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Genetics and Biosynthesis of Lipopolysaccharide O-Antigens
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Wendy J. Keenleyside, Chris Whitfield
Studies with Yersinia enterocolitica serotype 0:3 first showed intracellular O-PS accumulation in this pathway (82). Electron microscopy subsequently confirmed the cytoplasmic location of O-PS in K. pneumoniae Ol mutants (83). In both cases, surface assembly requires a plasma membrane ABC transporter encoded by the O-PS biosynthesis cluster (Fig. 2D) (82,83). There is therefore no requirement for a Wzx homolog in this pathway. The genes for the ABC transporters were identified based on predicted protein sequence homologies with the ABC-2 subfamily of transporters (84). ABC-2 transporters consist of an integral membrane protein with an average of six membrane-spanning domains and a hydrophilic protein containing an ATP-binding motif or Walker box. The genes for these two components have now been identified in a number of O-PS biosynthesis clusters (Table 2). As with other ABC transporters involved in transmembrane export, the membrane-spanning (Wzm) homologs for O-PS biosynthesis generally exhibit little primary sequence identity but have nearly identical hydropathy plots (83,85). In contrast, primary sequences of the ATP-binding (Wzt) homologs are much more highly conserved, with the highest degree of sequence homology in the nucleotide-binding region (83,85).
Relationship between the effect of polyunsaturated fatty acids (PUFAs) on brain plasticity and the improvement on cognition and behavior in individuals with autism spectrum disorder
Published in Nutritional Neuroscience, 2022
Isabel Barón-Mendoza, Aliesha González-Arenas
The FATPs are a family of six membrane proteins expressed differentially in adipose tissue, brain, heart, liver and muscle. In the brain, FATP1 and FATP4 are highly expressed. It has been reported that in humans, FATPs show bifunctionality; they display a binding motif for fatty acids to import them into the intracellular space, and also, an ATP- binding motif involved with their intrinsic activity of long-chain acyl-coenzyme A synthetase, which catalyzes the free-PUFAs transformation to their respective fatty acyl-CoA thioesters during its transport across the membrane [27,28]. The conversion of free PUFAs to thioesters is called the activation phase, which is a precondition for further elongation and desaturation processes, as well as for PUFAs oxidation in the mitochondrial or peroxisomal compartment, and the biosynthesis of glycerolipids, triacylglycerols and eicosanoid-derivatives [29].
A novel compound heterozygous mutation in DGKE in a Chinese patient causes atypical hemolytic uremic syndrome
Published in Hematology, 2020
Jitong Li, Yinsen Song, Yaodong Zhang, Hongjiang Li, Ming Tian, Di Li, Shufeng Zhang, Guanghai Cao, Cuihua Liu
To further investigate the effects of the DGKE mutations on protein structure and function, our in silico analysis for functional prediction indicated that the M1 mutation in DGKE was ‘disease causing’ according to Mutation Taster [15] and ‘probably damaging’ according to the PolyPhen2 algorithm [16]. Furthermore, the M2 mutation in DGKE was predicted to be ‘deleterious’ by PROVEAN [17] and SIFT analysis [18]. At the N terminus, DGKE contains two cysteine-rich motifs, which are similar to the C1 domains of protein kinase C (PKC) [19]. At the C terminus, DGKE contains a conserved catalytic region, DAGKc [20], and an accessory subdomain, DAGKa, whose function is unclear [21]. Further functional prediction of M1 variance was carried out using FATHMM algorithms [22] and showed a deleterious effect. The M2 mutation, however, is likely to cause the transcript to be degraded by nonsense-mediated mRNA decay [8,23]. Corresponding to the glycine-rich loops found in protein kinases [24,25], ATP-binding motifs were identified in the first C1 and the catalytic domains of DGKE [12,26,27]. Recent reports have suggested that DAGKa and DAGKc are ATP-binding domains for DGKE activity [12,27]. In addition, impaired protein folding can induce premature degradation and may be a major pathogenic factor of disease in genetic defects caused by missense mutations or deletions/insertions resulting from frameshift mutations [28]. Therefore, the two mutations may also disturb ATP binding and DGKE activity.
An explorative study on Staphylococcus aureus MurE inhibitor: induced fit docking, binding free energy calculation, and molecular dynamics
Published in Journal of Receptors and Signal Transduction, 2019
Mohammed Afzal Azam, Niladri Saha, Srikanth Jupudi
Like other Mur ligases, S. aureus MurE is composed of a three globular domains. The overall structure, secondary structure content and domain architecture are very similar as observed for both E. coli and Mycobacterium tuberculosis [13]. Domain 1 comprises residues 1–98 encompassing the uridine nucleoside-binding site of the UDP-MurNAc-tripeptide product. This domain consists of a seven-stranded β-sheet surrounded by three α-helices. Domain 2 extends from residues 99–332 and consists of a central 13-stranded β-sheet surrounded by eight α-helices. This domain encompasses rest of the UDP-MurNAc-tripeptide-binding pocket, closely resembling the central domain of MurD. Domain 3 consists of residues from 333 to 493, with the ATP-binding site formed between domains 2 and 3 (Figure 1(a)). This domain comprises eight-stranded β-sheet surrounded by five α-helices. As with the other Mur ligases, the nucleotide-binding region of the S. aureus ATP-binding site consists of the amino acid elements with a generalized ATP-binding motif sequence GXXGK (T/S) [14]. Site directed mutagenesis study showed decrease in affinity for l-lysine and catalytic activity when Asp406, Asn407, Pro408, or Glu460 was replaced by alanine and Ala409 was replaced by arginine to mimic the E. coli sequence. There also observation that the functionality of Asn407 is partly replaced by Glu460, which is present on a different loop structure connecting two β-sheet of the protein [13]. Further, in mutant strains of S. aureus for LysA, a decrease in virulence was observed in a murine bacteremia model of infection [15] with over 100-fold decrease in the minimum inhibitory concentration for methicillin in the methicillin resistance COL strain of S. aureus [16].