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At least 37 records · Page 2Linked to original sources
PubMed1993

Sialic acids in human gastric aspirates: detection of 9-O-lactyl- and 9-O-acetyl-N-acetylneuraminic acids and a decrease in total sialic acid concentration with age.

1. The total sialic acid content of human gastric aspirates was measured using a colorimetric assay. Care was taken to optimize the assay and to eliminate interference. 2. The sialic acid content of gastric aspirates collected under resting conditions from 77 patients with non-ulcer dyspepsia was found to decrease with age from > 100 micrograms/ml at 25 years and younger to < 20 micrograms/ml above 70 years of age. 3. Analysis of the sialic acids by gas chromatography, mass spectrometry and thin-layer chromatography showed the presence of N-acetylneuraminic acid and two O-acylated derivatives, 9-O-acetyl- and 9-O-lactyl-N-acetylneuraminic acids. These forms were predominantly glycosidically bound. 4. Thin-layer chromatographic analysis of individual aspirate samples showed that the O-acetylated sialic acids were present in all samples, with a maximum of 25% and a minimum of 5% of the total sialic acids.

Adult↗
PubMed1992

Synthesis and anti-HIV activity of some novel lactyl and glycolyl phosphate derivatives.

Novel phosphate triester derivatives of 3'-acetylthymidine, and of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials are designed to act as membrane-soluble pro-drugs of the bio-active free nucleotides. In particular, novel glycolate and lactate phosphate derivatives have been prepared. In vitro evaluation revealed the AZT compounds to have a pronounced and selective antiviral effect, the magnitude of which varied considerably with the nature of the phosphate blocking group.

Antiviral Agents↗
PubMed1996

Gain of D-alanyl-D-lactate or D-lactyl-D-alanine synthetase activities in three active-site mutants of the Escherichia coli D-alanyl-D-alanine ligase B.

Escherichia coli D-Ala-D-Ala ligase (Ddl) and the vancomycin resistance-conferring protein VanA are homologues, but VanA has gained the ability to activate D-lactate (D-Lac) and make the depsipeptide D-Ala-D-Lac as well as D-Ala-D-Ala. This depsipeptide ligase activity of VanA is its crucial catalytic function necessary for phenotypic vancomycin resistance. We report here that three E. coli DdlB active-site mutants that we made previously based on X-ray structure/function predictions have gained interesting new ligase activities. Y216, S150, and E15 form a hydrogen-bonding triad that orients an omega-loop to close over the active site and also to orient substrate D-Ala1. Mutants Y216F and S150A have gained depsipeptide (D-Ala-D-Lac, D-Ala-D-hydroxybutyrate) ligase activity with dipeptide/depsipeptide partition ratios that mimic the pH behavior of VanA. E15Q has negligible depsipeptide synthetase activity but now uniquely activates D-Lac as the electrophilic rather than the nucleophilic partner for condensation with D-Ala to make a regioisomeric D-Lac-D-Ala, an amide rather than an ester product. These results provide insights into the active-site architecture of the ligases and the subsites for recognition of D-Ala VS D-Lac and predict the Y216F substitution will impart D-Ala-D-Lac synthetase activity to Ddls from Grampositive bacteria with intrinsic resistance to vancomycin.

Alanine↗
PubMed1987

Chorismate aminations: partial purification of Escherichia coli PABA synthase and mechanistic comparison with anthranilate synthase.

Chorismate is converted by regiospecific amination/aromatization sequences to o-aminobenzoate and p-aminobenzoate (PABA) by anthranilate synthase (AS) and PABA synthase (PABS), respectively. We report here the first partial purification of the large subunit of Escherichia coli PABA synthase, previously reported to be quantitatively inactivated in purification attempts. The subunit encoded by the pabB gene was overexpressed from a T7 promoter and purified 9-fold to 25-30% homogeneity. The pabB subunit appears unusually sensitive to inactivation by glycerol so this cosolvent is contraindicated. The Km for chorismate is 42 microM in the ammonia-dependent conversion to PABA, and we estimate a turnover number of 2.6 min-1. A variety of chorismate analogues have been prepared and examined. Of these compounds, cycloheptadienyl analogue 11 has been found to be the most potent inhibitor of Serratia marcescens anthranilate synthase (Ki = 30 microM for an RS mixture) and of the E. coli pabB subunit of PABA synthase (Ki = 226 microM). Modifications in the substituents at C-3 [enolpyruyl ether, (R)- or (S)-lactyl ether, glycolyl ether] or C-4 (O-methyl) of chorismate lead to alternate substrates. The Vmax values for (R)- and (S)-lactyl ethers are down 10-20-fold for each enzyme, and V/K analyses show the (S)-lactyl chorismate analogue to be preferred by 12/1 over (R)-lactyl for anthranilate synthase while a 3/1 preference was observed for (R)-/(S)-lactyl analogues by PABA synthase. The glycolyl ether analogue of chorismate shows 15% Vmax vs. chorismate for anthranilate synthase but is actually a faster substrate (140%) than chorismate with PABA synthase, suggesting the elimination/aromatization step from an aminocyclohexadienyl species may be rate limiting with AS but not with PABS. Indeed, studies with (R)-lactyl analogue 14 and anthranilate synthase led to accumulation of an intermediate, isolable by high-performance liquid chromatography and characterized by NMR and UV-visible spectroscopy as 6-amino-5-[(1-carboxyethyl)oxy]-1,3-cyclohexadiene-1-carboxylic acid (17). This is the anticipated intermediate predicted by our previous work with conversion of synthetic trans-6-amino-5-[(1-carboxyethenyl)oxy]-1,3-cyclohexadiene-1-carbo xylic acid (2) to anthranilate by the enzyme. Compound 17 is quantitatively converted to anthranilate on reincubation with enzyme, but at a 1.3-10-fold lower Vmax than starting lactyl substrate 14 under the conditions investigated; the basis for this kinetic variation is not yet determined.

Anthranilate Synthase↗
PubMed2005

Poly(lactide) stereocomplexes: formation, structure, properties, degradation, and applications.

Poly(lactide)s [i.e. poly(lactic acid) (PLA)] and lactide copolymers are biodegradable, compostable, producible from renewable resources, and nontoxic to the human body and the environment. They have been used as biomedical materials for tissue regeneration, matrices for drug delivery systems, and alternatives for commercial polymeric materials to reduce the impact on the environment. Since stereocomplexation or stereocomplex formation between enantiomeric PLA, poly(L-lactide) [i.e. poly(L-lactic acid) (PLLA)] and poly(D-lactide) [i.e. poly(D-lactic acid) (PDLA)] was reported in 1987, numerous studies have been carried out with respect to the formation, structure, properties, degradation, and applications of the PLA stereocomplexes. Stereocomplexation enhances the mechanical properties, the thermal-resistance, and the hydrolysis-resistance of PLA-based materials. These improvements arise from a peculiarly strong interaction between L-lactyl unit sequences and D-lactyl unit sequences, and stereocomplexation opens a new way for the preparation of biomaterials such as hydrogels and particles for drug delivery systems. It was revealed that the crucial parameters affecting stereocomplexation are the mixing ratio and the molecular weight of L-lactyl and D-lactyl unit sequences. On the other hand, PDLA was found to form a stereocomplex with L-configured polypeptides in 2001. This kind of stereocomplexation is called "hetero-stereocomplexation" and differentiated from "homo-stereocomplexation" between L-lactyl and D-lactyl unit sequences. This paper reviews the methods for tracing PLA stereocomplexation, the methods for inducing PLA stereocompelxation, the parameters affecting PLA stereocomplexation, and the structure, properties, degradation, and applications of a variety of stereocomplexed PLA materials.

Absorbable Implants↗
PubMed2001

Enzymatic hydrolysis of poly(lactide)s: effects of molecular weight, L-lactide content, and enantiomeric and diastereoisomeric polymer blending.

Nonblended poly(L-lactide) (PLLA) films having different molecular weights and nonblended poly(lactide) (PLA) films, enantiomeric blend films from PLLA and poly(D-lactide) (PDLA), and diastereoisomeric blend films of poly(DL-lactide) (PDLLA) with either PLLA or PDLA, having different L-lactide (LLA) contents (X(LLA)s) in the range of 0-0.99, were amorphous made by melt-quenching. The effects of molecular weight, X(LLA), and average L- and D-lactyl unit sequence length (l(L) and l(D), respectively) on the enzymatic hydrolysis of the films were investigated in the presence of proteinase K. The enzymatic hydrolysis rate (R(EH)) of PLLA estimated by gravimetry increased monotonically with the inverse of number-average molecular weight (M(n)). The extrapolation of R(EH) of PLLA to M(n)(-1) = 0, where no exo-chain-scission takes place, gave a positive R(EH) value (1.75 microg/(mm(2).h)), meaning that the enzymatic hydrolysis of PLLA proceeds via both endo- and exo-chain-scission. The R(EH) of the nonblended films as well as the enantiomeric and diastereoisomeric blend films decreased monotonically with the decease in X(LLA) and finally became zero for X(LLA) below 0.3. The R(EH) values of the blend films of PLLA and PDLLA with PDLA (l(D) = infinity) were lower than expected, while the R(EH) values of the blend films of PLLA with PDLLA (l(D) = 4) agreed completely with the expected values. These results reveal that the nonblended PLA films are enzymatically hydrolyzable when X(LLA) and l(L) are higher than 0.3 and 3, respectively, and l(D) is lower than 10 and that the presence of long D-lactyl unit sequences (l(D) > 4) as in PDLA hinders the enzymatic hydrolysis of long L-lactyl unit sequences even when long D- and L-lactyl unit sequences are present in the different molecules.

Biocompatible Materials↗
PubMed2026

Inhibiting macrophage-derived lactate transport restores cGAS-STING signalling and enhances antitumour immunity in glioblastoma.

Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4-MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS-STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM.

Glioblastoma↗
PubMed2026

Proteomics combined with single-cell sequencing reveals key genes and computational lead compound related to ligamentum flavum hypertrophy, lactate metabolism and lactate modification.

Ligamentum flavum hypertrophy (LFH) is a hallmark pathological feature of lumbar spinal stenosis; however, its underlying molecular mechanisms remain incompletely understood. Lactate metabolism and related lactylation modifications have emerged as critical links between cellular metabolism and epigenetic regulation, with established roles in various fibrotic and inflammatory diseases. Nevertheless, the specific contribution of lactylation to LFH pathogenesis remains unexplored. In this study, we integrated proteomic profiling of ligamentum flavum tissues with single-cell transcriptomic data to identify differentially expressed proteins associated with LFH. Cross-referencing these genes with genes involved in lactate metabolism and lactylation yielded 16 candidate genes. Through functional enrichment analysis, protein-protein interaction network construction, and GraphBAN model prediction, we identified five hub genes (NDUFS2, HMOX1, SPR, FABP5, and PFKP) and two potential lead compounds (ZINC000014879975 and ZINC000242437513). Molecular docking analysis confirmed favorable binding affinities between these compounds, suggesting that they may serve as potential lead compounds worthy of further experimental investigation. Single-cell analysis further revealed that macrophages occupy a central position in the LFH microenvironment, resulting in pronounced metabolic reprogramming and remodeling of intercellular communication networks, particularly via the MIF-CD74/CD44 axis, under pathological conditions.

Proteomics↗
PubMed2026

Lactylome Reprogramming Mediates Therapeutic Response and Adaptation to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) exhibits high prevalence in China and poor prognosis despite neoadjuvant chemotherapy (NACT), with significant chemoresistance development. Tumor-associated metabolic reprogramming and NACT-induced cellular stress promote lactate accumulation, which serves as a precursor for lysine lactylation (Kla), a post-translational modification potentially regulating cancer progression. We hypothesized that systematic characterization of the lactylome in response to NACT could reveal critical molecular mechanisms underlying treatment and identify new therapeutic vulnerabilities in ESCC. Herein, through comprehensive proteomic and lactylome profiling of tumor and adjacent normal adjacent tissues from 31 ESCC patients (with or without NACT treatment), we identified 8281 proteins and 1836 Kla sites across 62 samples. NACT induced substantial lactylome alterations with 307 differentially expressed Kla sites predominantly in nonhistone proteins involved in DNA damage response and metabolic pathways. Our data revealed that while NACT-induced suppression of energy metabolism, coupled with upregulated 3-hydroxy-3-methylglutaryl reductase degradation 1 complex expression, may exert potential proapoptotic effects, the activation of ribosome biogenesis and increased nucleoprotein lactylation triggered tumor-protective mechanisms. Mechanistically, we demonstrated that DNA damage and elevated lactate levels induced poly(ADP-ribose) polymerase 1 K654 lactylation, enhancing its enzymatic activity and augmenting poly(ADP-ribosyl)ation of downstream targets, potentially playing a pivotal role in chemotherapy resistance-associated pathways. This comprehensive tissue-level landscape of Kla dynamics in ESCC response to chemotherapy establishes Kla as a critical regulatory mechanism in treatment response, potentially offering novel therapeutic targets and predictive biomarkers for personalized treatment strategies.

Humans↗
PubMed1993

Overexpression, purification, and mechanistic study of UDP-N-acetylenolpyruvylglucosamine reductase.

The recently isolated Escherichia coli murB gene (Pucci et al., 1992) has been cloned into an expression vector and the encoded UDP-N-acetylenolpyruvylglucosamine reductase (EC 1.1.1.158) was overproduced to about 10% of soluble cell protein. The encoded 38-kDa protein has been purified to near homogeneity. It was found to be a monomer and to contain stoichiometric amounts of bound FAD which is reducible in catalytic turnover. The enzyme utilizes the 4-pro-S hydrogen of NADPH to reduce the enolpyruvyl group of UDP-N-acetylglucosamine enolpyruvate to the lactyl ether in UDP-N-acetylmuramic acid. NMR analysis of products from 2H2O and 4S-[2H]NADPH incubations establishes that a hydride from NADPH via E.FADH2 is transferred to the beta-methyl of the 3-O-lactyl moiety and a proton from solvent to the alpha-carbon of the lactyl moiety of UDP-N-acetylmuramic acid. A mechanism for this unusual enolether reduction in bacterial cell wall assembly is proposed.

Base Sequence↗