Search

Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time‐lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion–fission–mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis. [ABSTRACT FROM AUTHOR]

The phosphinic acid functionality has emerged as an invaluable scaffold for the construction of biologically active compounds, in particular enzyme inhibitors. This article presents two examples of recent achievements in the preparation and application of phosphinic acids as ligands for hydrolases. Synthetic approaches to a dipeptide analog inhibitor of metalloaminopeptidases and a catechol-based inhibitor of urease are shown. The activity and mode of binding of phosphinic compounds to enzymes are further discussed. [ABSTRACT FROM AUTHOR]

Seven crystal structures of alanylaminopeptidase from Neisseria meningitides(the etiologicalagent of meningitis, NmAPN) complexed with organophosphoruscompounds were resolvedto determine the optimal inhibitor–enzyme interactions. Theenantiomeric phosphonic acid analogs of Leu and hPhe, which correspondto the P1 amino acid residues of well-processed substrates, were usedto assess the impact of the absolute configuration and the stereospecifichydrogen bond network formed between the aminophosphonate polar headand the active site residues on the binding affinity. For the hPheanalog, an imperfect stereochemical complementarity could be overcomeby incorporating an appropriate P1 side chain. The constitution ofP1′-extended structures was rationally designed and the lead,phosphinic dipeptide hPhePψ[CH2]Phe, was modifiedin a single position. Introducing a heteroatom/heteroatom-based fragmentto either the P1 or P1′ residue required new synthetic pathways.The compounds in the refined structure were low nanomolar and subnanomolarinhibitors of N. meningitides, porcine and humanAPNs, and the reference leucine aminopeptidase (LAP). The unnaturalphosphinic dipeptide analogs exhibited a high affinity for monozincAPNs associated with a reasonable selectivity versus dizinc LAP. Anotherset of crystal structures containing the NmAPN dipeptideligand were used to verify and to confirm the predicted binding modes;furthermore, novel contacts, which were promising for inhibitor development,were identified, including a π–π stacking interactionbetween a pyridine ring and Tyr372. [ABSTRACT FROM AUTHOR]

Peptide foldamers containing both cis-β-aminocyclopentanecarboxylic acid and α-amino acid residues combined in various sequence patterns (ααβ, αααβ, αβααβ, and ααβαααβ) were screened using CD and NMR spectroscopy for the tendency to form helices. ααβ-Peptides were found to fold into an unprecedented and well-defined 16/17/15/18/14/17-helix. By extending the length of the sequence or shifting a fragment of the sequence from one terminus to another in ααβ-peptides, the balance between left-handed and right-handed helix populations present in the solution can be controlled. Engineering of the peptide sequence could lead to compounds with either a strong propensity for the selected helix sense or a mixture of helical conformations of opposite senses., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)