Newsletter 05/2025 edited by Loredano Pollegioni

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The Editor’s pick selection of the most intriguing papers is underlined

D-AAs AND PATHOLOGIES:

Gut-Kidney Axis: Novel Insights in Kidney Diseases

Iwata Y, Nakade Y, Tokumaru T, Oshima M, Mita M, Toyama T, Linh HT, Wada T

Chem Biodivers. 2025 Sep 11:e01506. doi: 10.1002/cbdv.202501506

In recent years, gut microbiota reportedly contributes to the homeostasis of systemic organs and the pathogenesis of chronic kidney disease. D-Amino acids derived from gut microbiota change in concentration in the body concomitant with dysbiosis. D-serine and D-alanine have renal tubular protective effects in acute tubular necrosis, suggesting their potential as renal therapeutic agents. This paper provides an overview of new insights into kidney disease, gut microbiota, and its metabolites.

Prenatal Exposure to Lipopolysaccharide or Valproate Leads to Abnormal Accumulation of the NMDA Receptor Agonist D-Aspartate in the Adolescent Rat Brain

Di Maio A, Yahyavi I, Buzzelli V, Motta Z, Ascone F, Putignani L, Usiello A, Pollegioni L, Trezza V, Errico F

J Neurochem. 2025; 169(6):e70095. doi: 10.1111/jnc.70095

Autism spectrum disorder (ASD) is a neurodevelopmental psychiatric condition linked to glutamatergic neurotransmission disruption. The role of endogenous D-serine and D-aspartate in ASD remains elusive. This paper reports the levels of D-Asp, D-Ser, and other key neuroactive amino acids, and their direct precursors in brain regions, plasma, and feces of environmental ASD rat models prenatally exposed to lipopolysaccharide or valproate, both during adolescence and early adulthood, as well as in a genetic ASD model. A prominent accumulation of D-Asp was apparent in several brain regions of lipopolysaccharide- and valproate-exposed rats, selectively during adolescence, while D-Ser level variations were more limited. The assay of the activity of the main enzymes involved in cerebral D-Ser and D-Asp metabolism suggests that their regulation extends beyond their metabolic enzymes.

Molecular Underpinning of Treatment-Resistant Schizophrenia: A Putative Different Neurobiology from Treatment-Responsive Schizophrenia

Barone A, Vellucci L, Ciccarelli M, Matrone M, De Simone G, Iannotta F, Iasevoli F, de Bartolomeis A

Int J Mol Sci. 2025 Sep 4;26(17):8598. doi: 10.3390/ijms26178598

This review outlines current knowledge of treatment-resistant schizophrenia, focusing on alterations in glutamate signaling, imbalances between excitatory and inhibitory activity, disruptions in D-amino acid metabolism, and evidence of neuroinflammation, oxidative stress, and mitochondrial or endoplasmic reticulum dysfunction. Understanding the interplay of these complex mechanisms will bring to the identification of potential biomarkers, essential for improving care and guiding personalized therapeutic strategies.

Metagenomic analysis of the gut microbiota in major depressive disorder with different antidepressant efficacy: A prospective cohort study

Du JY, Qin FL, Yang RN, Chen YL, Tan GF, Li WJ, Yang L, Cai J, Shen DL, Zhu HR, Yuan ML, Zhang W

J Affect Disord. 2025 Nov 13;394(Pt B):120709. doi: 10.1016/j.jad.2025.120709

This study compared baseline gut microbiota in major depressive disorder (MDD) patients who later responded or did not respond to Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) treatment. While clinical and demographic factors were similar, responders and non-responders showed distinct microbial compositions and metabolic pathways. Non-responders had higher levels of certain Bacteroides species and enrichment of steroid biosynthesis pathways, whereas responders showed higher levels of Hungatella and enrichment of D-amino acid metabolism pathways. These findings suggest that gut microbiota may help predict antidepressant response and guide future therapeutic strategies, though validation in larger cohorts is needed.

D-Tryptophan Promotes Skin Wound Healing via Extracellular Matrix Remodeling in Normal and Diabetic Models

Tadese DA, Mwangi J, Michira BB, Wang Y, Cao K, Yang M, Khalid M, Wang Z, Lu Q, Lai R

Int J Mol Sci. 2025;26(15):7158. doi: 10.3390/ijms26157158

Diabetic wounds are a devastating complication that cause chronic pain, recurrent infections, and limb amputations due to impaired healing. This work studied the therapeutic potential of D-Trp in streptozotocin (STZ)-induced diabetic mice, comparing it with phosphate-buffered saline controls and vascular endothelial growth factor (VEGF) as a positive control. D-Trp accelerated wound healing by modulating extracellular matrix remodeling, signaling, and apoptosis. It upregulated matrix metalloproteinases, JAK2, and MAPK proteins while reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). D-Trp also suppressed caspase-3 and enhanced angiogenesis through HIF-1α activation.

The significance of dysregulated serine metabolism in depression

Yan L, Lv M, Zhao C, Pei J, Zhou M

Biomed Pharmacother. 2025; 191:118458. doi: 10.1016/j.biopha.2025.118458

Serine is a non-essential amino acid that supports multiple key metabolic processes. The central or peripheral dysregulation of serine metabolism in patients with depression has sparked interest in targeted treatment of serine metabolism. This article reports on the synthesis and metabolic pathways of serine, and its metabolism dysregulation related to the etiology and pathogenesis of depression.
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The role of D-amino acids in neurodegeneration associated with Alzheimer’s disease

Litvinov VV, Freynd GG, Stepanova MV

Clinical and Experimental Morphology. 2025 14 (3), pp. 5 – 14, doi: 10.31088/CEM2025.14.3.5-14

This paper presents data on the relationship between glial dysfunction, excitotoxicity, and neurodegeneration with D-amino acid metabolism and discusses the potential of using D-amino acids to diagnose Alzheimer’s disease.

D-AAs AND ENVIRONMENT:

Free L- and D-amino acids in PM(2.5) in a megacity in central China, from the perspectives of pollution characteristics, atmospheric processes and sources

Jiang N, Wang Z, Zhang Y, Gong K, Guo Z, Guo J, Li M, Zhang R, Yuan H, Zhao Y

Environ Pollut. 2025;385:127055. doi: 10.1016/j.envpol.2025.127055

This study examines the concentrations, seasonal variations, sources, and atmospheric interactions of 15 pairs of free L- and D-amino acids in PM2.5 of a central region of China. D-amino acids were more concentrated than L-amino acids, with L-Ala, L- Ser, L-Arg, D-Ala, D- Asn, and D-Arg dominant. L- and D-amino acids peaked in autumn and spring, respectively. Pollen and plant debris were the main sources of L- and D-amino acids, accounting for 40.4 % and 42.6 %, respectively.

D-AAs AND CHIRALITY:

Stereoselectivity of Aminoacyl-RNA Loop-Closing Ligation

Kim S, Todisco M, Radakovic A, Szostak JW

J Am Chem Soc. 2025; 147(23):19539-19546. doi: 10.1021/jacs.4c16905

The origin of amino acid homochirality remains an unresolved question in the origin of life. Previous studies have reported moderate stereoselectivity for various aminoacyl-RNA transfer reactions. Here, aminoacyl-RNA loop-closing ligation was investigated. The rate of this reaction is much higher for RNA aminoacylated with L-AAs than with D-AAs. The ligation of aminoacyl-L-RNA results in an inverse stereoselectivity for D-AAs. The observed stereochemical link between D-RNA and L-AA in the synthesis of RNA stem-loops containing bridging amino acids constitutes a stereoselective structure-building process. The authors suggested that this process led to a selection for the evolution of aminoacyl-RNA synthetase ribozymes that were selective for L-AAs.

ENZYMES ACTIVE ON D-AAs:

Int J Mol Sci. 2025;26(17):8536. doi: 10.3390/ijms26178536Contribution of Second-Shell Residues to PLP-Dependent Transaminase Catalysis: A Case Study of D-Amino Acid Transaminase from Desulfomonile tiedjei

Bakunova AK, Rudina IV, Popov VO, Bezsudnova EY

Angew Chem Int Ed Engl. 2025:e202511739. doi: 10.1002/anie.202511739

This paper reports on the functional characterization of a novel PLP-dependent fold type IV transaminase from Desulfomonile tiedjei, alongside a detailed analysis of PLP binding and holoenzyme stability. This transaminase shows activity toward various D-amino acids and (R)-phenylethylamine.

Electron-Deficient Aromatic D-Amino Acids

Buslov I, Desmons S, Wang W, Massaad LE, Hu X

Angew Chem Int Ed Engl. 2025:e202511739. doi: 10.1002/anie.202511739

This work reports on the rational engineering of phenylalanine ammonia lyase from Planctomyces brasiliensis (PbPAL) to enable asymmetric hydroamination for the enantioselective synthesis of D-aromatic amino acids. The L205F variant enables the transformation of electron-deficient aryl acrylates with >99% enantiomeric excess. The synthetic utility of this platform was demonstrated by gram-scale synthesis of D-benzoxazole and substituted 2-pyridylalanines.

Improving the Thermostability and Catalytic Activity of RgDAAO by a Combinatorial Strategy Using Sequence Consensus Design and SpyTag/SpyCatcher Self-Cyclization

Li M, Zhuang W, Zhang J, Zhang K, Xu J, Wang Z

J Agric Food Chem. 2025. doi: 10.1021/acs.jafc.5c03902

D-Amino acid oxidase from Rhodotorula gracilis (RgDAAO) is valuable for pharmaceutical and chemical synthesis. This study proposed a synergistic strategy of “sequence consensus design coupled with structure modification” to enhance RgDAAO thermostability. A triple variant (S18T/V7I/Y132F) shows a 3.7-fold extension in half-life at 50 and a 5 °C increase in melting temperature (Tm) versus wild-type (WT). Furthermore, N/C-terminal autocyclized variants (TDC-WT, CDT-WT, etc.) were constructed using the SpyTag/SpyCatcher system, demonstrating 2-3-fold higher half-life at 50 °C. The combination of these modifications yielded the LCDT-M3 variant enzyme which exhibited a 12.8-fold longer half-life, a 9 °C increase in Tm, and a 2.2-fold greater specific activity compared to WT at 50 °C.

Crystal structure of D-aspartate oxidase from Cryptococcus humicola UJ1

Goto M, Nonaka R, Mizobuchi T, Imanishi D, Takahashi S

Acta Crystallogr F Struct Biol Commun. 2025. doi: 10.1107/S2053230X25008192

The enzyme D-aspartate oxidase (DDO or DASPO) differs from D-amino-acid oxidase (DAAO) for the substrate specificity. Here, the structure of DASPO derived from Cryptococcus humicola strain UJ1 (chDDO) was determined by X-ray crystallography at 1.70 Å resolution. Notably, it forms a homotetramer.

D-AAs AND BIOTECHNOLOGY:

Identification of a novel D-amino acid oxidase and its application in deracemization of D, L-phosphinothricin

Jin LQ, Liu MD, Guan ZY, Li YX, Xue YP, Liu ZQ, Zheng YG

Bioprocess Biosyst Eng. 2025. doi: 10.1007/s00449-025-03219-0

Herein, a novel DAAO derived from Cladophialophora carrionii (CcDAAO) was identified, which demonstrated good kinetic parameters toward D-Ala, along with remarkable thermostability and broad substrate spectrum. CcDAAO was fused with catalase from Geobacillus sp. CHB1 (GbCAT) and applied in a D-amino acid aminotransferase (DAAT)-mediated cascade system. In a 2 L reaction system, this system achieved complete conversion (> 99%) of 1 M D,L-PPT within 8 h, exhibiting a yield of 11.26 g/L/h for PPO.

Designing a mesoporous cascade reactor for enhanced enzymatic performance

Chen Z, Fan Q, Wang J, Zhang J, Zhang Y, Tan T, Lv Y

Bioresour Technol. 2025 Dec;438:133224. doi: 10.1016/j.biortech.2025.133224

This work reports on a hierarchical and modular strategy for constructing robust biocatalytic cascade reactors by spatially organizing dual enzymes, D-amino acid oxidase (DAAO) and cytochrome c (Cyt c), within defect-engineered covalent organic frameworks (COFs), followed by surface encapsulation with a polydopamine (PDA) shell to mimic cellular compartmentalization. Compared to their free counterparts, the COF-immobilized enzymes exhibited significantly improved catalytic performances, while the PDA coating further improved enzyme resilience to high temperatures, organic solvents, proteases, and alkaline pH.

Integrating experimental and computational insights into D-amino acid inhibition of aluminum alloy 7075-T6 corrosion in saline media

Vejar N, Pineda F, Hidalgo-Rosa, Y, Schott Ed, Abarca R L., Páez M

Progress in Organic Coatings (2025) 209, art. no. 109583, DOI: 10.1016/j.porgcoat.2025.109583

D-amino acids have emerged as promising eco-friendly corrosion inhibitors due to their biodegradability, low toxicity, and aqueous solubility. In this work, the inhibition performance of D-leucine and D-methionine on aluminum alloy 7075-T6 exposed to a 0.1 M NaCl solution was investigated. D-Leu showed high inhibition efficiencies.

D-AAs IN BACTERIA:

Mutant gltS alleles enable a Vibrio fischeri D-glutamate auxotroph to grow with lower requirements for exogenous D-glutamate

Coppinger M, Helm RF, Yang L, Ruby EG, Popham DL, Stabb EV

Microbiol Spectr. 2025:e0102525. doi: 10.1128/spectrum.01025-25

D-Glu is a key component of peptidoglycan (PG). Here, PG biosynthesis was modified leading to either replacement of D-glu in the PG peptide or alternative pathways to D-glu incorporation. Nine additional prototrophic suppressors of the murI racD mutant were selected: each suppressor had a mutation in gltS gene, which encodes a putative sodium:glutamate symporter. Increased copy numbers of mutant gltS alleles enabled growth on unsupplemented LBS and resulted in PG containing D-Glu. The mutations in gltS enabled growth with similarly low D-glu concentrations, but also increased sensitivity to homocysteic acid. The expression of mutant gltS in the auxotroph leads to incorporation of lysine into PG, in addition to canonical D-Glu. When seawater is supplemented with D-Glu, this V. fischeri mutant still colonized Euprymna scolopes and triggered PG-induced morphogenesis.

D-AAs IN PEPTIDES AND PROTEINS:

Rational Engineering of a Brevinin-2 Peptide: Decoupling Potency from Toxicity Through C-Terminal Truncation and N-Terminal Chiral Substitution

Yao A, Zhang Z, Song Z, Yuan Y, Chen X, Ma C, Chen T, Shaw C, Zhou M, Wang L

Antibiotics (Basel). 2025 Aug 1;14(8):784. doi: 10.3390/antibiotics14080784

This work focused on brevinin-2OS (B2OS), a peptide from the skin of Odorrana schmackeri with potent haemolytic activity. A dual-modification strategy involving C-terminal truncation and subsequent N-terminal D-amino acid substitution was employed: this dual-modification strategy provided a powerful design principle for developing safer, more effective peptide-based therapeutics.

Exploring zinc(II) ion binding and antimicrobial activity via D-amino acid substitution and retro-inverso modifications in MUC7 peptide from human saliva

Wątły J, Szarszoń K, Kola A, Zobi F, Janek T, Valensin D

Dalton Trans. 2025; 54(32):12189-12200. doi: 10.1039/d5dt00562k

To improve the proteolytic stability of antimicrobial peptides modifications, such as D-amino acid substitution or retro-inverso strategy, are a worthy alternative. In this work, peptidomimetic modified fragments of MUC7, a protein present in human saliva, and their complexes with Zn(II) ions were generated and studied.

Optimizing the Synthesis of Desotamides and Related Cyclic Antimicrobial Peptides

Bansal A, Li Y, Ziora ZM, Mishra P, Moyle PM

Methods Mol Biol. 2025; 2931:299-311. doi: 10.1007/978-1-0716-4562-8_23

Here, the protocol for the synthesis of Desotamides, a cyclic hexapeptide antibiotic from Streptomyces species which often include D-amino acids and non-proteogenic amino acids, is reported. These synthetic processes permit the scalable production and engineering of Desotamides and novel-related antimicrobial species.

D-AAs AND ANALYTICAL METHODS:

A green and effective determination of derivatized chiral amino acids in the six types of Chinese tea using supercritical fluid chromatography-triple quadrupole mass spectrometry

Zhang S, Ee KH, Goh RMV, Huang Y, Pua A, Li L, Jublot L, Liu SQ, Yu B

Food Chem. 2025;493(Pt 4):146028. doi: 10.1016/j.foodchem.2025.146028

In this study, a sensitive and green method was developed using supercritical fluid chromatography-triple quadrupole mass spectrometry (SFC-QQQ/MS) for the simultaneous separation and quantification of 20 pairs of chiral AAs in six types of Chinese tea. Seventeen chiral AA pairs were quantified in teas: dark and black tea have a significantly detectable D-amino acids ratio than other teas.

Untargeted Discovery and Localization of Isomerized Residues in Neuropeptides

Okyem S, Rubakhin SS, Protya SS, Gunnarson C, Sweedler JV

Anal Chem. 2025; 97(32):17570-17579. doi: 10.1021/acs.analchem.5c02612

This study reports on a comprehensive untargeted analytical workflow to predict possible peptide isomers from peptidomics data and then localizes the isomerized residues by using collision-induced dissociation-trapped ion mobility spectrometry (CID-TIMS) and protein isoaspartyl methyltransferase (PIMT) activity. The approach allows for the discovery and characterization of isomerized isoaspartate (isoAsp) residues and D-amino acids within the peptide. This workflow successfully identified a D-amino acid-containing form of small cardioactive peptide B, FMRFamide, and another D-amino acid-containing peptide from an uncharacterized protein in the sea slug A. californica.

Chiral Growth of Gold Horns on Polyhedrons for SERS Identification of Enantiomers and Polarized Light-Induced Photothermal Sterilization

Shang B, Guan G

Materials (Basel) 2025; 18(11):2627. doi: 10.3390/ma18112627

In this work, novel chiral horned gold nanostructures (HNS) were produced by controlling the concentration of chiral ligands L-/D-cysteine (Cys). The unique three-dimensional morphology with horns-rotational arrangement enables synergistic optimization of chiral optical responses and surface-enhanced Raman scattering (SERS) performance. Chiral HNSs have achieved SERS detection of bacteria and efficient polarization photothermal sterilization, which helps further develop applications based on chiral nanomaterials.

Determining the purity of four D-amino acids through mass balance and quantitative nuclear magnetic resonance

Deng F, Wang R, Wu L, Liu Y

Microchemical Journal. 2025 217, art. no. 114993, doi: 10.1016/j.microc.2025.114993

This study aimed at determining the purity of four D-amino acids, namely D-leucine, D-isoleucine, D-aspartic acid, and D-valine, and at developing reference materials based on two different methods: the mass balance method and quantitative nuclear magnetic resonance. The final purity results obtained were 0.993 g/g for D-leucine, 0.991 g/g for D-isoleucine, 0.994 g/g for D-aspartic acid, and 0.992 g/g for D-valine, with an extended uncertainty of 0.003 g/g for all four D-amino acids.

Chiral derivatization-based HPLC-MS/MS analysis revealed the presence of D-amino acids in market-available edible seaweeds

Zhang Q, Wang Xi, Li, S, Qi X, Chen M, Zheng L, Ping E, Ren Y, Li Q, Cui Y

LWT. 2025, 229, art. no. 118204, doi: 10.1016/j.lwt.2025.118204

The abundant amino acid compositions in seaweeds make them a promising alternative protein source. However, little is known about D-amino acids (D-AAs) in seaweeds. This study developed a (S)-NIFE pre-column derivatization HPLC-MS/MS method to investigate the composition and content of D-AAs in different market-available edible seaweed species. Brown seaweeds exhibited higher D-AAs levels than red and green seaweeds. Salted seaweed samples showed even greater diversity, with all 15 D-AAs detected at higher concentrations. D-serine (D-Ser) was exclusively identified in sun-dried and salted Sargassum fusiforme.

INFORMATION

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).

Info@d-aminoacids.com

director@d-aminoacids.com

D-AMINO ACIDS INTERNATIONAL RESEARCH CENTER

INFO@D-AMINOACIDS.COM