Newsletter 03/2020

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 CANCER THERAPY:

• CLyta-DAAO, free and immobilized in magnetic nanoparticles, induces cell death in human cancer cells

Fuentes-Baile, M., Bello-Gil, D., Pérez-Valenciano, E., Sanz, J.M., García-Morales, P., Ventero, M.P., Alenda, C., Barberá, V.M., Saceda, M.
BiomoleculesOpen Access, Volume 10, Issue 2, 2020, Article number 222.

In this work, a CLytA-DAAO chimera, both free and bound to magnetic nanoparticles, was demonstrated to induce cell death in most of the cancer cell lines tested, while in non-tumor cells there was not cell death induction, or it was significantly lower than in tumor cells. CLytA-DAAO could represent a useful therapy against cancer that could be used as an enhancer of other treatments. MORE

BACTERIAL CELL WALL & ANTIBACTERIAL ACTIVITY:

• Involvement of penicillin-binding proteins in the metabolism of a bacterial peptidoglycan containing a non-canonical D-amino acid

Miyamoto, T.,Katane, M., Saitoh, Y., Sekine, M., Homma, H.
Amino Acids, Volume 52, Issue 3, 2020, Pages 487-497.

This work investigated whether penicillin-binding proteins PBP4 and PBP5, low molecular mass (LMM) PBPs from Escherichia coli and Bacillus subtilis, are involved in peptidoglycan remodelling. PBP4 and PBP5 from both species have peptidase activity toward substrates containing D-Asn, D-His, or D-Trp. These D-amino acids slowed the growth of dacA- or dacB-deficient E. coli strain and affected biofilm formation. The authors concluded that PBP4 and PBP5 are involved in the cleavage of peptidoglycan containing non-canonical D-amino acids, and these properties affect growth and biofilm formation. MORE

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• Plantaricin NC8 αβ exerts potent antimicrobial activity against Staphylococcus spp. and enhances the effects of antibiotics.

Bengtsson, T., Selegård, R., Musa, A., Hultenby, K., Utterström, J., Sivlér, P., Skog, M., Nayeri, F., Hellmark, B., Söderquist, B., Aili, D., Khalaf, H.
Scientific Reports, Volume 10, Issue 1, 2020, Article number 3580

With the aim to identify novel approaches to fight bacterial infections, here, the activities of the two-peptide bacteriocin PLNC8 αβ were investigated against different Staphylococcus spp. These peptides were modified, either through truncation or replacement of all L-amino acids with D-amino acids. Both L- and D-PLNC8 αβ caused rapid disruption of lipid membrane integrity and were effective against both susceptible and antibiotic resistant strains: only the one containing the D-amino acids was stable against proteolytic degradation. The peptides diffused rapidly through the bacterial cell wall and permeabilized the membrane. Notably, sub-MIC concentrations of PLNC8 αβ enhanced the effects of different antibiotics in an additive or synergistic manner. MORE  

AA ISOMERIZATION IN PROTEINS:

• A single Asp isomer substitution in an αA-crystallin-derived peptide induces a large change in peptide properties

Magami, K., Kim, I., Fujii, N.
Experimental Eye Research, Volume 192, 2020, Article number 107930

The eye lens is mainly composed of crystallins which undergo modifications: the residues Asp58, Asp76, Asp84, and Asp151 are specifically isomerized to L-iso, D-, and D-iso isomers in aged-related cataract lenses. In addition, the αA66–80 peptide, which contains Asp76, is detected in aged lens, induces protein aggregation and causes loss of the chaperone function of α-crystallin. The authors demonstrated that normal αA66–80 peptide containing the L-Asp76 isomer increased the aggregation of selected model proteins while the peptide containing D- or D-isoAsp76 had similar or no effects. By contrast, the αA66–80 peptide containing L-isoAsp76 inhibited the aggregation of all investigated proteins, pointing to a chaperone activity. Indeed, only the L-isoAsp-containing αA66–80 peptide showed a β-sheet structure and generates amyloid fibrils. MORE

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• Age-related isomerization of Asp in human immunoglobulin G kappa chain

Ha, S., Kinouchi, T., Fujii, N. 

Biochimica et Biophysica Acta – Proteins and Proteomics, Volume 1868, Issue 6, 2020, Article number 140410

In this study, the presence of isomerized Asp residues was investigated in human immunoglobulin G (IgG) kappa chain by liquid chromatography tandem mass spectrometry. Two isomerized Asp residues, i.e. Asp151 and Asp170, were detected in the IgG kappa chain, and their D/L ratio increased with aging. Notably, a peptide containing normal Lα-Asp170 showed type II β-turn structure, while the other isomeric peptides showed random structure. Asp isomerization in IgG may reflect changes of structure and decrease in immune function. MORE

D-AA AND MICROBIOTA:

• D-glutamate and gut microbiota in Alzheimer’s disease

 Chun-Hung Chang, Chieh-Hsin Lin, Hsien-Yuan Lane

International Journal of Molecular Sciences Int. J. Mol. Sci. 2020, 21, 2676; doi:10.3390/ijms2108267

In this paper, a review for all studies on glutamate and gut microbiota in dementia published up until Feb 2020 were analysed. Several pilot studies have reported alterations of gut microbiota and metabolites in AD patients and other forms of dementia. Gut microbiota can affect glutamate metabolism and decrease the glutamate metabolite 2-keto-glutaramic acid, as well as convert L-glutamate into D-glutamate. These findings suggest that D-glutamate metabolized by the gut bacteria may influence the activity of glutamate N-methyl-D-aspartate receptor and thus cognitive function in dementia patients. MORE

D-AAs AND PATHOLOGIES:

• Development of a cognitive function marker based on D-amino acid proportions using new chiral tandem LC-MS/MS systems

Kimura, R., Tsujimura, H., Tsuchiya, M., Soga, S.,  Ota, N., Tanaka, A., Kim, H. 

Scientific Reports, Volume 10, Issue 1, Article number 804

This work is aimed to the development of a chiral metabolomics method for detecting slight differences in chiral amino acid levels. Chiral tandem liquid chromatography-tandem mass spectrometry systems were applied along with chiral species determination based on anion and zwitterion exchange mechanisms. Analyses of control, mild-cognitive-impairment (MCI), and dementia groups identified higher D-Pro (D-Pro/(D-Pro + L-Pro)) proportion in MCI vs the controls. The authors suggested this proportion as a useful biomarker for MCI, which accuracy was further improved in combination with D-Ser proportion. MORE

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• Current treatment options and emerging agents for Schizophrenia

Correll, C.U. 

The Journal of Clinical Psychiatry, Volume 81, Issue 3, 2020

This review reports about currently available antipsychotics, that mostly treat the positive symptoms of schizophrenia and have at least one adverse effect as a potential liability. At present, different mechanisms of action are under investigation. Among these, D-amino acid oxidase inhibition and glycine transporter-1 inhibition, that could affect the NMDA receptor functionality. This brief report discusses recently approved novel agents and potential new treatment options for schizophrenia that are being investigated. MORE

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• D-Amino acids and kidney diseases

Kimura, T., Hesaka, A., Isaka, Y. 
Clinical and Experimental Nephrology, Volume 24, Issue 5, 2020, Pages 404-410

D-Serine levels in the blood are related with the glomerular filtration rate and are useful for estimating the function of the kidney. Actually, the kidney proximal tubule reabsorbs serine with chiral-selectivity: the D-enantiomer is reabsorbed much less efficiently than the L- one. Accordingly, the urinary excretion of D-serine is sensitive to the presence of kidney diseases: detection of its level in blood and urinary excretion can be used to identify kidney diseases and assess pathophysiology. MORE

ENZYMES ACTIVE ON D-AA &  BIOTECHNOLOGICAL APPLICATIONS:

• D-Aspartate oxidase: distribution, functions, properties, and biotechnological applications

Takahashi, S. 
Applied Microbiology and Biotechnology, Volume 104, Issue 7, 2020, Pages 2883-2895

This mini-review focuses on D-aspartate oxidase (DDO or DASPO), the flavoenzyme which degrades acidic D-amino acids. DDO is present in many eukaryotic organisms and may play important roles in acidic D-amino acid utilization, elimination, and intracellular level regulation. Moreover, owing to its absolute enantioselectivity and stereoselectivity, DDO is a valuable tool in biotechnology, such as the identification and quantification of acidic D-amino acids. MORE

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• Advances in enzymatic synthesis of D-amino acids

Pollegioni, L., Rosini, E., Molla, G. 
International Journal of Molecular Sciences, Volume 21, Issue 9, 2, 2020, Article number 3206

This review is reporting the recent advances in synthesis of D-amino acids based on five main classes of enzymes. These enzymes have been combined and applied to cascade, multi-enzymatic processes. The aim of these studies was to increase the D-amino acid derivatives generated, to improve the intrinsic atomic economy and cost-effectiveness, and to generate processes at low environmental impact. 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 (Director Loredano Pollegioni). 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.

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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