We are happy to announce that the website of the
has been activated: https://bsne.lakecomoschool.org/
The School is organized by our member Loredano Pollegioni. We are not sure again about the mode of teaching (face-to-face or online), but we trust in the proposed programme and period.
Do you have news concerning the D-amino acids field to announce? Is there a relevant published paper to mention? Write us and take the advantage of this bimonthly Newsletter.
From this issue we introduce the Editor’s pick selection of the most intriguing papers (the ones with the title highlighted in yellow).
- Antimicrobial D‑amino acid oxidase‑derived peptides specify gut microbiota.
Giulia Murtas, Silvia Sacchi, Gabriella Tedeschi, Elisa Maffioli, Eugenio Notomista, Valeria Cafaro, Monica Abbondi, Jean‑Pierre Mothet, Loredano Pollegioni
Cellular and Molecular Life Sciences, 2021 in press, https://doi.org/10.1007/s00018-020-03755-w
It has been suggested that the goblet cells of the mucosal epithelia secrete into the lumen of intestine, a processed and active form of the enzyme D-amino acid oxidase (DAAO) that uses the intestinal D-amino acids to generate hydrogen peroxide, an immune messenger that helps fighting gut pathogens. Here, it was reported that the DAAO form lacking the 1–16 amino acid residues (the putative secretion signal) is unstable and inactive, and that DAAO is present in the epithelial layer and the mucosa of mouse gut, where it is largely proteolyzed. In silico predicted DAAO-derived antimicrobial peptides show activity against various Gram-positive and Gram-negative bacteria but not on Lactobacilli species. Peptidomic analysis reveals the presence of such peptides in the mucosal fraction. This represents a novel mechanism for gut microbiota selection and an additional, ancillary role for mammalian DAAO, unrelated to its enzymatic activity. MORE
- Sp4 controls constitutive expression of neuronal serine racemase and NF-E2-related factor-2 mediates its induction by valproic acid.
Zhang H, Lu J, Wu S.
Biochim Biophys Acta Gene Regul Mech. 2020 Sep;1863(9):194597. doi: 10.1016/j.bbagrm.2020.194597.
The reason why serine racemase (SR) is mostly expressed in neurons is still unkown. Here the authors reported that in Neuro-2a cell line, SR transcript and protein levels were increased by the neuron differentiation stimulator valproic acid (VPA). An analysis of the mammalian SR encoding gene revealed conserved putative Sp-binding elements in the proximal promoter and anti-oxidant elements (AREs) in exon 1. These important elements for promoter activity were shown to bind Sp4 and Nrf2, respectively, two transcription factors involved in differentiation. Sp4 maintains high levels of constitutive SR expression in neurons, while under differentiation, Nrf2 controls SR up-regulation in response to VPA. MORE
ROLE OF D-AAs:
- Prenatal and Early Postnatal Cerebral D-Aspartate Depletion Influences L-Amino Acid Pathways, Bioenergetic processes, and Developmental Brain Metabolism.
Manuela Grimaldi, Carmen Marino, Michela Buonocore, Angelo Santoro, Eduardo Sommella, Fabrizio Merciai, Emanuela Salviati, Arianna De Rosa, Tommaso Nuzzo, Francesco Errico, Pietro Campiglia, Alessandro Usiello, Anna Maria D’Ursi
Journal of Proteome Research 2021 20 (1), 727-739 DOI: 10.1021/acs.jproteome.0c00622
Concerning the role of D-Asp in the central nervous system, this work used a recently generated knockin mouse model (R26Ddo/Ddo), which was designed to express DDO beginning at the zygotic stage: in this way D-Asp was almost eliminated in both prenatal and postnatal lives. By performing a metabolomic and lipidomic study of Ddo knockin brains at different stages of embryonic and postnatal development, combining nuclear magnetic resonance and high-resolution mass spectrometry techniques, the authors showed that D-Asp deficiency in the brain influences amino acid pathways such as threonine, glycine, alanine, valine, and glutamate. Notably, D-Asp is also correlated with metabolites involved in brain development and functions (choline, creatine, phosphocholine, glycerophosphocholine, sphingolipids, and glycerophospholipids) as well as metabolites involved in brain energy metabolism (glucose and lactate). MORE
- Advances in D-Amino Acids in Neurological Research.
Seckler, James M., Lewis, Stephen J.
2020 Int. J. Mol. Sci. 21, no. 19: 7325. https://doi.org/10.3390/ijms21197325
This review gives a concise overview of the recent advances in D-amino acid research and their relationships with brain and neurological disorders. This work has largely been focused on modulation of the N-methyl-D-aspartate receptor and its relationship to Alzheimer’s disease and schizophrenia: recently, a wealth of novel studies has elucidated a novel role for several D-amino acids in altering brain chemistry in a neuroprotective manner. D-amino acids which have no currently known activity in the brain but which have active derivatives have been also reviewed. MORE
- Advancing D-amino acid-containing peptide discovery in the metazoan.
Mast DH, Checco JW, Sweedler JV.
Biochim Biophys Acta Proteins Proteom. 2021 Jan;1869(1):140553. doi: 10.1016/j.bbapap.2020.140553. Epub 2020 Sep 28. PMID: 33002629; PMCID: PMC7736501
The authors’ statement “discovery of enzyme-derived D-amino acid-containing peptides (DAACPs) that have physiological importance in the metazoan challenges previous assumptions about the homochirality of animal proteins while simultaneously revealing new analytical challenges in the structural and functional characterization of peptides” is of main scientific relevance. Peptide characterization experiments are increasingly dominated by high throughput mass spectrometry-based peptidomics, with stereochemistry rarely considered due to technical challenges. This review reports about the prevalence of enzyme-derived DAACPs among animals and the physiological consequences of peptide isomerization. Indeed, it focuses on the analytical methods that have been applied for structural characterization/discovery of DAACPs, including results of several recent studies using non-targeted discovery methods for revealing novel DAACPs. MORE
D-AAs AND PATHOLOGIES:
- Brain activity of benzoate, a D-amino acid oxidase inhibitor, in patients with mild cognitive impairment in a randomized, double-blind, placebo controlled clinical trial
Hsien-Yuan Lane, Cheng-Hao Tu, Wei-Che Lin, Chieh-Hsin Lin
International Journal of Neuropsychopharmacology, pyab001, https://doi.org/10.1093/ijnp/pyab001
The D-amino acid oxidase (DAAO) inhibitor sodium benzoate has been found to improve the cognitive function of patients with early-phase Alzheimer’s disease (AD). This study aimed to evaluate the influence of benzoate (250-1500 mg/day) on fMRI in 21 patients with amnestic MCI. Following benzoate treatment, resting-state regional homogeneity (ReHo) decreased in right orbitofrontal cortex, the change in working memory was positively correlated with ReHo; the change in verbal learning and memory was positively correlated with the change in ReHo in left precuneus. This study demonstrated that DAAO inhibition alters brain activity as well as cognitive functions in the MCI individuals. MORE
- Cerebrospinal Fluid and Serum D-Serine Levels in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis.
Chang CH, Kuo HL, Ma WF, Tsai HC.
J Clin Med. 2020 Nov 26;9(12):E3840. doi: 10.3390/jcm9123840
Dysfunction of the N-methyl-D-aspartate receptor (NMDAR) has been found to be involved in synapse dysfunction and neurotoxicity of Alzheimer’s disease (AD) mechanisms. D-Serine has been proposed as a potential new biomarker for AD. However, the results of serum and cerebrospinal fluid (CSF) D-s
erine levels are conflicting. Here, a meta-analysis was performed to investigate the serum and CSF D-serine levels in patients with AD. A total of 7 trials, with 1186 participants, were included: D-serine levels in AD were significantly higher than those in controls in serum and CSF. MORE
- Serum D-serine levels are altered in early phases of Alzheimer’s disease: towards a precocious biomarker.
Luciano Piubelli, Loredano Pollegioni, Valentina Rabattoni, Marco Mauri, Lucia Princiotta Cariddi, Maurizio Versino, Silvia Sacchi
Translational Psychiatry (2021) 11:77 https://doi.org/10.1038/s41398-021-01202-3
This work investigated the levels of D-serine and D-aspartate in serum of Alzheimer’s disease (AD) patients. HPLC data obtained from age-matched healthy subjects (HS) and AD patients were evaluated by considering age, gender, and disease progression. Minor changes were apparent in the serum L- and D-aspartate levels in AD patients compared to HS, while a positive correlation for the D-serine level and age was apparent in the AD cohort. Notably, the serum D-serine level and the D-/total serine ratio signiﬁcantly increased with the progression of the disease. The authors propose that the serum D-serine level and D-/total serine ratio values as novel and valuable biomarkers for the progression of AD. Interestingly, the latter parameter allows to discriminate CDR 2 and CDR 1 patients from healthy (CDR 0) individuals. MORE
- Overexpression of D-amino acid oxidase prevents retinal neurovascular pathologies in diabetic rats.
Jiang H, Zhang H, Jiang X, Wu S.
Diabetologia. 2020 Dec 14. doi: 10.1007/s00125-020-05333-y
Recent studies indicate that abnormal levels of D-Ser and serine racemase are involved in diabetic retinopathy, a common complication of diabetes mellitus. Here the role of D-amino acid oxidase (DAAO) was explored, using 2 months rats subjected to an i.p. injection of streptozotocin (STZ) as a model of diabetes. The authors discovered that Dao proximal promoter is hypermethylated in diabetic rats’ retinas and this yields to reduced DAAO mRNA and protein levels compared to controls. Notably the induced overexpression of DAAO in rats’s retinas before STZ administration exerts a neuroprotective effect: preventing retinal neurodegeneration and gliosis and protecting against neurovascular abnormalities typically accompanying this pathological condition. MORE
- Automated Chiral Analysis of Amino Acids Based on Chiral Derivatization and Trapped Ion Mobility-Mass Spectrometry.
Will JM, Behrens A, Macke M, Quarles CD Jr, Karst U.
Anal Chem. 2021 Jan 19;93(2):878-885. doi: 10.1021/acs.analchem.0c03481. Epub 2020 Dec 18. PMID: 33337156
This paper reported on the set up of a fast and fully automated method for chiral analysis based on the combination of a chiral derivatization approach with high-resolution trapped ion mobility separation. An autosampler with an integrated chromatography system was used for inline chiral derivatization with (S)-naproxen chloride and subsequent preseparation: derivatized amino acids were introduced into the electrospray interface of a trapped ion mobility-mass spectrometer for rapid diastereomer separation in the gas phase. This enabled rapid chiral analysis (3 min per sample), that was independent of alkali salts or other metal ions and showed high sensitivity (down to the lower nanomolar concentration range). Alanine and other amino acids were analyzed from soy sauces and seasonings. MORE
ENZYMES ACTIVE ON D-AAs & BIOTECHNOLOGICAL APPLICATIONS:
- Highly selective synthesis of D-amino acids from readily available L-amino acids by a one-pot biocatalytic stereoinversion cascade
Danping Zhang Xiaoran Jing Wenli Zhang , Yao Nie, Yan Xu RSC Adv., 2019,9, 29927-29935, https://doi.org/10.1039/C9RA06301C
D-Amino acids are key intermediates required for the synthesis of important pharmaceuticals. In this study, a cascade enzymatic route involving L-amino acid deaminase (LAAD) and D-amino acid dehydrogenase was set up for the biocatalytic stereoinversions of L-amino acids into D-amino acids, using L-phenylalanine (L-Phe) as a model substrate. The authors used recombinant Escherichia coli cells expressing LAAD from Proteus mirabilis followed by stereoselective reductive amination with recombinant meso-diaminopimelate dehydrogenase from Symbiobacterium thermophilum to produce D-phenylalanine (D-Phe). By incorporating a NADPH-recycling system, D-Phe was obtained in quantitative yield with an enantiomeric excess greater than 99%. This cascade system was also used to stereoinvert a variety of aromatic and aliphatic L-amino acids to the corresponding D-amino acids. MORE
- The Use of D-Amino Acids for Peptide Self-assembled Systems
Cringoli, M.C., Marchesan, S.
RSC Soft Matter, vol. 2021(11) 2021, 174-216 CHAPTER 6
This chapter analyses existing literature on the use of D-amino acids in self-assembled systems for biomedical applications, their biological roles and consequences that arise from their presence in a peptide sequence, as well as their application in medicine and related fields with a view towards the future. MORE
- Antibacterial and anti-inflammatory activity of an antimicrobial peptide synthesized with D-amino acids
Brunetti, J., Carnicelli, V., Ponzi, A., Di Giulio, A., Lizzi, A.R., Cristiano, L., Cresti, L., Cappello, G., Pollini S., Mosconi, L., Rossolini, G.M., Bracci, L., Falciani, C., Pini A.
Antibiotics, Vol 9(12), December 2020, 1-17, https://doi.org/10.3390/antibiotics9120840
The peptide SET-M33 is a molecule synthesized in tetra-branched form which is being developed as a new antibiotic against Gram-negative bacteria. Its isomeric form with D-amino acids instead of the L-enantiomers (SET-M33D) is also able to kill Gram-positive bacteria because of its higher resistance to bacterial proteases. Here, the authors reported the strong in vitro activity of SET-M33D (MIC range 0.7–6.0 µM) against multiresistant pathogens of clinical interest, and in vivo activity against a MRSA strain of S. aureus with doses perfectly compatible with clinical use (5 and 2.5 mg/kg). Moreover, SET-M33D strongly neutralized lipopolysaccharide and lipoteichoic acid, thus exerting a strong anti-inflammatory effect. These results SET-M33D a strong candidate for the development of a new broad spectrum antibiotic. MORE
- TK1211 Encodes an Amino Acid Racemase towards Leucine and Methionine in the Hyperthermophilic Archaeon Thermococcus kodakarensis
Zheng RC, Lu XF, Tomita H, Hachisuka SI, Zheng YG, Atomi H.
J Bacteriol. 2021 Jan 19:JB.00617-20. doi: 10.1128/JB.00617-20.
In this paper the authors reported the biochemical properties of a new protein from a hyperthermophilic archeon, belonging to a poorly characterized group of class III aminotransferases. It turned out to be a PLP-dependent racemase preferentially active (among other amino acids) on leucine and methionine, involved in the assimilation of their D-enantiomers and possibly in their biosynthesis. MORE
The D-amino acids International Research Center “DAAIR“ has been established in Gerenzano (Varese, Italy) in 2019 with the aim to support and perform scientific research projects and activities on the field of D-amino acids. The Center, located inside the Fondazione Istituto Insubrico Ricerca per la Vita, is aimed to represent a pole of excellence at international level for dissemination and research involving the D-amino acids (Director Silvia Sacchi).
The guiding principle is support the research projects aimed to investigate the involvement of D-amino acids in main physiological processes, from bacteria to humans. The ultimate goal is to actively participate to the elucidation of the mechanisms by which the D-amino acids perform specific functions, and to identify their presence and concentration in different organisms and compartments, also with regards to well-established functional states, with particular emphasis to pathological states. Understand the involvement of D-amino acids in important diseases as a way to set up novel therapeutic strategies.
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