Richard W. Meek's research while affiliated with University of Southampton and other places
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Publications (21)
Correction for ‘Molecular basis of sulfolactate synthesis by sulfolactaldehyde dehydrogenase from Rhizobium leguminosarum’ by Jinling Li et al., Chem. Sci., 2023, 14, 11429–11440, https://doi.org/10.1039/D3SC01594G.
The modification of nucleocytoplasmic proteins by O -linked N-acetylglucosamine ( O -GlcNAc) is an important regulator of cell physiology. O -GlcNAc is installed on over a thousand proteins by just one enzyme, O -GlcNAc transferase (OGT). How OGT is regulated is therefore a topic of interest. To gain insight into these questions, we used OGT to per...
![(a) Rate data for reactions catalyzed by RlGabD when [NAD⁺] was varied...](publication/374179147/figure/fig4/AS:11431281196001797@1696513279591/a-Rate-data-for-reactions-catalyzed-by-RlGabD-when-NAD-was-varied-under-several_Q320.jpg)
Sulfolactate (SL) is a short-chain organosulfonate that is an important reservoir of sulfur in the biosphere. SL is produced by oxidation of sulfolactaldehyde (SLA), which in turn derives from sulfoglycolysis of the sulfosugar sulfoquinovose, or through oxidation of 2,3-dihydroxypropanesulfonate. Oxidation of SLA is catalyzed by SLA dehydrogenases...
The modification of nucleocytoplasmic proteins by O-linked N-acetylglucosamine ( O -GlcNAc) is an important regulator of cell physiology. O -GlcNAc is installed on over a thousand proteins by just one enzyme, O -GlcNAc transferase (OGT). How OGT is therefore regulated is therefore a topic of interest. To gain insight into these questions, we used O...
![Figure 4. a) Rate data for reactions catalyzed by RlGabD when [NAD + ]...](publication/369240829/figure/fig1/AS:11431281126944108@1678884588129/a-Rate-data-for-reactions-catalyzed-by-RlGabD-when-NAD-was-varied-under-several_Q320.jpg)
Sulfolactate (SL) is a short-chain organosulfonate that is an important reservoir of sulfur in the biosphere. SL is produced by oxidation of sulfolactaldehyde (SLA), which in turns derives from sulfoglycolysis of the sulfosugar sulfoquinovose, or through oxidation of 2,3-dihydroxypropanesulfonate, which are themselves important organosulfur compoun...
Glycosyltransferases are a superfamily of enzymes that are notoriously difficult to inhibit. Here we apply an mRNA display technology integrated with genetic code reprogramming, referred to as the RaPID (random non‐standard peptides integrated discovery) system, to identify macrocyclic peptides with high binding affinities for O‐GlcNAc transferase...
Glycosyltransferases are a notoriously difficult to inhibit superfamily of enzymes. Here we apply an mRNA display technology integrated with genetic code reprogramming, referred to as the RaPID (random non‐standard peptides integrated discovery) system, to identify macrocyclic peptides with high binding affinities for O‐GlcNAc transferase (OGT). Th...
Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosida...
Enzymatic hydrolysis of α-L-fucose from fucosylated glycoconjugates is consequential in bacterial infections and the neurodegenerative lysosomal storage disorder fucosidosis. Understanding human α-L-fucosidase catalysis, in an effort toward drug design, has been hindered by the absence of three-dimensional structural data for any animal fucosidase....
The O-linked β-N-acetylglucosamine modification is a core signalling mechanism, with erroneous patterns leading to cancer and neurodegeneration. Although thousands of proteins are subject to this modification, only a single essential glycosyltransferase catalyses its installation, the O-GlcNAc transferase, OGT. Previous studies have provided trunca...
Glycolysis and gluconeogenesis are central pathways of metabolism across all domains of life. A prominent enzyme in these pathways is phosphoglucose isomerase (PGI), which mediates the interconversion of glucose-6-phosphate and fructose-6-phosphate. The predatory bacterium Bdellovibrio bacteriovorus leads a complex life cycle, switching between int...
Glycolysis and gluconeogenesis are central pathways of metabolism across all domains of life. A prominent enzyme in these pathways is phosphoglucose isomerase (PGI) which mediates the interconversion of glucose-6-phosphate and fructose-6-phosphate (F6P). The predatory bacterium Bdellovibrio bacteriovorus leads a complex lifecycle, switching between...
The asymmetric Gram-negative outer membrane (OM) is the first line of defence for bacteria against environmental insults and attack by antimicrobials. The key component of the OM is lipopolysaccharide, which is transported to the surface by the essential lipopolysaccharide transport (Lpt) system. Correct folding of the Lpt system component LptD is...
The asymmetric Gram-negative outer membrane (OM) is the first line of defence for bacteria against environmental insults and attack by antimicrobials. The key component of the OM is lipopolysaccharide, which is transported to the surface by the essential lipopolysaccharide transport (Lpt) system. Correct folding of the Lpt system component LptD is...
Glycosyltransferases carry out important cellular functions in species ranging from bacteria to humans. Despite their essential roles in biology, simple and robust activity assays that can be easily applied to high‐throughput screening for inhibitors of these enzymes have been challenging to develop. Herein, we report a bead‐based strategy to measu...
More and more bacterial infections are becoming resistant to antibiotics. This has made treatment of many infections very difficult. One of the reasons this is such a large problem is that bacteria are able to share their genetic material with other bacteria, and these shared genes often include resistance to a variety of antibiotics, including som...
A robust fluorescence-based assay accurately reports on the sugar-transfer activity of glycosyltransferases. This assay is amenable to high-throughput screening and should be applicable to a diverse set of group-transfer enzymes. This assay is validated by screening of a library of known bioactive molecules to identify a new O-GlcNAc transferase an...
The bacterial second messenger cyclic-di-GMP is a widespread, prominent effector of lifestyle change. An example of this occurs in the predatory bacterium Bdellovibrio bacteriovorus, which cycles between free-living and intraperiplasmic phases after entering (and killing) another bacterium. The initiation of prey invasion is governed by DgcB (GGDEF...
Bacterial usage of the cyclic dinucleotide c-di-GMP is widespread, governing the transition between motile/sessile and unicellular/multicellular behaviors. There is limited information on c-di-GMP metabolism, particularly on regulatory mechanisms governing control of EAL c-di-GMP phosphodiesterases. Herein, we provide high-resolution structures for...
The asymmetric Gram-negative outer membrane is the first line of defence for the bacterium against environmental insults and attack by antimicrobials. The key component of this barrier is lipopolysaccharide, which is transported to the surface by the essential lipopolysaccharide transport (Lpt) system. Correct folding of the Lpt system component, L...
The global crisis of antibiotic resistance has reached a point where, if action is not taken, human medicine will enter a postantibiotic world and simple injuries could once again be life threatening. New antibiotics are needed urgently, but better use of existing agents is just as important. More appropriate use of antibiotics in medicine is vital...
Citations
... Apart from TPR, some other factors are found to be involved in OGT substrate recognition. Notably, two publications highlighted the biological importance of the Int-D of OGT in substrate selectivity (28,29). Using peptide phage display, both studies enriched a PxYx[I/L/M/F] motif in OGT binding via the Int-D. ...
Reference: OGT and OGA: Sweet Guardians of the Genome
... saturation, preventing determination of k cat and K M values but still allowing determination of k cat /K M = 0.0052 s −1 mM −1 (Fig. 2D). We independently confirmed the LCMS rate measurements and obtained a commensurate estimate of k cat /K M (at [S] << K M ) using a stopped assay in which NAD(P)Hdependent SLA dehydrogenase GabD was used to quantify SLA production (see Experimental procedures) (20). The specificity of both enzymes was examined with the structural analog fructose bisphosphate, a metabolic intermediate from glycolysis/gluconeogenesis. ...
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... On the other side of this interaction, the SMG9 Y147 residue is highly conserved in our motif and makes substantial interactions with OGT Int-D (Fig. 2c), signaling its importance for binding. Using the same FP competition assay as before, mutant peptide SMG9 Y147F demonstrated a more than tenfold shift in EC 50 (Fig. 2e), further supporting the SMG9 binding modes observed in our crystal structure. Interestingly, Y147 is a major SMG9 phosphorylation site. ...
... Briefly, O-GlcNAc Transferase (OGT) OGT is an enzyme that is composed of two domains, an N-terminal domain containing tetratricopeptide repeats (TPR domain), and a C-terminal catalytic domain (Figure 4a). There is evidence of inter-domain allostery in this system, such that binding of ligands, such as L4, to the TPR domain inhibits catalytic activity (Alteen et al., 2022). This allostery is often studied by comparing the fulllength OGT to truncated domains: the isolated TPR domain and a construct that contains the catalytic domain and a subset of the TPR repeats (9-13.5), ...
... In addition to our inhibitory and activating peptides, there remained two potent binders, PAD4_1 and PAD4_7, which neither inhibited nor activated PADI4 catalytic activity in vitro ( Figure 2A, Figure 4A). Cyclic peptides with similar affinities to other protein targets, have previously been functionalised as probes for a variety of assays 61,62 . We therefore sought to generate a pull-down probe from PADI4_7 (the tighter binder of the two peptides). ...
... It plays a role in cell movement and organization. The MYORG protein is an αgalactosidase and has a conserved domain architecture consisting of a short N-terminal cytoplasmic domain (aa 1-58), single transmembrane fragment (aa 59-79), glycoside hydrolase family 31 domain (GH31) (aa 311-714), and domain of unknown function (aa 80-310) (Meek et al., 2022;Yao et al., 2018). The GH31 domain is a common glycosidase domain responsible for the decomposition of complex sugars. ...
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... GH29 enzymes are divided into GH29-A and GH29-B, displaying broad and narrow substrate specificity, respectively. The acid/ base residues of GH29-B enzymes are conserved and assignable from primary sequence alignments 53 in contrast to GH29-A where catalytic residues are less conserved 35,[48][49][50][51]54,55 . Here, we first showed using SSN that GH29-A sequences were spread within 18 clusters as compared to 3 clusters for GH29-B sequences, in line with the high variability characteristic of GH29-A enzymes. ...
... We next determined the structure of OGT at an overall resolution of 3.69 Å using single-particle cryo-EM (Fig. 1d, Supplementary Fig. 2, and Supplementary Fig. 3). As previously reported 41 , OGT formed a scissor-shaped dimer (Fig. 1d). The TPR domain of each monomer consists of 27 antiparallel α-helices, which stack together in a right-handed superhelical conformation with a lumen of 22 Å in diameter (Fig. 1d). ...
... The pgi in KEGG pathway is glucose-6-phosphate isomerase. Glucose-6-phosphate isomerase exists in eukaryotes and prokaryotes, and it is a multifunctional enzyme whose main function is to catalyze the mutual conversion between glucose-6-phosphate and fructose-6-phosphate in the process of glycolysis [32][33][34][35][36]. tpiA encodes triose-phosphate isomerase, an enzyme in the glycolytic pathway. ...
... Based on the presence of conserved domains or motifs, subcellular localization, signal peptides, and COG functional clustering, we selected 358 proteins that are divided into 182 low conserved (Table S3) and 176 specific (Table S4) Table S5. These domains are found in several pathogens, including Pseudomonas aeruginosa [39], Vibrio cholera [40], Yersinia pestis [41], Escherichia coli [42], and Salmonella typhimurium [43]. Due to their proteolytic capacity, peptidases can cause physiological dysfunction, promote microbial invasion, tissue damage, and inflammation [44]. ...
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