Investigation of the in vivo interaction between β-lactamaseand its inhibitor protein

Gökgöz, Nilay Büdeyri; Yalaz, Simay; Avci, Naze G.; Buldum, Gizem; Ölmez, Elif Özkırımlı; Akbulut, Berna Sarıyar

doi:10.3906/biy-1409-83

Cited by 3 publications

(1 citation statement)

References 32 publications

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“…S4 , Supplementary Material online). Periplasmatic beta-lactamase proteins were extracted from E. coli cells as previously described ( BÜDeyrİ GÖKgÖZ et al. 2015 ).…”

Section: Methodsmentioning

confidence: 99%

The Codon Usage of Lowly Expressed Genes Is Subject to Natural Selection

Yannai

Katz

Hershberg

2018

Genome Biology and Evolution

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Codon usage bias affects the genomes of organisms from all kingdoms of life and results from both background substitution biases and natural selection. Natural selection on codon usage to increase translation accuracy and efficiency has long been known to affect gene sequences. Such selection is stronger on highly, compared with lowly expressed genes, resulting in higher levels of codon bias within genes with higher expression levels. Additionally, selection on translation accuracy affects more strongly codons encoding conserved amino acids, since these will more often affect protein folding and/or function. By applying tests of selection on the gene sequences of the bacterium Escherichia coli, we demonstrate that both highly and lowly expressed genes display signals of selection on codon usage. Such signals are found for both conserved and less conserved amino acid positions, even within the 10% of E. coli genes expressed at the lowest levels. We further demonstrate experimentally that single synonymous codon replacements within a lowly expressed, essential gene can carry substantial effects on bacterial fitness. Combined, our results demonstrate that even within genes expressed at relatively low levels there is substantial selection on codon usage and that single synonymous codon replacements within such genes can have a marked effect on bacterial fitness.

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“…S4 , Supplementary Material online). Periplasmatic beta-lactamase proteins were extracted from E. coli cells as previously described ( BÜDeyrİ GÖKgÖZ et al. 2015 ).…”

Section: Methodsmentioning

confidence: 99%

The Codon Usage of Lowly Expressed Genes Is Subject to Natural Selection

Yannai

Katz

Hershberg

2018

Genome Biology and Evolution

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An evolutionarily conserved allosteric site modulates beta-lactamase activity

Avcı

Altinisik

Vardar‐Ulu

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Declining efficiency of antibiotic-inhibitor combinatorial therapies in treating beta-lactamase mediated resistance necessitates novel inhibitor development. Allosteric inhibition offers an alternative to conventional drugs that target the conserved active site. Here, we show that the evolutionarily conserved PWP triad located at the N-terminus of the H10 helix directly interacts with the allosteric site in TEM-1 beta-lactamase and regulates its activity. While point mutations in the PWP triad preserve the overall secondary structures around the allosteric site, they result in a more open and dynamic global structure with decreased chemical stability and increased aggregation propensity. These mutant enzymes with a less compact hydrophobic core around the allosteric site displayed significant activity loss. Detailed sequence and structure conservation analyses revealed that the PWP triad is an evolutionarily conserved motif unique to class A beta-lactamases aligning its allosteric site and hence is an effective potential target for enzyme regulation and selective drug design.

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Identification and prediction of the consequences of nonsynonymous SNPs in glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene of zebrafish Danio rerio

Rasal¹,

Chakrapani²,

Patra³

et al. 2016

Turk J Biol

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The recent progress in DNA sequencing and computational algorithms dramatically heightened the value of single nucleotide polymorphism (SNP) databases. The experimental studies of mutation for the particular gene of interest are laborious and timeconsuming. In this study, we used several computational algorithms to investigate the structural and functional consequences of SNPs on the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene of zebrafish (Danio rerio). The GAPDH gene is involved in multiple cellular activities, in addition to its association with classical glycolytic pathway. It has most commonly been used as the housekeeping gene for differential gene expression profiling, including western blots. The computational analysis, which used sequence-based tools such as SIFT, PANTHER, PROVEAN, and I-Mutant2.0, predicted deleterious nonsynonymous SNPs (nsSNPs) at p.W194R in the GAPDH gene. The SWISS Model tool generated a homology-modeled 3D structure of GAPDH by applying homologous protein structures retrieved from the RCSB PDB databank (PDB ID: 1U8F_O, 1ZNQ_O, 1J0X_O, 3GPD_R, and 1SZJ_G). The sequence identities of the above selected models were 86%, 86%, 86%, 83%, and 75%, respectively. The Procheck quality assessment in the Ramachandran plot showed that the incorporated mutation (p.W194R) led to a shifting of amino acid residues from the most favored regions towards the disallowed region, as compared to the native counterpart. The lowered ERRAT and PROSA Z scores in the mutant confirmed the overall deteriorating quality of mutant GAPDH. We also predicted an effect of mutation on increased H-bonding patterns due to mutant residue. The molecular docking analysis, while binding GAPDH to its ligand (NAD +), also revealed elevated global energy in the mutant. Altogether, this study demonstrated the impact of nsSNPs on the protein structure and function. The results of work provide an insight/ roadmap for future investigations with regard to the pathological consequences of nsSNPs using in vivo methods.

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Investigation of the in vivo interaction between β-lactamaseand its inhibitor protein

Cited by 3 publications

References 32 publications

The Codon Usage of Lowly Expressed Genes Is Subject to Natural Selection

The Codon Usage of Lowly Expressed Genes Is Subject to Natural Selection

An evolutionarily conserved allosteric site modulates beta-lactamase activity

Identification and prediction of the consequences of nonsynonymous SNPs in glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene of zebrafish Danio rerio

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