Dataset Information

In-silico study of arylalkylamine-nacetyltransferase enzyme to regulate circadian rhythmicity.

ABSTRACT: Circadian Rhythmicity is present in the sleeping and breeding patterns of animals, including human beings and also related with brain wave activity, hormone production, cell regeneration and other biological activities. Melatonin is thought to play important roles in regulating circadian rhytmicity of the animals. Arylalkylamine-N-acetyltransferase (AANAT) is an enzyme which is responsible for the melatonin metabolism. In this study AANAT enzyme is targeted for the control of sleeping sickness and other irregular circadian rhythmicity by regulating the melatonin formation. AANAT protein 3D-structure was modeled, followed by loop modeling, refinement through energy minimization processes by molecular dynamics simulation and validation. Analysis of the Ramachandran plot shows 90.9% amino acids falls in the allowed region. The modeled protein was docked with N-Acetyl Serotonin. Combinatorial library was generated by using N-Acetyl Serotonin as a reference molecule and molecules having 80% similarity to N-Acetyl Serotonin was selected from Zinc database. These molecules were virtually screened by MOLEGRO virtual docker and top 5 molecules were selected and docked by using AutoDock. The AutoDock result shows that the ZINC01587152 molecule is having best interactions with the receptor protein. On the basis of this study we can suggest that the ZINC01587152 molecule is the best ligand against AANAT enzyme. It may be further synthesized and tested for sleep related disorders.

SUBMITTER: Prashant K

PROVIDER: S-EPMC3766309 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

in-silico study of arylalkylamine-nacetyltransferase enzyme to regulate circadian rhythmicity.

Prashant Kumar K Kumar Himansu H Prasad Chekkara Venkata Satya Siva CV

Bioinformation 20130828 15

Circadian Rhythmicity is present in the sleeping and breeding patterns of animals, including human beings and also related with brain wave activity, hormone production, cell regeneration and other biological activities. Melatonin is thought to play important roles in regulating circadian rhytmicity of the animals. Arylalkylamine-N-acetyltransferase (AANAT) is an enzyme which is responsible for the melatonin metabolism. In this study AANAT enzyme is targeted for the control of sleeping sickness a ...[more]

PMID: 24023419

Similar Datasets

Project description:In mammals, the suprachiasmatic nucleus (SCN) is the central pacemaker organizing circadian rhythms of behavior and physiology. At the cellular level, the mammalian clock consists of autoregulatory feedback loops involving a set of "clock genes," including the Cryptochrome (Cry) genes, Cry1 and Cry2. Experimental evidence suggests that Cry1 and Cry2 play distinct roles in circadian clock function. In mice, Cry1 is required for sustained circadian rhythms in dissociated SCN neurons or fibroblasts but not in organotypic SCN slices or at the behavioral level, whereas Cry2 is not required at any of these levels. It has been argued that coupling among SCN cellular oscillators compensates for clock gene defects to preserve oscillatory function. Here we test this hypothesis in Cry1(-/-) mice by first disrupting intercellular coupling in vivo using constant light (resulting in behavioral arrhythmicity) and then examining circadian clock gene expression in SCN slices at the single cell level. In this manner, we were able to test the role of intercellular coupling without drugs and while preserving tissue organization, avoiding the confounding influences of more invasive manipulations. Cry1(-/-) mice (as well as control Cry2(-/-) mice) bearing the PER2::LUC knock-in reporter were transferred from a standard light:dark cycle to constant bright light (~650 lux) to induce arrhythmic locomotor patterns. In SCN slices from these animals, we used bioluminescence imaging to monitor PER2::LUC expression in single cells. We show that SCN slices from rhythmic Cry1(-/-) and Cry2(-/-) mice had similarly high percentages of functional single-cell oscillators. In contrast, SCN slices from arrhythmic Cry1(-/-) mice had significantly fewer rhythmic cells than SCN slices from arrhythmic Cry2(-/-) mice. Thus, constant light in vivo disrupted intercellular SCN coupling to reveal a cell-autonomous circadian defect in Cry1(-/-) cells that is normally compensated by intercellular coupling in vivo.

Project description:Like neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in the brain, single fibroblasts can function as independent oscillators. In the SCN, synaptic and paracrine signaling among cells creates a robust, synchronized circadian oscillation, whereas there is no evidence for such integration in fibroblast cultures. However, interactions among single-cell fibroblast oscillators cannot be completely excluded, because fibroblasts were not isolated in previous work. In this study, we tested the autonomy of fibroblasts as single-cell circadian oscillators in high- and low-density culture, by single-cell imaging of cells from PER2::LUC circadian reporter mice. We found greatly reduced PER2::LUC rhythmicity in low-density cultures, which could result from lack of either constitutive or rhythmic paracrine signals from neighboring fibroblasts. To discriminate between these 2 possibilities, we mixed PER2::LUC wild-type (WT) cells with nonluminescent, nonrhythmic Bmal1-/- cells, so that density of rhythmic cells was low but overall cell density remained high. In this condition, WT cells showed clear rhythmicity similar to high-density cultures. We also mixed PER2::LUC WT cells with nonluminescent, long period Cry2-/- cells. In this condition, WT cells showed a period no different from cells cultured with rhythmic WT cells or nonrhythmic Bmal1-/- cells. In previous work, we found that low K? suppresses fibroblast rhythmicity, and we and others have found that either low K? or low Ca²? suppresses SCN rhythmicity. Therefore, we attempted to rescue rhythmicity of low-density fibroblasts with high K? (21 mM), high Ca²? (3.6 mM), or conditioned medium. Conditioned medium from high-density fibroblast cultures rescued rhythmicity of low-density cultures, whereas high K? or Ca²? medium did not consistently rescue rhythmicity. These data suggest that fibroblasts require paracrine signals from adjacent cells for normal expression of rhythmicity, but that these signals do not have to be rhythmic, and that rhythmic signals from other cells do not affect the intrinsic periods of fibroblasts.

Project description:Traditionally, circadian clocks have been thought of as a neurobiological phenomenon. This view changed somewhat over recent years with the discovery of peripheral tissue circadian oscillators. In mammals, however, the suprachiasmatic nucleus (SCN) in the hypothalamus still retains the critical role of a central synchronizer of biological timing. Zebrafish, in contrast, have always reflected a more highly decentralized level of clock organization, as individual cells and tissues contain directly light responsive circadian pacemakers. As a consequence, clock function in the zebrafish brain has remained largely unexplored, and the precise organization of rhythmic and light-sensitive neurons within the brain is unknown. To address this issue, we used the period3 (per3)-luciferase transgenic zebrafish to confirm that multiple brain regions contain endogenous circadian oscillators that are directly light responsive. In addition, in situ hybridization revealed localised neural expression of several rhythmic and light responsive clock genes, including per3, cryptochrome1a (cry1a) and per2. Adult brain nuclei showing significant clock gene expression include the teleost equivalent of the SCN, as well as numerous hypothalamic nuclei, the periventricular grey zone (PGZ) of the optic tectum, and granular cells of the rhombencephalon. To further investigate the light sensitive properties of neurons, expression of c-fos, a marker for neuronal activity, was examined. c-fos mRNA was upregulated in response to changing light conditions in different nuclei within the zebrafish brain. Furthermore, under constant dark (DD) conditions, c-fos shows a significant circadian oscillation. Taken together, these results show that there are numerous areas of the zebrafish central nervous system, which contain deep brain photoreceptors and directly light-entrainable circadian pacemakers. However, there are also multiple brain nuclei, which possess neither, demonstrating a degree of pacemaker complexity that was not previously appreciated.

Dataset Information

In-silico study of arylalkylamine-nacetyltransferase enzyme to regulate circadian rhythmicity.

Publications

in-silico study of arylalkylamine-nacetyltransferase enzyme to regulate circadian rhythmicity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets