Bioactive poly(amino acid)s for multi-modal cancer therapy.

The interplay between the tumor cells and their microenvironments is as inseparable as the relationship between "seeds" and "soil." The tumor microenvironments (TMEs) exacerbate malignancy by enriching malignant cell subclones, generating extracellular matrices, and recruiting immunosuppressive cells, thereby diminishing the efficacy of clinical therapies. Modulating TMEs has emerged as a promising strategy to enhance cancer therapy. However, the existing drugs used in clinical settings do not target the TMEs specifically, underscoring the urgent need for advanced strategies. Bioactive materials present unique opportunities for modulating TMEs. Poly(amino acid)s with precisely controllable structures and properties offer exceptional characteristics, such as diverse structural units, excellent biosafety, ease of modification, sensitive biological responsiveness, and unique secondary structures. These attributes hold significant potential for the modulation of TMEs and clinical applications further. Consequently, developing bioactive poly(amino acid)s capable of modulating the TMEs by elucidating structure-activity relationships and mechanisms is a promising approach for innovative clinical oncology therapy. This review summarizes the recent progress of our research team in developing bioactive poly(amino acid)s for multi-modal tumor therapy. First, a brief overview of poly(amino acid) synthesis and their advantages as nanocarriers is provided. Subsequently, the pioneering research of our research group on synthesizing the biologically responsive, dynamically allosteric, and immunologically effective poly(amino acid)s are highlighted. These poly(amino acid)s are designed to enhance tumor therapy by modulating the intracellular, extracellular matrix, and stromal cell microenvironments. Finally, the future development of poly(amino acid)s is discussed. This review will guide and inspire the construction of bioactive poly(amino acid)s with promising clinical applications in cancer therapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Peptide-Based Structures.

Molecular self-assembled helix peptide nanotubes based on some amino acid molecules and their dipeptides: molecular modeling studies.

CONTEXT: The paper considers the features of the structure and dipole moments of several amino acids and their dipeptides which play an important role in the formation of the peptide nanotubes based on them. The influence of the features of their chirality (left L and right D) and the alpha-helix conformations of amino acids are taken into account. In particular, amino acids with aromatic rings, such as phenylalanine (Phe/F), and branched-chain amino acids (BCAAs)-leucine (Leu/L) and isoleucine (Ile/I)-as well as corresponding dipeptides (diphenylalanine (FF), dileucine (LL), and diisoleucine (II)) are considered. The main features and properties of these dipeptide structures and peptide nanotubes (PNTs), based on them, are investigated using computational molecular modeling and quantum-chemical semi-empirical calculations. Their polar, piezoelectric, and photoelectronic properties and features are studied in detail. The results of calculations of dipole moments and polarization, as well as piezoelectric coefficients and band gap width, for different types of helical peptide nanotubes are presented. The calculated values of the chirality indices of various nanotubes are given, depending on the chirality of the initial dipeptides-the results obtained are consistent with the law of changes in the type of chirality as the hierarchy of molecular structures becomes more complex. The influence of water molecules in the internal cavity of nanotubes on their physical properties is estimated. A comparison of the results of these calculations by various computational methods with the available experimental data is presented and discussed. METHOD: The main tool for molecular modeling of all studied nanostructures in this work was the HyperChem 8.01 software package. The main approach used here is the Hartree-Fock (HF) self-consistent field (SCF) with various quantum-chemical semi-empirical methods (AM1, PM3, RM1) in the restricted Hartree-Fock (RHF) and in the unrestricted Hartree-Fock (UHF) approximations. Optimization of molecular systems and the search for their optimal geometry is carried out in this work using the Polak-Ribeire algorithm (conjugate gradient method), which determines the optimized geometry at the point of their minimum total energy. For such optimized structures, dipole moments D and electronic energy levels (such as EHOMO and ELUMO), as well as the band gap Eg = ELUMO - EHOMO, were then calculated. For each optimized molecular structure, the volume was calculated using the QSAR program implemented also in the HyperChem software package.

Insight into the interaction between amino acids and SO2: Detailed bonding modes.

CONTEXT: Amino acids are a highly effective and environmentally friendly adsorbent for SO2. However, there has been no comprehensive study of the binding modes between amino acids and SO2 at the molecular level. In this paper, the binding modes of three amino acids (Asp, Lys, and Val) with SO2 are studied comprehensively and in detail using quantum chemical calculations. The results indicate that each amino acid has multiple binding modes: 22 for Asp, 49 for Lys, and 10 for Val. Both the amino and carboxyl groups in amino acids, as well as those in side chains, can serve as binding sites for chalcogen bonds. The binding energies range from - 6.42 to - 1.06 kcal/mol for Asp, - 12.43 to - 1.63 kcal/mol for Lys, and - 7.42 to - 0.60 kcal/mol for Val. Chalcogen and hydrogen bonds play a crucial role in the stronger binding modes. The chalcogen bond is the strongest when interacting with an amino group, with an adiabatic force constant of 0.475 mDyn/Å. Energy decomposition analysis indicates that the interaction is primarily electrostatic attraction, with the orbital and dispersive interactions dependent on the binding mode. METHODS: Amino acids and complexes of amino acids with SO2 were used to do semi-empirical MD using Molclus combined with xtb at the GFN2 level. Optimization and frequency calculations of the structures were conducted using density-functional theory (DFT) B3LYP/6-311G* (with DFT-D3 correction). Single-point energy calculations were performed for all structures using DLPNO-CCSD(T)/aug-cc-pVTZ with tightPNO. Further analysis of the structures was conducted using ESP, AIM, IGMH, and sob-EDA to gain a deeper understanding of the interactions between amino acids and SO2.

The Ninhydrin Reaction Revisited: Optimisation and Application for Quantification of Free Amino Acids.

The ninhydrin reaction is commonly used for the detection of amino acids. However, in the literature, different conditions with respect to the buffer system, its pH and concentration, type of organic solvent, incubation time, and temperature, as well as the concentrations of the reagents, are described. To identify the most suitable conditions, colour development with reagents of varying compositions and different reaction temperatures and times were investigated using asparagine as a model amino acid. Asparagine was selected since it is one of the most abundant free amino acids in many types of samples. The optimal reaction mixture consisted of 0.8 mol L-1 potassium acetate, 1.6 mol L-1 acetic acid, 20 mg mL-1 ninhydrin and 0.8 mg mL-1 hydrindantin in DMSO/acetate buffer 40/60 (v/v) (final concentrations). The best reaction condition was heating the samples in 1.5 mL reaction tubes to 90 °C for 45 min. Afterwards, the samples were diluted with 2-propanol/water 50/50 (v/v) and the absorbance was measured at 570 nm. The proteinogenic amino acids showed a similar response except for cysteine and proline. The method was highly sensitive and showed excellent linearity as well as intra-day and inter-day reproducibility.

Amino-Acid Characteristics in Protein Native State Structures.

The molecular machines of life, proteins, are made up of twenty kinds of amino acids, each with distinctive side chains. We present a geometrical analysis of the protrusion statistics of side chains in more than 4000 high-resolution protein structures. We employ a coarse-grained representation of the protein backbone viewed as a linear chain of Cα atoms and consider just the heavy atoms of the side chains. We study the large variety of behaviors of the amino acids based on both rudimentary structural chemistry as well as geometry. Our geometrical analysis uses a backbone Frenet coordinate system for the common study of all amino acids. Our analysis underscores the richness of the repertoire of amino acids that is available to nature to design protein sequences that fit within the putative native state folds.

Analysis of Polypeptides by Amino Acid Analysis.

Amino acid analysis is an accurate method for the composition and quantitation of polypeptides and among these synthetic peptides. Combined with mass spectrometry, it yields a reliable control of peptide quality and quantity prior to conjugation and immunization.Initially peptides are hydrolyzed, preferably in the gas phase, with 6-M HCl at 110 °C for 20-24 h and the resulting amino acids analyzed by chromatography, where the most reliable form is ion exchange chromatography with post-column ninhydrin derivatization. Depending on the hydrolysis conditions, tryptophan is destroyed, and likewise cysteine, unless derivatized, and the amides, glutamine, and asparagine are deamidated to glutamic acid and aspartic acid, respectively. Three different ways of calculating results are suggested, and taking the above limitations into account, a quantitation better than 5% can usually be obtained.

Fmoc Solid-Phase Peptide Synthesis.

Synthetic peptides are important as drugs and in research. Currently, the method of choice for producing these compounds is solid-phase peptide synthesis. Here, we describe the scope and limitations of Fmoc solid-phase peptide synthesis. Furthermore, we provide a detailed protocol for Fmoc peptide synthesis.

Sequential Enzymatic Hydrolysis and Ultrasound Pretreatment of Pork Liver for the Generation of Bioactive and Taste-Related Hydrolyzates.

In the study of protein-rich byproducts, enzymatic hydrolysis stands as a prominent technique, generating bioactive peptides. Combining exo- and endopeptidases could enhance both biological and sensory properties. Ultrasound pretreatment is one of the most promising techniques for the optimization of enzymatic hydrolysis. This research aimed to create tasteful and biologically active pork liver hydrolyzates by using sequential hydrolysis with two types of enzymes and two types of ultrasound pretreatments. Sequential hydrolyzates exhibited a higher degree of hydrolysis than single ones. Protana Prime hydrolyzates yielded the largest amount of taste-related amino acids, enhancing sweet, bittersweet, and umami amino acids according to the Taste Activity Value (TAV). These hydrolyzates also displayed significantly higher antioxidant activity. Among sequential hydrolyzates, Flavourzyme and Protana Prime hydrolyzates pretreated with ultrasound showed the highest ferrous ion chelating activity. Overall, employing both Alcalase and Protana Prime on porcine livers pretreated with ultrasound proved to be highly effective in obtaining potentially tasteful and biologically active hydrolyzates.

Amino Acids and Their Biological Derivatives Modulate Protein-Protein Interactions in an Additive Way.

Protein-protein interactions (PPIs) differ when measured in test tubes and cells due to the complexity of the intracellular environment. Free amino acids (AAs) and their derivatives constitute a significant fraction of the intracellular volume and mass. Recently, we have found that AAs have a generic property of rendering protein dispersions more stable by reducing the net attractive part of PPIs. Here, we study the effects on PPIs of different AA derivatives, AA mixtures, and short peptides. We find that all the tested AA derivatives modulate PPIs in solution as effectively as AAs. Furthermore, we show that the modulation effect is additive when AAs form mixtures or are bound into short peptides. Therefore, this study demonstrates the additive effects of a class of small molecules (i.e., AAs and their biological derivatives) on PPIs and provides insights into rationally designing biocompatible molecules for stabilizing protein interactions and consequently tuning protein functions.

A Comparison of Phenolic, Flavonoid, and Amino Acid Compositions and In Vitro Antioxidant and Neuroprotective Activities in Thai Plant Protein Extracts.

The leaves of mulberry, Azolla spp., sunflower sprouts, cashew nut, and mung bean are considered rich sources of plant protein with high levels of branched-chain amino acids. Furthermore, they contain beneficial phytochemicals such as antioxidants and anti-inflammatory agents. Additionally, there are reports suggesting that an adequate consumption of amino acids can reduce nerve cell damage, delay the onset of memory impairment, and improve sleep quality. In this study, protein isolates were prepared from the leaves of mulberry, Azolla spp., sunflower sprouts, cashew nut, and mung bean. The amino acid profile, dietary fiber content, phenolic content, and flavonoid content were evaluated. Pharmacological properties, such as antioxidant, anticholinesterase, monoamine oxidase, and γ-aminobutyric acid transaminase (GABA-T) activities, were also assessed. This study found that concentrated protein from mung beans has a higher quantity of essential amino acids (52,161 mg/100 g protein) compared to concentrated protein from sunflower sprouts (47,386 mg/100 g protein), Azolla spp. (42,097 mg/100 g protein), cashew nut (26,710 mg/100 g protein), and mulberry leaves (8931 mg/100 g protein). The dietary fiber content ranged from 0.90% to 3.24%, while the phenolic content and flavonoid content ranged from 0.25 to 2.29 mg/g and 0.01 to 2.01 mg/g of sample, respectively. Sunflower sprout protein isolates exhibited the highest levels of dietary fiber (3.24%), phenolic content (2.292 ± 0.082 mg of GAE/g), and flavonoids (2.014 mg quercetin/g of sample). The biological efficacy evaluation found that concentrated protein extract from sunflower sprouts has the highest antioxidant activity; the percentages of inhibition of 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical were 20.503 ± 0.288% and 18.496 ± 0.105%, respectively. Five plant-based proteins exhibited a potent inhibition of acetylcholinesterase (AChE) enzyme activity, monoamine oxidase (MAO) inhibition, and GABA-T ranging from 3.42% to 24.62%, 6.14% to 20.16%, and 2.03% to 21.99%, respectively. These findings suggest that these plant protein extracts can be used as natural resources for developing food supplements with neuroprotective activity.

Characterization, DFT study and evaluation of antioxidant potentials of mycosporine-like amino acids (MAAs) in the cyanobacterium Anabaenopsis circularis HKAR-22.

The physiological parameters such as growth, Chl a content, and photosynthetic performance of the experimental cyanobacterium Anabaenopsis circularis HKAR-22 were estimated to evaluate the cumulative effects of photosynthetically active radiation (PAR) and ultraviolet (UV) radiation. Maximum induction of UV-screening molecules, MAAs, was observed under the treatment condition of PAR + UV-A + UV-B (PAB) radiations. UV/VIS absorption spectroscopy and HPLC-PDA detection primarily confirmed the presence of MAA-shinorine (SN) having absorption maxima (λmax) at 332.3 nm and retention time (RT) of 1.47 min. For further validation of the presence of SN, HRMS, FTIR and NMR were utilized. UV-stress elevated the in vivo ROS scavenging and in vitro enzymatic antioxidant capabilities. SN exhibited substantial and concentration-dependent antioxidant capabilities which was determined utilizing 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate (ABTS), ferric reducing power (FRAP) and superoxide radical scavenging assay (SRSA). The density functional theory (DFT) method using B3LYP energy model and 6-311G++(d,p) basis set was implied to perform the quantum chemical calculation to systematically investigate the antioxidant nature of SN. The principal pathways involved in the antioxidant reactions along with the basic molecular descriptors affecting the antioxidant potentials of a compound were also studied. The results favor the potential of SN as an active ingredient to be used in cosmeceutical formulations.

Perspective: intrinsic interactions of metal ions with biological molecules as studied by threshold collision-induced dissociation and infrared multiple photon dissociation.

In this perspective, gas-phase studies of group 1 monocations and group 12 dications with amino acids and small peptides are highlighted. Although the focus is on two experimental techniques, threshold collision-induced dissociation and infrared multiple photon dissociation action spectroscopy, these methods as well as complementary approaches are summarized. The synergistic interplay with theory, made particularly powerful by the small sizes of the systems explored and the absence of solvent and support, is also elucidated. Importantly, these gas-phase methods permit quantitative insight into the structures and thermodynamics of metal cations interacting with biological molecules. Periodic trends in how these interactions vary as the metal cations get heavier are discussed as are quantitative trends with changes in the amino acid side chain and effects of hydration. Such trends allow these results to transcend the limitations associated with the biomimetic model systems.

Electrochemical chiral sensor for recognition of amino acid enantiomers with cyclodextrin-based microporous organic networks.

BACKGROUND: Chirality is a ubiquitous phenomenon in nature, but enantiomers exhibit different pharmacological activities and toxicological effects. Therefore, Chiral recognition plays a pivotal role in various fields such as life sciences, chemical synthesis, drug development, and materials science. The synthesis of novel chiral composites with well-defined loading capabilities and ordered structures holds significant potential for electrochemical chiral recognition applications. However, the design of selective and stable electrochemical chiral recognition materials remains a challenging task. RESULT: In this work, we construct a simple and rapid electrochemical sensing platform for tryptophan (Trp) enantiomer recognition using cyclodextrin-modified microporous organic network as chiral recognition agent. CD-MON with chiral microenvironment was prepared by Sonogashira-Hagihara coupling reaction of the chiral molecule heptyl-6-iodo-6-deoxyß-cyclodextrin and 1, 4-Diethynylbenzene. The adhesion of BSA makes CD-MON firmly fixed on the electrode surface, and as a chiral protein, it can improve the chiral recognition ability through synergistic effect. Chiral amino acids are in full contact with the chiral microenvironment during pore conduction of MON, and L-Trp is more stably bound to CD-MON/BSA due to steric hindrance, host-guest recognition and hydrogen bonding. Therefore, the electrochemical sensor can effectively identify tryptophan enantiomers (IL-Trp/ID-Trp = 2.02), and it exhibits a detection limit of 2.6 µM for L-Trp. UV-Vis spectroscopy confirmed the adsorption capacity of CD-MON towards tryptophan enantiomers in agreement with electrochemistry results. SIGNIFICANCE: The prepared chiral sensor has excellent stability, reproducibility (RSD = 3.7%) and selectivity, realizes the quantitative detection of single isomer in tryptophan racemic and quantitative analysis in real samples with 94.0%-101.0% recovery. This work represents the first application of MON in chiral electrochemistry which expands the application scope of chiral sensors and holds great significance in separation science and electrochemical sensing.

Preparation and study of a capillary electrochromatographic column prepared by conjugating ß-CD COFs and gold-poly glycidyl methacrylate nanoparticles.

A new enantioselective open-tubular capillary electrochromatography (OT-CEC) was developed employing ß-cyclodextrin covalent organic frameworks (ß-CD COFs) conjugated gold-poly glycidyl methacrylate nanoparticles (Au-PGMA NPs) as a stationary phase. The resulting coating layer on the inner wall of the fabricated capillary column was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), energy dispersive spectroscopy (EDS), and electroosmotic flow (EOF) experiments. The performance of the fabricated capillary column was evaluated by CEC using enantiomers of seven model analytes, including two proton pump inhibitors (PPIs, omeprazole and tenatoprazole), three amino acids (AAs, tyrosine, phenylalanine, and tryptophan), and two fluoroquinolones (FQs, gatifloxacin and sparfloxacin). The influences of coating time, buffer concentration, buffer pH, and applied voltage on enantioseparation were investigated to obtain satisfactory enantioselectivity. In the optimum conditions, the enantiomers of seven analytes were fully resolved within 10 min with high resolutions of 3.03 to 5.25. The inter- to intra-day and column-to-column repeatabilities of the fabricated capillary column were lower than 4.26% RSD. Furthermore, molecular docking studies were performed based on the chiral fabricated column and as ligand isomers of analytes using Auto Dock Tools. The binding energies and interactions acquired from docking results of analytes supported the experimental data.

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer.

The cell membrane functions as a semipermeable barrier that governs the transport of materials into and out of cells. The bilayer features a distinct dielectric gradient due to the amphiphilic nature of its lipid components. This gradient influences various aspects of small molecule permeation and the folding and functioning of membrane proteins. Here, we employ polarizable molecular dynamics simulations to elucidate the impact of the electronic environment on the permeation process. We simulated eight distinct amino-acid side chain analogs within a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer using the Drude polarizable force field (FF). Our approach includes both unbiased and umbrella sampling simulations. By using a polarizable FF, we sought to investigate explicit dipole responses in relation to local electric fields along the membrane normal. We evaluate molecular dipole moments, which exhibit variation based on their localization within the membrane, and compare the outcomes with analogous simulations using the nonpolarizable CHARMM36 FF. This comparative analysis aims to discern characteristic differences in the free energy surfaces of permeation for the various amino-acid analogs. Our results provide the first systematic quantification of the impact of employing an explicitly polarizable FF in this context compared to the fixed-charge convention inherent to nonpolarizable FFs, which may not fully capture the influence of the membrane dielectric gradient.

Construction of the Glycolysis Metabolic Pathway Inside an Artificial Cell for the Synthesis of Amino Acid and Its Reversible Deformation.

The bottom-up construction of artificial cells is beneficial for understanding cell working mechanisms. The glycolysis metabolism mimicry inside artificial cells is challenging. Herein, the glycolytic pathway (Entner-Doudoroff pathway in archaea) is reconstituted inside artificial cells. The glycolytic pathway comprising glucose dehydrogenase (GDH), gluconate dehydratase (GAD), and 2-keto-3-deoxygluconate aldolase (KDGA) converts glucose molecules to pyruvate molecules. Inside artificial cells, pyruvate molecules are further converted into alanine with the help of alanine dehydrogenase (AlaDH) to build a metabolic pathway for synthesizing amino acid. On the other hand, the pyruvate molecules from glycolysis stimulate the living mitochondria to produce ATP inside artificial cells, which further trigger actin monomers to polymerize to form actin filaments. With the addition of methylcellulose inside the artificial cell, the actin filaments form adjacent to the inner lipid bilayer, deforming the artificial cell from a spherical shape to a spindle shape. The spindle-shaped artificial cell reverses to a spherical shape by depolymerizing the actin filament upon laser irradiation. The glycolytic pathway and its further extension to produce amino acids (or ATP) inside artificial cells pave the path to build functional artificial cells with more complicated metabolic pathways.

Direct Enantiomer Differentiation of Drugs and Drug-Like Compounds via Noncovalent Copper-Amino Acid Complexation and Ion Mobility-Mass Spectrometry.

Drug enantiomers can possess vastly different pharmacological properties, yet they are identical in their chemical composition and structural connectivity. Thus, resolving enantiomers poses a great challenge in the field of separation science. Enantiomer separations necessitate interaction of the analyte with a chiral environment─in mass spectrometry-based analysis, a common approach is through a three-point interaction with a chiral selector commonly introduced during sample preparation. In select cases, the structural difference imparted through noncovalent complexation results in enantiomer-specific structural differences, facilitating measurement using a structurally selective analytical technique such as ion mobility-mass spectrometry (IM-MS). In this work, we investigate the direct IM-MS differentiation of chiral drug compounds using mononuclear copper complexes incorporating an amino acid chiral selector. A panel of 20 chiral drugs and drug-like compounds were investigated for separation, and four l-amino acids (l-histidine, l-tryptophan, l-proline, and l-tyrosine) were evaluated as chiral selectors (CS) to provide the chiral environment necessary for differentiation. Enantiomer differentiation was achieved for four chiral molecule pairs (R/S-thalidomide, R/S-baclofen, R/S-metoprolol, and d/l-panthenol) with two-peak resolution (Rp-p) values ranging from 0.7 (>10% valley) to 1.5 (baseline separation). Calibration curves relating IM peak areas to enantiomeric concentrations enabled enantiomeric excess quantitation of racemic thalidomide and metoprolol with residuals of 5.7 and 2.5%, respectively. Theoretical models suggest that CuII and l-histidine complexation around the analyte chiral center is important for gas-phase stereoselectivity. This study demonstrates the potential of combining enantioselective noncovalent copper complexation with structurally selective IM-MS for differentiating chiral drugs and drug-like compounds.

Numbers of Exchangeable Hydrogens from LC-MS Data of Heavy Water Metabolically Labeled Samples.

Labeling with deuterium oxide (D2O) has emerged as one of the preferred approaches for measuring the synthesis of individual proteins in vivo. In these experiments, the synthesis rates of proteins are determined by modeling mass shifts in peptides during the labeling period. This modeling depends on a theoretical maximum enrichment determined by the number of labeling sites (NEH) of each amino acid in the peptide sequence. Currently, NEH is determined from one set of published values. However, it has been demonstrated that NEH can differ between species and potentially tissues. The goal of this work was to determine the number of NEH for each amino acid within a given experiment to capture the conditions unique to that experiment. We used four methods to compute the NEH values. To test these approaches, we used two publicly available data sets. In a de novo approach, we compute NEH values and the label enrichment from the abundances of three mass isotopomers. The other three methods use the complete isotope profiles and body water enrichment in deuterium as an input parameter. They determine the NEH values by (1) minimizing the residual sum of squares, (2) from the mole percent excess of labeling, and (3) the time course profile of the depletion of the relative isotope abundance of monoisotope. In the test samples, the method using residual sum of squares performed the best. The methods are implemented in a tool for determining the NEH for each amino acid within a given experiment to use in the determination of protein synthesis rates using D2O.

Stereoselective Synthesis of meso- and l,l-Diaminopimelic Acids from Enone-Derived α-Amino Acids.

The stereoselective synthesis of meso-diaminopimelic acid (meso-DAP), the key cross-linking amino acid of the peptidoglycan cell wall layer in Gram-negative bacteria, and its biological precursor, l,l-DAP, is described. The key step involved stereoselective reduction of a common enone-derived amino acid by substrate- or reagent-based control. Overman rearrangement of the resulting allylic alcohols, concurrent alkene hydrogenation and trichloroacetamide reduction, and subsequent ruthenium-catalyzed arene oxidation completed the synthesis of each stereoisomer. The synthetic utility of this approach was demonstrated with the efficient preparation of an l,l-DAP-derived dipeptide.