.
    MAJOR CONCLUSIONS: In this study we report the comparative interactions of lysozyme with the polyamine analogue, 1-naphthyl acetyl spermine in comparison with the biogenic polyamines through spectroscopy, calorimetry, imaging and docking techniques. The findings revealed that the affinity of binding varied as spermidine > 1-naphthyl acetyl spermine > spermine. Also the biogenic polyamines accelerated the rate of fibrillation significantly, whereas the analogue inhibited the rate of fibrillation to a considerable extent. The polyamines bind near the catalytic diad residues viz. Glu35 and Asp52, and in close proximity of Trp62 residue. However, the analogue showed dual nature of interaction where its alkyl amine region bind in same way the biogenic polyamines bind to the catalytic site, while the naphthyl group makes hydrophobic contacts with Trp62 and Trp63, thereby suggesting its direct influence on fibrillation.
    GENERAL SIGNIFICANCE: This study, thus, potentiates, the development of a polyamine analogue that can perform as an effective inhibitor targeted towards aggregation of amyloidogenic proteins.
    Keywords:  1-napthyl acetyl spermine (NASPM); Amyloidosis; Atomic force microscopy; Lysozyme; Neurodegenerative diseases; Polyamine; Protein aggregation
  2. Int J Biol Macromol. 2020 Feb 11. pii: S0141-8130(20)30238-5. [Epub ahead of print]
    Sekula B, Ruszkowski M, Dauter Z.
      S-adenosylmethionine synthases (MATs) are responsible for production of S-adenosylmethionine, the cofactor essential for various methylation reactions, production of polyamines and phytohormone ethylene, etc. Plants have two distinct MAT types (I and II). This work presents the structural analysis of MATs from Arabidopsis thaliana (AtMAT1 and AtMAT2, both type I) and Medicago truncatula (MtMAT3a, type II), which, unlike most MATs, are dimers where three-domain subunits are sandwiched flat with one another. Although MAT types are very similar, their subunits are differently oriented within the dimer. Structural snapshots along the enzymatic reaction reveal the exact conformation of precatalytic methionine in the active site and show a binding niche, characteristic only for plant MATs, that may serve as a lock of the gate loop. Nevertheless, plants, in contrary to mammals, lack the MAT regulatory subunit, and the regulation of plant MAT activity is still puzzling. Our structures open a possibility of an allosteric activity regulation of type I plant MATs by linear compounds, like polyamines, which would tighten the relationship between S-adenosylmethionine and polyamine biosynthesis.
    Keywords:  AdoMet; Methionine adenosyltransferase; S-adenosylmethionine synthase
  3. J Biol Chem. 2020 Feb 11. pii: jbc.RA119.011692. [Epub ahead of print]
    Min KB, Yoon SS.
      The stringent response (SR) is a highly conserved stress response in bacteria. It is composed of two factors, (i) a nucleotide alarmone, guanosine tetra- and pentaphosphate ((p)ppGpp), and (ii) an RNA polymerase-binding protein, DksA, that regulates various phenotypes including bacterial virulence. The clinically significant opportunistic bacterial pathogen Pseudomonas aeruginosa possesses two genes, dksA1 and dksA2, that encode DksA proteins. It remains elusive, however, which of these two genes plays a more important role in SR regulation. In this work, we compared genome-wide, RNASeq-based transcriptome profiles of ΔdksA1, ΔdksA2, and ΔdksA1ΔdksA2 mutants to globally assess the effects of these gene deletions on transcript levels coupled with phenotypic analyses. The ΔdksA1 mutant exhibited substantial defects in a wide range of phenotypes, including quorum sensing (QS), anaerobiosis, and motility, whereas the ΔdksA2 mutant exhibited no significant phenotypic changes, suggesting that the dksA2 gene may not have an essential function in P. aeruginosa under the conditions used here. Of note, the ΔdksA1 mutants displayed substantially increased transcription of genes involved in polyamine biosynthesis, and we also detected increased polyamine levels in these mutants. Since SAM is a shared precursor for the production of both QS autoinducers and polyamines, these findings suggest that DksA1 deficiency skews the flow of SAM toward polyamine production rather than to QS signaling. Together, our results indicate that DksA1, but not DksA2, controls many important phenotypes in P. aeruginosa. We conclude that DksA1 may represent a potential target whose inhibition may help manage recalcitrant P. aeruginosa infections.
    Keywords:  Pseudomonas aeruginosa (P. aeruginosa); quorum sensing; stress response; transcription regulation; virulence factor
  4. Anal Biochem. 2020 Feb 10. pii: S0003-2697(20)30009-9. [Epub ahead of print] 113618
    Wilson LA, Garcia D, Pedroso MM, Schulz BL, Guddat LW, Schenk G.
      Ureohydrolases are members of the metallohydrolase family of enzymes. Here, a simple continuous assay for agmatinase (AGM) activity was established by following the degradation of agmatine to urea and putrescine using isothermal titration calorimetry (ITC). ITC is particularly useful for kinetic assays when substrates of interest do not possess suitable chromophores that facilitate the continuous spectrophotometric detection of substrate depletion and/or product formation. In order to assess the accuracy of the ITC-based assay, catalytic parameters were also determined using a discontinuous, colorimetric assay. Both methods resulted in comparable kinetic parameters. From the colorimetric assay the kcat and KM values are 131 s-1 and 0.25 mM, respectively, and from the ITC assay the corresponding parameters are 30 s-1 and 0.45 mM, respectively. The continuous ITC-based assay will facilitate functional studies for an enzyme that is an emerging target for the development of addiction treatments.
    Keywords:  Agmatinase; Enzyme kinetics; Metallohydrolases; Ureohydrolase