scholarly journals Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 870
Author(s):  
Giovanna Cardiero ◽  
Gennaro Musollino ◽  
Maria Grazia Friscia ◽  
Rosario Testa ◽  
Lucrezia Virruso ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Molecular Mechanisms ◽  
Southern Italy ◽  
Globin Genes ◽  
Normal Amount ◽  
Hba1 C ◽  
Molecular Modeling Studies ◽  
Protein Instability ◽  
In Cis

We identified two unstable variants in the third exon of α-globin genes: Hb Bernalda/Groene Hart (HBA1:c.358C>T), and Hb Caserta (HBA2:c.79G>A) in cis to Hb Sun Prairie (HBA2:c.391G>C), also named Hb Southern Italy. These mutations occurred in the H helix of the α-globin that is involved in heme contacting, specific recognition of α-hemoglobin-stabilizing protein (AHSP), and α1β1 interactions. The carriers showed α-thalassemia phenotype, but one also jaundice and cholelithiasis. Molecular identification of clusters of families in Southern Italy encouraged molecular characterization of mRNA, globin chain analyses, molecular modeling studies, and comparison with globin variants to understand the mechanisms causing the α-thalassemia phenotype. A normal amount of Hb Bernalda/Groene Hart mRNA were found, and molecular modeling highlighted additional H bonds with AHSP. For Hb Southern Italy, showing an unexpected α/β biosynthetic ratio typical of the β-thalassemia type, two different molecular mechanisms were shown: Reduction of the variant mRNA, likely due to the No-Go Decay for the presence of unused triplet ACG at cod 26, and protein instability due to the impairment of AHSP interaction. The UDP glucuronosyltransferase 1A (UGT1A1) genotyping was conclusive in the case of jaundice and cholelithiasis. Multiple approaches are needed to properly identify the mechanisms leading to unstable variants and the effect of a mutation.

scholarly journals Carbapenem use is driving the evolution of IMiPenemase (IMP)-1 variants

2021 ◽  
Author(s):  
Zishuo Cheng ◽  
Christopher R. Bethel ◽  
Pei W. Thomas ◽  
Ben A. Shurina ◽  
John-Paul Alao ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Molecular Modeling ◽  
Genetic Background ◽  
Molecular Mechanisms ◽  
Clinical Impact ◽  
Survival Advantage ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Selective Pressures ◽  
Molecular Modeling Studies

Metallo-β-lactamases (MBLs) are a growing clinical threat because they inactivate nearly all β-lactam-containing antibiotics, and there are no clinically-available inhibitors. A significant number of variants have already emerged for each MBL subfamily. To understand the evolution of IMiPenemase (IMP) genes (blaIMP) and their clinical impact, twenty clinically-derived IMP-1 like variants were obtained using site-directed mutagenesis and expressed in a uniform genetic background in Escherichia coli DH10B. Strains of IMP-1-like variants harboring S262G or V67F substitutions exhibited increased resistance towards carbapenems and decreased resistance towards ampicillin. Strains expressing IMP-78 (S262G/V67F) exhibited the largest changes in MIC values as compared to IMP-1. In order to understand the molecular mechanisms of increased resistance, biochemical, biophysical, and molecular modeling studies were conducted to compare IMP-1, IMP-6 (S262G), IMP-10 (V67F), and IMP-78 (S262G/V67F). Finally, unlike most NDM and VIM variants, the IMP-1 like variants do not confer any additional survival advantage if zinc availability is limited. Therefore, the evolution of MBL subfamilies (i.e. IMP-6, -10, and -78) appears to be driven by different selective pressures.

Characterization of a unique tomaymycin-d(CICGAATTCICG)2 adduct containing two drug molecules per duplex by NMR, fluorescence, and molecular modeling studies

Biochemistry ◽  
1990 ◽  
Vol 29 (9) ◽  
pp. 2387-2403 ◽  
Author(s):  
F. Leslie Boyd ◽  
Diana Stewart ◽  
William A. Remers ◽  
Mary D. Barkley ◽  
Laurence H. Hurley
Keyword(s):  
Molecular Modeling ◽  
Drug Molecules ◽  
Modeling Studies ◽  
Molecular Modeling Studies

Characterization of hemoglobin Würzburg (α2ß2 4(A1)Thr→Asn), a new electrophoretically silent variant, by mass spectrometry and molecular modeling studies

2006 ◽  
Vol 1115 (1-2) ◽  
pp. 118-124 ◽  
Author(s):  
Emmanuel Bissé ◽  
Nathalie Zorn ◽  
Stéphanie Boussert ◽  
Thomas Epting ◽  
Alain Van Dorsselaer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Modeling ◽  
Modeling Studies ◽  
Molecular Modeling Studies
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