Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway

Vertebrate Hedgehog signals are transduced through the primary cilium, a specialized lipid microdomain that is required for Smoothened activation. Cilia-associated sterol and oxysterol lipids bind to Smoothened to activate the Hedgehog pathway, but how ciliary lipids are regulated is incompletely understood. Here we identified DHCR7, an enzyme that produces cholesterol, activates the Hedgehog pathway, and localizes near the ciliary base. We found that Hedgehog stimulation negatively regulates DHCR7 activity and removes DHCR7 from the ciliary microenvironment, suggesting that DHCR7 primes cilia for Hedgehog pathway activation. In contrast, we found that Hedgehog stimulation positively regulates the oxysterol synthase CYP7A1, which accumulates near the ciliary base and produces oxysterols that promote Hedgehog signaling in response to pathway activation. Our results reveal that enzymes involved in lipid biosynthesis in the ciliary microenvironment promote Hedgehog signaling, shedding light on how ciliary lipids are established and regulated to transduce Hedgehog signals.     

Scope of Archaea in Fish Feed: a New Chapter in Aquafeed Probiotics?

Probiotics and Antimicrobial Proteins - The outbreak of diseases leading to substantial loss is a major bottleneck in aquaculture. Over the last decades, the concept of using feed probiotics was...     

In-Silico Proteomic Exploratory Quest: Crafting T-Cell Epitope Vaccine Against Whipple’s Disease

International Journal of Peptide Research and Therapeutics - Whipple’s disease is one of the rare maladies in terms of spread but very fatal one as it is linked with many disorders (like...     

Identification and characterization of candidates involved in production of OMEGAs in microalgae: a gene mining and phylogenomic approach

Abstract

Optimizing the production of the high-value renewables such as OMEGAs through pathway engineering requires an in-depth understanding of the structure–function relationship of genes involved in the OMEGA biosynthetic pathways. In this preliminary study, our rationale is to identify and characterize the ～221 putative genes involved in production of OMEGAs using bioinformatic analysis from the Streptophyte (plants), Chlorophyte (green algae), Rhodophyta (red algae), and Bacillariophyta (diatoms) lineages based on their phylogenomic profiling, conserved motif/domain organization and physico-chemical properties. The MEME suite predicted 12 distinct protein domains, which are conserved among these putative genes. The phylogenomic analysis of the putative candidate genes [such as FAD2 (delta-12 desaturase); ECR (enoyl-CoA reductase); FAD2 (delta-12 desaturase); ACOT (acyl CoA thioesterase); ECH (enoyl-CoA hydratase); and ACAT (acetyl-CoA acyltransferase)] with similar domains and motif patterns were remarkably well conserved. Furthermore, the subcellular network prediction of OMEGA biosynthetic pathway genes revealed a unique interaction between the light-dependent chlorophyll biosynthesis and glycerol-3-phosphate dehydrogenase, which predicts a major cross-talk between the key essential pathways. Such bioinformatic analysis will provide insights in finding the key regulatory genes to optimize the productivity of OMEGAs in microalgal cell factories.     

Association of resistin (rs3745367) and urotensin II (rs228648 and rs2890565) gene polymorphisms with risk of type 2 diabetes mellitus in Indian population

Molecular Biology Reports - Insulin resistance may become the most powerful predictor of future development of type 2 diabetes mellitus (T2DM) and a therapeutic target for the treatment of the...     

Development of polymorphic EST-SSR markers and their applicability in genetic diversity evaluation in Rhododendron arboreum

Molecular Biology Reports - The genus Rhododendron, known for large impressive flowers is widely distributed throughout the world. Rhododendrons have limited genetic information, despite of...     

A profound computational study to prioritize the natural compound inhibitors against the P. falciparum orotidine-5-monophosphate decarboxylase enzyme

Abstract

In the current contribution, a multicomplex-based pharmacophore modeling approach was employed on the structural proteome of Plasmodium falciparum orotidine-5-monophosphate decarboxylase enzyme (PfOMPDC). Among the constructed pharmacophore models, the representative hypotheses were selected as the primary filter to screen the molecules with the complementary features responsible for showing inhibition. Thereafter, auxiliary evaluations were performed on the screened candidates via drug-likeness and molecular docking studies. Subsequently, the stability of the docked protein-ligand complexes was scrutinized by employing molecular dynamics simulations and molecular mechanics-Poisson Boltzmann surface area based free binding energy calculations. The stability the docked candidates was compared with the highly active crystallized inhibitor (3S9Y-FNU) to seek more potential candidates. All the docked molecules displayed stable dynamic behavior and high binding free energy in comparison to 3S9Y-FNU. The employed workflow resulted in the retrieval of five drug-like candidates with diverse scaffolds that may show inhibitory activity against PfOMPDC and could be further used as the novel scaffold to develop novel antimalarials.

Communicated by Ramaswamy H. Sarma