It is a pleasure to announce that the 6th International Conference of D-Amino Acid Research (IDAR2024) and 18th Joint Conference of the D-Amino Acid Research Society Japan will be held at Kanazawa University in August 2024 between 21 (Wednesday) and 24 (Saturday). 
The website of IDAR2024 is open now, please visit the following:

The key dates are as follows.
March 1, 2024    Call for abstract open
March 1, 2024    Online registration open
June 14, 2024     Deadline for abstract submission
June 30, 2024     Deadline for early bird registration





The Editor’s pick selection of the most intriguing papers is highlighted in yellow.


Imarisio A., Yahyavi I., Avenali M., Di Maio A., Buongarzone G., Galandra C., Picascia M., Filosa A., Gasparri C., Monti M.C., Rondanelli M., Pacchetti C., Errico F., Valente E.M., Usiello A.
Blood D-serine levels correlate with aging and dopaminergic treatment in Parkinson’s disease
Neurobiology of Disease (2024) 192, 106413,
In this work, the serum levels of D- and L-serine, L-glutamate, L-glutamine, L-aspartate, L-asparagine and glycine were determined by enantiomeric HPLC. In age- and sex-adjusted analyses, no differences emerged in the serum levels of D-Ser, L-Ser and other NMDAR-related amino acids between Parkinson’s disease (PD) and healthy controls (HC). Anyway, the D-Ser and D−/total serine ratio positively correlated with age in PD but not in HC, and also with PD age at onset; higher levodopa equivalent daily dose (LEDD)  correlated with lower levels of D-Ser and the other excitatory amino acids. By adding LEDD as covariate the analyses disclosed a selective significant increase of D-serine in PD compared to HC, suggesting that serum D-Ser and D−/total serine may represent a valuable biochemical signature of PD.

Protective effect of D-Cys on renal function in mice with chronic kidney disease
Xiang X., Tao C., Ren J.
(2024) Food Frontiers.
Recent studies uncovered potential physiological effects of D-amino acids (D-AAs) in nephropathy. This paper explored the protective effects of exogenous D-AAs on chronic kidney disease (CKD). Among the four tested amino acids (namely, D-Glu, D-Asp, D-Ala, and D-Cys), the latter most significantly enhanced the viability of hypoxia-induced injured HK-2 cells, even better than its L-enantiomer. The use of 10 and 100 mM D-Cys significantly reduce the mitochondrial functionality, protect renal function and increase water intake in CKD mice. Furthermore, H2S produced from D-Cys resisted oxidative stress and inhibited inflammation, thus slowing down the process of renal fibrosis.

Indazole derivatives as novel inhibitors of monoamine oxidase and D-amino acid oxidase
Stear C., Petzer A., Crous C., Petzer J.P.
(2024) Medicinal Chemistry Research, 33 (1), pp. 164 – 176.
The monoamine oxidase (MAO) enzymes metabolize neurotransmitter amines in the peripheral and central tissues, and inhibitors of these enzymes find application in the treatment of neuropsychiatric and neurodegenerative disorders. Here, a synthetic series of 15 C5- and C6-substituted indazole derivatives were tested on human MAO-A and MAO-B (some with submicromolar IC50 values and a competitive mode of action): the substitution on C5 of indazole yielded particularly potent MAO-B inhibition. They were also evaluated as potential inhibitors of porcine D-amino acid oxidase (DAAO): none was a DAAO inhibitor, except 1H-indazol-5-ol, a synthetic precursor, with an IC50 value of 2 µM.

D-alanine inhibits murine intestinal inflammation by suppressing IL-12 and IL-23  production in macrophages
Hashimoto H, Takagi T, Asaeda K, Yasuda T, Kajiwara M, Sugaya T, Mizushima K, Inoue K, Uchiyama K, Kamada K, Higashimura Y, Inoue R, Naito Y, Itoh Y

J Crohns Colitis. 2024 Jan 2:jjad217. Online ahead of print.
This paper focuses on the inhibitory effects of D-alanine on the pathogenesis of intestinal inflammation. The serum D-amino acid levels in 40 patients with ulcerative colitis and 34 healthy volunteers was determined as well in C57BL/6J mice where acute colitis was induced using dextran sulfate sodium and was treated with D-Ala via intraperitoneal injection. The serum D-Ala levels were significantly lower in patients with ulcerative colitis than in healthy controls, as well as in dextran sulfate sodium-treated mice. D-Ala-treated mice had significantly lower disease activity index than control mice, lower levels of inflammation markers. Finally, D-Ala suppressed naïve T cell differentiation into Th1 cells in vitro and suppressed the production of IL-12p35 and IL-23p19 in bone marrow-derived macrophages.

Aggregation of E121K mutant D-amino acid oxidase and ubiquitination-mediated autophagy mechanisms leading to amyotrophic lateral sclerosis
Dave U, Narain P, Mishra D, Gomes J
J Neurol Sci. 2024 Jan 15;456:122845. Epub 2023 Dec 17.
Amyotrophic Lateral Sclerosis (ALS) is a terminal adult-onset neuromuscular disorder. In this work, the E121K mutation in the D-amino acid oxidase (DAAO) encoding gene was studied. In SH-SY5Y cells, the expression of the E121K variant results in the accumulation of protein aggregates, a change in cell morphology, and the death of neuronal cells. These protein aggregates get ubiquitinated and cause an imbalance in autophagy regulation. Confocal microscopy shows the binding of p62 with ubiquitinated aggregates and that its recruitment to LC3II mediates autophagosome generation. These relative changes in the key partners in autophagy increase cell death in cells harboring the E121K DAAO and is a probable mechanism leading to ALS.


Relations between Glucose and D-Amino Acids in the Modulation of Biochemical and Functional Properties of Rodent Islets of Langerhans
Lee CJ, Lee DK, Wei IA, Qiu TA, Rubakhin SS, Roper MG, Sweedler JV
ACS Omega. 2023 Dec 7;8(50):47723-47734. eCollection 2023 Dec 19.

Little is known about the regulation of D-AA levels in the pancreatic islets during glucose stimulation, as well as the response of islets to different levels of extracellular D-AAs. In this study, the intracellular and extracellular levels of D-Ser, D-Ala, and D-Asp were measured in cultures of isolated rodent islets exposed to different levels of extracellular glucose. The intracellular levels of the selected amino acids showed large variability and were not affected by extracellular glucose levels. However, significantly lower levels of extracellular D-Ser and D-Ala were measured in the islet media supplemented with 20 mM glucose compared to the control (3 mM glucose). Glucose-induced oscillations of intracellular free calcium ion concentration, a proxy for insulin secretion, were modulated by the exogenous application of D-Ser and D-Ala but not by their L-enantiomers. Our results provide new insights into the roles of D-AAs in the biochemistry and function of pancreatic islets

D-Alanine Affects the Circadian Clock to Regulate Glucose Metabolism in Kidney
Sakai S, Tanaka Y, Tsukamoto Y, Kimura-Ohba S, Hesaka A, Hamase K, Hsieh CL, Kawakami E, Ono H, Yokote K, Yoshino M, Okuzaki D, Matsumura H, Fukushima A, Mita M, Nakane M, Doi M, Isaka Y, Kimura T
Kidney360. 2023 Dec 15. doi: 10.34067/KID.0000000000000345. Online ahead of print.

Similar to glucose metabolism in kidney and liver, D-alanine shows circadian alteration. Here, the D-Ala levels of blood and urine in mice were measured by two-dimensional HPLC. D-Ala levels in blood exhibited a clear intrinsic circadian rhythm. In kidney, D-Ala induced expressions of genes involved in gluconeogenesis and circadian rhythm. Treatment of D-Ala mediated glucose production in mice. Ex vivo glucose production assay demonstrated that D-Ala treatment induced glucose production in primary culture of kidney proximal tubular cells but not in liver cells. Gluconeogenetic effect of D-Ala has an intraday variation, and this effect was in part mediated through circadian transcriptional network. Under constant darkness, treatment of D-Ala normalized the circadian cycle of behaviour and kidney gene expressions.

Chemistry of Hydrogen Sulfide-Pathological and Physiological Functions in Mammalian Cells
Andrés CMC, Pérez de la Lastra JM, Andrés Juan C, Plou FJ, Pérez-Lebeña E
Cells. 2023 Nov 22;12(23):2684. doi: 10.3390/cells12232684.
Hydrogen sulfide (H2S) is a gaseous signaling molecule. This review provides an overview of the formation of H2S in the human body. It is synthesized by enzymatic processes involving cysteine and cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), cysteine aminotransferase (CAT), 3-mercaptopyruvate sulfurtransferase (3MST) and D-amino acid oxidase (DAAO). Here, an overview of the physiological significance of H2S in the human body is reported, highlighting the various sources of H2S production in different situations and examines existing techniques for its detection.



D-tyrosine enhances disoctyl dimethyl ammonium chloride on alleviating SRB corrosion
Zhou J., Li H., Gong S., Wang S., Yuan X., Song C.
(2023) Heliyon, 9 (11), art. no. e21755. DOI: 10.1016/j.heliyon.2023.e21755
Microbiologically influenced corrosion (MIC) is due to sulfate reducing bacteria (SRB). On this side, D-amino acids are potential enhancers for bactericides for their ability to inhibit biofilm formation. This work focused on D-tyrosine (D-Tyr)and disoctyl dimethyl ammonium chloride (DDAC), as typical D-amino acid and bactericide, and studied the inhibition on the corrosion caused by Desulfovibrio vulgaris. D-Tyr increased the DDAC-induced inhibition of corrosion. The authors concluded that D-Tyr can reduce the coverage of biofilm, thereby reducing its protective effect on SRB and achieving better corrosion inhibition effect.


Correlation Analysis of Key Residue Sites between Computational-Aided Design Thermostability D-Amino Acid Oxidase and Ancestral Enzymes
Wang L.-Y., Tang H., Zhao J.-Q., Wang M.-N., Xue Y.-P., Zheng Y.-G.
(2023) Journal of Agricultural and Food Chemistry, 71 (50), pp. 20177 – 20186. DOI: 10.1021/acs.jafc.3c06865
D-amino acid oxidase from Rhodotorula taiwanensis (RtwDAAO) shows a limited thermal stability that hampers its application. In this work, starting from the variant SHVG of RtwDAAO, the following substitutions were introduced: A43S, T45M, C234L, E195Y. The SHVG/SMLY enzyme variant showed a longer half-life and melting temperature. The ancestral sequence reconstruction revealed the conservation of the variant sites. Molecular dynamics simulations indicated that the increased hydrophobicity of the variant SHVG/SMLY RtwDAAO was relevant for the increased stability, as well as strengthened intersubunit interactions and the physical properties of the amino acids themselves.


Evaluation of D-amino acid oxidase activity in rat kidney using a D-kynurenine derivative, 6-methylthio-D-kynurenine: An in vivo microdialysis study
Fukushima T, Kansaku A, Umino M, Sakamoto T, Onozato M
Drug Discov Ther. 2024 Jan 12;17(6):434-439. doi: 10.5582/ddt.2023.01083. Epub 2023 Dec 3.
D-Amino acid oxidase (DAAO) is associated with schizophrenia. DAAO catalyzes the conversion of nonfluorescent 6-methylthio-D-kynurenine (MeS-D-KYN) to fluorescent 5-methylthiokynurenic acid (MeS-KYNA) in vitro. Here, the potential of MeS-D-KYN in evaluating DAAO activity in vivo using renal microdialysis technique in rats was evaluated. In details, male Sprague-Dawley rats were subjected to linear microdialysis probe implantation in the left kidney. Continuous perfusion of MeS-D-KYN was maintained: the DAAO activity in the kidney cortex was evaluated by measuring the MeS-KYNA content in the microdialysate. A significant production of MeS-KYNA was observed during infusion of MeS-D-KYN, indicating that this compound is not endogenous. MeS-KYNA production was suppressed by the co-infusion of a DAAO inhibitor, suggesting that MeS-D-KYN was converted to MeS-KYNA by renal DAAO. This suggests the potential use of this compound in evaluating DAAO activity.

Targeted Mutation of a Non-catalytic Gating Residue Increases the Rate of Pseudomonas aeruginosa D-Arginine Dehydrogenase Catalytic Turnover
Quaye JA, Ouedraogo D, Gadda G
J Agric Food Chem. 2023 Nov 7;71(45):17343-52. doi: 10.1021/acs.jafc.3c05328. Online ahead of print.

Pseudomonas aeruginosa D-arginine dehydrogenase (PaDADH) oxidizes most D-amino acids and is a good candidate for application in the L-amino acid and food industries. The side chain of the loop L2 E246 residue located at the entrance of the PaDADH active site pocket potentially favors the closed active site conformation and secures the substrate upon binding. Here, site-directed mutagenesis, steady-state, and rapid reaction kinetics were used to investigate whether increasing the rate of product release could translate to an increased enzyme turnover rate. For E246G variant an increased rate of D-Arg turnover is evident. Likewise, the kcat values increased 2-fold for the glutamine or leucine variants.



Prophage enhances the ability of deep-sea bacterium Shewanella psychrophila WP2 to utilize D-amino acid
Tan X, Zhang M, Liu S, Xiao X, Zhang Y, Jian  H
Microbiol Spectr. 2024 Jan 3:e0326323. doi: 10.1128/spectrum.03263-23. Online ahead of print.

This work represents the first exploration of the impact of prophages on the D-amino acid metabolism of deep-sea bacteria. By using S. psychrophila WP2 and its integrated prophage SP1 as a representative system, it was discovered that SP1 significantly increases the catabolism rate of D-Glu by WP2 and produces higher concentrations of ammonium, resulting in faster growth and competitive advantages.

Synergistic D-Amino Acids Based Antimicrobial Cocktails Formulated via High-Throughput Screening and Machine Learning
Yang J, Ran Y, Liu S, Ren C, Lou Y, Ju P, Li G, Li X, Zhang D
Adv Sci (Weinh). 2023 Dec 21:e2307173. doi: 10.1002/advs.202307173. Online ahead  of print.
The combination of multiple drugs with enhanced efficacy and/or reduced toxicity may represent a promising approach to treat antimicrobial resistance (AMR). D-amino acids mixtures coupled with antibiotics can provide new therapies. This paper is aimed to speed up the exploration of desirable antimicrobial formulations via high-throughput screening and machine learning optimization, e.g., D-amino acid mixtures and antibiotics. The optimized drug cocktails exhibit high antimicrobial efficacy while remaining non-toxic, as demonstrated   from in vitro assessments and in vivo study using a lung infection mouse model.

Peptide Epimerase Responsible for D-Amino Acid Introduction in Poly-γ-glutamic Acid Biosynthesis
Kato H, Sakuta M, Tsunoda T, Nakashima Y, Morita H, Ogasawara Y, Dairi T
Biomacromolecules. 2024 Jan 8;25(1):349-354. doi: 10.1021/acs.biomac.3c01000. Epub 2023 Dec 14.
Poly-γ-glutamic acid (PGA) is a natural polymer made of D- and/or L-glutamic acid (Glu) linked by isopeptide bonds. PGA synthetase, an enzyme complex composed of PgsB, PgsC, and PgsA, uses only L-Glu for polymerization, and D-Glu residues are introduced by peptide epimerization. Here, gene exchange experiments allowed to demonstrate that PgsA is responsible for the epimerization reaction. The authors suggested that D/L-ratio of the PGA product can be altered by introducing amino acid substitutions in a specific enzyme region.

NlpI-Prc Proteolytic Complex Mediates Peptidoglycan Synthesis and Degradation via Regulation of Hydrolases and Synthases in Escherichia coli
Liu X, den Blaauwen T
Int J Mol Sci. 2023 Nov 15;24(22):16355. doi: 10.3390/ijms242216355.
Balancing peptidoglycan (PG) synthesis and degradation with precision is essential for bacterial growth: our comprehension of this process remains limited. The NlpI-Prc proteolytic complex plays a crucial but poorly understood role in the regulation of multiple enzymes involved in PG metabolism. In this paper, the fluorescent 7-hydroxycoumarincarbonylamino-D-alanine (HADA) in labelling and immunolabeling assays. This allowed to demonstrate that the NlpI-Prc complex regulates the activity of PG transpeptidases and subcellular localization of PBP3 under certain growth conditions. PBP7 (a PG hydrolase) and MltD (a lytic transglycosylase) were confirmed to be negatively regulated by the NlpI-Prc complex by an in vivo degradation assay. Furthermore, the absence of NlpI-Prc complex alleviates the lethality of the mepS mepM mepH mutant. A function of PG lytic transglycosylases MltA and MltD as “space makers” was proposed through multiple gene deletions.


CHRISTMAS: Chiral Pair Isobaric Labeling Strategy for Multiplexed Absolute Quantitation of Enantiomeric Amino Acids
Zhu Z., Xu S., Wang Z., Delafield D.G., Rigby M.J., Lu G., Gu T.-J., Liu P.-K., Ma M., Puglielli L., Li L.
(2023) Analytical Chemistry, 95 (50), pp. 18504 – 18513. DOI: 10.1021/acs.analchem.3c03847
To address the critical gaps in mass spectrometry-based analysis of low-abundance D-AAs, N,N-dimethyl-L-leucine (L-DiLeu) tags were validated as novel chiral derivatization reagents for chromatographic separation of 20 pairs of D- and L-AAs. Then, N,N-dimethyl-D-leucine (D-DiLeu) was used to generate analytically equivalent internal references of D-AAs. The ensuing quantitative strategy was named CHRISTMAS. Here, 20 L-AAs and 5 D-AAs were quantified from wild-type and Alzheimer’s disease (AD) mouse brains.



Hydrodynamic Control of Alzheimer Aβ Fibrillation with Glucosaminic Acid Containing Click-Cyclized β-Bodies
Zhang Y, Borch LA, Fischer NH, Meldal M
J Am Chem Soc. 2023 Dec 21. doi: 10.1021/jacs.3c12118. Online ahead of print.
This work reports on five novel cyclic D-amino acid-containing peptides that inhibit fibrillation by affecting the dynamic hydration shell of Aβ(1-42) in vitro. Three of them were cyclic all-D-AA peptides incorporating the same polyhydroxy building block derived from D-glucosaminic acid (GA). The GA-containing peptides exhibited improved inhibition of Aβ(1-42) aggregation: the inhibition was dramatically improved by the use of two GA peptides targeting each end of the growing fibril. The present study may facilitate future developments of intervention strategies for Alzheimer’s disease and similar neurodegenerative diseases.

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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