16 research outputs found
High-Density Hydration Layer of Lysozymes:Â Molecular Dynamics Decomposition of Solution Scattering Data
Increase of both Order and Disorder in the First Hydration Shell with Increasing Solute Polarity
Polymorphisms of <i>CYP51A1</i> from Cholesterol Synthesis: Associations with Birth Weight and Maternal Lipid Levels and Impact on CYP51 Protein Structure
<div><p>We investigated the housekeeping cytochrome P450 <i>CYP51A1</i> encoding lanosterol 14α-demethylase from cholesterol synthesis that was so far not directly linked to human disorders. By direct sequencing of <i>CYP51A1</i> in 188 women with spontaneous preterm delivery and 188 unrelated preterm infants (gestational age <37 weeks) we identified 22 variants where 10 are novel and rare. In infants there were two novel <i>CYP51A1</i> variants where damaging effects of p.Tyr145Asp from the substrate recognition region, but not p.Asn193Asp, were predicted by PolyPhen2 and SIFT. This was confirmed by molecular modeling showing that Tyr145Asp substitution results in changed electrostatic potential of the CYP51 protein surface and lengthened distance to the heme which prevents hydrogen bonding. The CYP51 Tyr145Asp mutation is rare and thus very interesting for further structure/function relationship studies. From the 12 identified known variants rs6465348 was chosen for family based association studies due to its high minor allele frequency. Interestingly, this <i>CYP51A1</i> common variant associates with small for gestational age weight in newborns (p = 0.028) and lower blood total cholesterol and low density lipoprotein cholesterol levels in mothers in 2nd trimester of pregnancy (p = 0.042 and p = 0.046 respectively). Our results indicate a new link between a cholesterol synthesis gene <i>CYP51A1</i> and pregnancy pathologies.</p></div
Experimental design and workflow.
<p>Panels show <i>CYP51A1</i> analysis workflow by direct sequencing (searching for novel functional variants) and the analysis on population level by genotyping of common<i>CYP51A1</i> variants and family based studies.</p
Novel polymorphisms identified in <i>CYP51A1</i> with sequencing approach and PolyPhen 2 and SIFT predictions.
<p><sup>a</sup> Amino acid residue numbering in RefSeq database NP_000777.1 and in UniProt database Q16850;</p
Cholesterol biosynthesis pathway with genes associated with preterm delivery and low birth weight according to Steffen at all [7] and with input from our study.
<p>Cholesterol biosynthesis pathway with genes associated with preterm delivery and low birth weight according to Steffen at all <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082554#pone.0082554-Steffen1" target="_blank">[7]</a> and with input from our study.</p
Relative positions of Tyr145 and Asp145 with respect to the heme.
<p>Dashed lines correspond to the temporary distances in Ã… between the heme oxygen and the corresponding hydrogen atoms which undergo time variations during the simulation. Occasionally, Tyr145 forms a hydrogen bond to the heme when internal motion of the protein brings Tyr145 closer to the heme. There is no hydrogen bond formed between Asp145 and heme as they are too far apart from each other.</p
One-Way ANOVA testing for association between listed parameters and SNP genotypes.
<p>*P-value <0.05.</p