scholarly journals Ghrelin octanoylation by ghrelin O -acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling

Open Biology ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 210080
Author(s):  
Tasha R. Davis ◽  
Mariah R. Pierce ◽  
Sadie X. Novak ◽  
James L. Hougland
Keyword(s):  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Structural Model ◽  
Peptide Hormone ◽  
Protein Biochemistry ◽  
Physiological Processes ◽  
Current State ◽  
Enzyme Superfamily ◽  
Wide Range ◽  
Membrane Bound

The acylated peptide hormone ghrelin impacts a wide range of physiological processes but is most well known for controlling hunger and metabolic regulation. Ghrelin requires a unique posttranslational modification, serine octanoylation, to bind and activate signalling through its cognate GHS-R1a receptor. Ghrelin acylation is catalysed by ghrelin O -acyltransferase (GOAT), a member of the membrane-bound O -acyltransferase (MBOAT) enzyme family. The ghrelin/GOAT/GHS-R1a system is defined by multiple unique aspects within both protein biochemistry and endocrinology. Ghrelin serves as the only substrate for GOAT within the human proteome and, among the multiple hormones involved in energy homeostasis and metabolism such as insulin and leptin, acts as the only known hormone in circulation that directly stimulates appetite and hunger signalling. Advances in GOAT enzymology, structural modelling and inhibitor development have revolutionized our understanding of this enzyme and offered new tools for investigating ghrelin signalling at the molecular and organismal levels. In this review, we briefly summarize the current state of knowledge regarding ghrelin signalling and ghrelin/GOAT enzymology, discuss the GOAT structural model in the context of recently reported MBOAT enzyme superfamily member structures, and highlight the growing complement of GOAT inhibitors that offer options for both ghrelin signalling studies and therapeutic applications.

Ghrelin octanoylation by ghrelin O-acyltransferase: Unique protein biochemistry underlying metabolic signaling

2019 ◽  
Vol 47 (1) ◽  
pp. 169-178 ◽  
Author(s):  
James L. Hougland
Keyword(s):  
Metabolic Regulation ◽  
Peptide Hormone ◽  
Acyl Donor ◽  
Post Translational Modification ◽  
Small Peptide ◽  
Protein Biochemistry ◽  
Physiological Processes ◽  
Unique Protein ◽  
The Status ◽  
Membrane Bound

Abstract Ghrelin is a small peptide hormone that requires a unique post-translational modification, serine octanoylation, to bind and activate the GHS-R1a receptor. Ghrelin signaling is implicated in a variety of neurological and physiological processes, but is most well known for its roles in controlling hunger and metabolic regulation. Ghrelin octanoylation is catalyzed by ghrelin O-acyltransferase (GOAT), a member of the membrane-bound O-acyltransferase (MBOAT) enzyme family. From the status of ghrelin as the only substrate for GOAT in the human genome to the source and requirement for the octanoyl acyl donor, the ghrelin–GOAT system is defined by multiple unique aspects within both protein biochemistry and endocrinology. In this review, we examine recent advances in our understanding of the interactions and mechanisms leading to ghrelin modification by GOAT, discuss the potential sources for the octanoyl acyl donor required for ghrelin's activation, and summarize the current landscape of molecules targeting ghrelin octanoylation through GOAT inhibition.

scholarly journals Physiologically-induced adipocyte browning

2018 ◽  
Vol 72 ◽  
pp. 499-511
Author(s):  
Oskar Wojciech Wiśniewski ◽  
Malwina Malinowska ◽  
Magdalena Gibas-Dorna
Keyword(s):  
Central Nervous System ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Sympathetic Stimulation ◽  
Physiological Factors ◽  
Or Management ◽  
Factors Associated ◽  
Current State ◽  
Wide Range ◽  
Tissue Modelling

The data consistently suggests that expansion and activation of beige/brite adipose tissue may possibly serve as a novel cure for obesity and obesity-related complications. Interestingly, besides well-known agents affecting adipocyte transformation, such as cold-induced sympathetic stimulation, the vast majority of biological systems (e.g. cardiovascular, endocrine, immune, musculoskeletal and central nervous system) also play a role in an adipose tissue modelling and maintaining energy homeostasis. Therefore, we decided to describe in detail the browning of the adipose tissue with a wide range of physiological factors associated with this process and to present the significant distinctions between “classical” brown and beige/brite adipocytes. Here, we review the current state of knowledge about browning phenomenon with regard to obesity prevention and/or management.

scholarly journals Molecular architecture of a membrane-spanning hormone acyltransferase required for metabolic regulation

2019 ◽  
Author(s):  
Maria B. Campaña ◽  
Flaviyan Jerome Irudayanathan ◽  
Tasha R. Davis ◽  
Kayleigh R. McGovern-Gooch ◽  
Rosemary Loftus ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Metabolic Regulation ◽  
Structural Model ◽  
Integral Membrane Proteins ◽  
Molecular Architecture ◽  
Biochemical Validation ◽  
Synergistic Approach ◽  
Membrane Bound ◽  
Membrane Spanning ◽  
Complex Integral

AbstractIntegral membrane proteins represent a large and essential portion of the proteome that often prove challenging for structural studies. We demonstrate a synergistic approach to structurally model topologically complex integral membrane proteins by combining co-evolutionary constraints and computational modeling with biochemical validation. We report the first structural model of a eukaryotic membrane-bound O-acyltransferase (MBOAT), ghrelin O-acyltransferase (GOAT), which modifies the metabolism-regulating hormone ghrelin. Our structure suggests an unanticipated strategy for trans-membrane protein acylation, with catalysis occurring in an internal channel as GOAT acts as an “enzyme inside a pore”. Our structure opens the door to structure-guided inhibitor design targeting GOAT and other MBOAT family members while validating the power of our approach to generate predictive structural models for other experimentally challenging integral membrane proteins.

Bacterial Protein Mimetic of Peptide Hormone as a New Class of Protein- based Drugs

2019 ◽  
Vol 26 (3) ◽  
pp. 546-553 ◽  
Author(s):  
Sergueï O. Fetissov ◽  
Romain Legrand ◽  
Nicolas Lucas
Keyword(s):  
Energy Homeostasis ◽  
In Silico Analysis ◽  
Peptide Hormone ◽  
Intercellular Signaling ◽  
E Coli ◽  
Melanocyte Stimulating Hormone ◽  
New Class ◽  
Bacterial Proteins ◽  
Physiological Processes ◽  
New Type

Specific peptide molecules classified as hormones, neuropeptides and cytokines are involved in intercellular signaling regulating various physiological processes in all organs and tissues. This justifies the peptidergic signaling as an attractive pharmacological target. Recently, a protein mimetic of a peptide hormone has been identified in Escherichia coli suggesting the potential use of specific bacterial proteins as a new type of peptide-like drugs. We review the scientific rational and technological approaches leading to the identification of the E. coli caseinolytic protease B (ClpB) homologue protein as a conformational mimetic of α-melanocyte-stimulating hormone (α-MSH), a melanocortin peptide critically involved in the regulation of energy homeostasis in humans and animals. Theoretical and experimental backgrounds for the validation of bacterial ClpB as a potential drug are discussed based on the known E. coli ClpB amino acid sequence homology with α-MSH. Using in silico analysis, we show that other protein sources containing similar to E. coli ClpB α-MSH-like epitopes with potential biological activity may exist in Enterobacteriaceae and in some Brassicaceae. Thus, the original approach leading to the identification of E. coli ClpB as an α-MSH mimetic protein can be applied for the identification of mimetic proteins of other peptide hormones and development of a new type of peptide-like protein-based drugs.

scholarly journals Sirtuins and their role as physiological modulators of metabolism

2020 ◽  
Vol 74 ◽  
pp. 489-497
Author(s):  
Grażyna Sygitowicz ◽  
Dariusz Sitkiewicz
Keyword(s):  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Whole Body ◽  
Acid Oxidation ◽  
Special Role ◽  
Cellular Functions ◽  
Current State ◽  
Expression Of Genes ◽  
Wide Range ◽  
Adp Ribosyltransferase

The sirtuins are a family of highly evolutionary conserved NAD+-dependent deacetylases (SIRT1, 2, 3, 5). Certain human sirtuins (SIRT4, 6) have, in addition, an ADP-ribosyltransferase activity. SIRT1 and SIRT2 are located in the nucleus and cytoplasm; SIRT3 exists predominantly in mitochondria, and SIRT6 is located in the nucleus. The mammalian sirtuins have emerged as key metabolic sensors that directly link environmental nutrient signals to metabolic homeostasis. SIRT1 is involved in the regulation of gluconeogenesis and fatty acid oxidation, as well as inhibiting lipogenesis and inflammation in the liver. In addition, they contribute to the mobilization of fat in white adipose tissue, sense nutrient availability in the hypothalamus; regulate insulin secretion in the pancreas; as well as modulating the expression of genes responsible for the activity of the circadian clock in metabolic tissues. Sirtuins are implicated in a variety of cellular functions ranging from gene silencing, through the control of the cell cycle, to energy homeostasis. Caloric restriction, supported by polyphenols, including resveratrol, which is the SIRT1 activator, plays a special role in maintaining energy homeostasis. On a whole body level, the wide range of cellular activities of the sirtuins suggests that they could constitute a therapeutic target to combat obesity and related metabolic diseases. In addition, this work presents the current state of knowledge in the field of sirtuin activity in relation to nutritional status and lifespan.

Strongly Coupled Redox-Linked Conformational Switching at the Active Site of the Non-Heme Iron-Dependent Dioxygenase, TauD

2019 ◽  
Author(s):  
Christopher John ◽  
Greg M. Swain ◽  
Robert P. Hausinger ◽  
Denis A. Proshlyakov
Keyword(s):  
Active Site ◽  
Structural Model ◽  
Heme Iron ◽  
Chemical Transformations ◽  
Experimental Conditions ◽  
Strongly Coupled ◽  
Non Heme Iron ◽  
Reversible Redox ◽  
Wide Range ◽  
Complex Structural

2-Oxoglutarate (2OG)-dependent dioxygenases catalyze C-H activation while performing a wide range of chemical transformations. In contrast to their heme analogues, non-heme iron centers afford greater structural flexibility with important implications for their diverse catalytic mechanisms. We characterize an <i>in situ</i> structural model of the putative transient ferric intermediate of 2OG:taurine dioxygenase (TauD) by using a combination of spectroelectrochemical and semi-empirical computational methods, demonstrating that the Fe (III/II) transition involves a substantial, fully reversible, redox-linked conformational change at the active site. This rearrangement alters the apparent redox potential of the active site between -127 mV for reduction of the ferric state and 171 mV for oxidation of the ferrous state of the 2OG-Fe-TauD complex. Structural perturbations exhibit limited sensitivity to mediator concentrations and potential pulse duration. Similar changes were observed in the Fe-TauD and taurine-2OG-Fe-TauD complexes, thus attributing the reorganization to the protein moiety rather than the cosubstrates. Redox difference infrared spectra indicate a reorganization of the protein backbone in addition to the involvement of carboxylate and histidine ligands. Quantitative modeling of the transient redox response using two alternative reaction schemes across a variety of experimental conditions strongly supports the proposal for intrinsic protein reorganization as the origin of the experimental observations.

Young Scholars Conference “Slavic World: Commonality and Diversity”. 21–22 May 2019. Session “Linguistics”

2019 ◽  
Vol 14 (1-2) ◽  
pp. 295-297
Author(s):  
Sergej A. Borisov
Keyword(s):  
Czech Republic ◽  
Middle Ages ◽  
The Czech Republic ◽  
International Context ◽  
Slavic Languages ◽  
Russian Academy Of Sciences ◽  
Current State ◽  
Wide Range ◽  
History Of ◽  
Academy Of Sciences

For more than twenty years, the Institute of Slavic Studies of the Russian Academy of Sciences celebrates the Day of Slavic Writing and Culture with a traditional scholarly conference.”. Since 2014, it has been held in the young scholars’ format. In 2019, participants from Moscow, St. Petersburg, Kazan, Togliatti, Tyumen, Yekaterinburg, and Rostov-on-Don, as well as Slovakia, the Czech Republic, Hungary, and Romania continued this tradition. A wide range of problems related to the history of the Slavic peoples from the Middle Ages to the present time in the national, regional and international context were discussed again. Participants talked about the typology of Slavic languages and dialects, linguo-geography, socio- and ethnolinguistics, analyzed formation, development, current state, and prospects of Slavic literatures, etc.

Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation

2021 ◽  
Vol 80 (5) ◽  
pp. 467-475
Author(s):  
Yu-Qing Li ◽  
C Shun Wong
Keyword(s):  
Cell Fate ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Neuronal Development ◽  
Adenosine Monophosphate ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Wild Type ◽  
Newborn Neuron ◽  
Negative Effect

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

scholarly journals Thermodynamics of Mg–Al Order-Disorder Reaction in MgAl2O4-Spinel: Constrained by Prolonged Annealing Experiments at 773–1123 K

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 872
Author(s):  
Yunlu Ma ◽  
Xinjian Bao ◽  
Xi Liu
Keyword(s):  
Spinel Structure ◽  
Structural Model ◽  
Molar Fraction ◽  
Thermodynamic Models ◽  
Mgal2o4 Spinel ◽  
Cation Order ◽  
Prolonged Annealing ◽  
Wide Range ◽  
History Of ◽  
Annealing Experiments

MgAl2O4-spinel has wide industrial and geological applications due to its special structural and physical–chemical features. It is presumably the most important endmember of complex natural spinel solid solutions, and therefore provides a structural model for a large group of minerals with the spinel structure. There exists a well known but still inadequately understood phenomenon in the structure of MgAl2O4-spinel, the Mg–Al cations readily exchanging their positions in response to variations of temperature, pressure, and composition. A large number of experiments were performed to investigate the Mg–Al cation order-disorder process usually quantified by the inversion parameter x (representing either the molar fraction of Al on the tetrahedral T-sites or the molar fraction of Mg on the octahedral M-sites in the spinel structure), and some thermodynamic models were thereby constructed to describe the x-T relation. However, experimental data at some key T were absent, so that the different performance of these thermodynamic models could not be carefully evaluated. This limited the interpolation and extrapolation of the thermodynamic models. By performing some prolonged annealing experiments with some almost pure natural MgAl2O4-spinel plates and quantifying the x values with single-crystal X-ray diffraction technique, we obtained some critical equilibrium x values at T down to 773 K. These new x-T data, along with those relatively reliable x values at relatively high T from early studies, clearly indicate that the CS94 Model (a model constructed by Carpenter and Salje in 1994) better describes the Mg–Al cation order-disorder reaction in MgAl2O4-spinel for a wide range of T. On the basis of the CS94 Model, a geothermometer was established, and its form is T-closure = 21362 × x3 − 12143 × x2 + 6401 × x − 10 (T-closure standing for the closure temperature of the Mg–Al cation exchange reaction). This geothermometer can be used to constrain the thermal history of the geological bodies containing MgAl2O4-spinel.

scholarly journals PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8298
Author(s):  
Hugo Christian Monroy-Ramirez ◽  
Marina Galicia-Moreno ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Arturo Santos ◽  
...  
Keyword(s):  
Liver Diseases ◽  
Metabolic Regulation ◽  
Structural Changes ◽  
Critical Role ◽  
The Body ◽  
Molecular Characteristics ◽  
Signal Pathways ◽  
Virus Infections ◽  
Physiological Processes ◽  
Hepatic Level

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

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