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1.
Amino Acid-Induced Impairment of Insulin Signaling and Involvement of G-Protein Coupling Receptor.
Zakaria, NF, Hamid, M, Khayat, ME
Nutrients. 2021;(7)
Abstract
Amino acids are needed for general bodily function and well-being. Despite their importance, augmentation in their serum concentration is closely related to metabolic disorder, insulin resistance (IR), or worse, diabetes mellitus. Essential amino acids such as the branched-chain amino acids (BCAAs) have been heavily studied as a plausible biomarker or even a cause of IR. Although there is a long list of benefits, in subjects with abnormal amino acids profiles, some amino acids are correlated with a higher risk of IR. Metabolic dysfunction, upregulation of the mammalian target of the rapamycin (mTOR) pathway, the gut microbiome, 3-hydroxyisobutyrate, inflammation, and the collusion of G-protein coupled receptors (GPCRs) are among the indicators and causes of metabolic disorders generating from amino acids that contribute to IR and the onset of type 2 diabetes mellitus (T2DM). This review summarizes the current understanding of the true involvement of amino acids with IR. Additionally, the involvement of GPCRs in IR will be further discussed in this review.
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2.
The complex relationship between metabolic syndrome and sweeteners.
Gómez-Fernández, AR, Santacruz, A, Jacobo-Velázquez, DA
Journal of food science. 2021;(5):1511-1531
Abstract
Metabolic syndrome is a multifactorial disorder originating from central obesity through a high caloric intake and a sedentary lifestyle. Metabolic syndrome increases the risk of type 2 diabetes (T2D) disease, converting it to one of the costliest chronic diseases, which reduces life quality. A strategy proposed by the food industry to reduce this problem is the generation of low-caloric products using sweeteners, which are compounds that can substitute sucrose, given their sweet taste. For many years, it was assumed that sweeteners did not have a relevant interaction in metabolism. However, recent studies have demonstrated that sweeteners interact either with metabolism or with gut microbiota, in which sweet-taste receptors play an essential role. This review presents an overview of the industrial application of most commonly consumed sweeteners. In addition, the interaction of sweeteners within the body, including their absorption, distribution, metabolism, gut microbiota metabolism, and excretion is also reviewed. Furthermore, the complex relationship between metabolic syndrome and sweeteners is also discussed, presenting results from in vivo and clinical trials. Findings from this review indicate that, in order to formulate sugar-free or noncaloric food products for the metabolic syndrome market, several factors need to be considered, including the dose, proportions, human metabolism, and interaction of sweeteners with gut microbiota and sweet-taste receptors. More clinical studies, including the metabolic syndrome, are needed to better understand the interaction of sweeteners with the human body, as well as their possible effect on the generation of dysbiosis.
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3.
An online GPCR structure analysis platform.
Kooistra, AJ, Munk, C, Hauser, AS, Gloriam, DE
Nature structural & molecular biology. 2021;(11):875-878
Abstract
We present an online, interactive platform for comparative analysis of all available G-protein coupled receptor (GPCR) structures while correlating to functional data. The comprehensive platform encompasses structure similarity, secondary structure, protein backbone packing and movement, residue-residue contact networks, amino acid properties and prospective design of experimental mutagenesis studies. This lets any researcher tap the potential of sophisticated structural analyses enabling a plethora of basic and applied receptor research studies.
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4.
Activation of the G-Protein-Coupled Receptor Rhodopsin by Water.
Chawla, U, Perera, SMDC, Fried, SDE, Eitel, AR, Mertz, B, Weerasinghe, N, Pitman, MC, Struts, AV, Brown, MF
Angewandte Chemie (International ed. in English). 2021;(5):2288-2295
Abstract
Visual rhodopsin is an important archetype for G-protein-coupled receptors, which are membrane proteins implicated in cellular signal transduction. Herein, we show experimentally that approximately 80 water molecules flood rhodopsin upon light absorption to form a solvent-swollen active state. An influx of mobile water is necessary for activating the photoreceptor, and this finding is supported by molecular dynamics (MD) simulations. Combined force-based measurements involving osmotic and hydrostatic pressure indicate the expansion occurs by changes in cavity volumes, together with greater hydration in the active metarhodopsin-II state. Moreover, we discovered that binding and release of the C-terminal helix of transducin is coupled to hydration changes as may occur in visual signal amplification. Hydration-dehydration explains signaling by a dynamic allosteric mechanism, in which the soft membrane matter (lipids and water) has a pivotal role in the catalytic G-protein cycle.
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5.
G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases.
DeLeon, C, Wang, DQ, Arnatt, CK
Frontiers in endocrinology. 2020;:578536
Abstract
There are gender differences between men and women in many physiological functions and diseases, which indicates that female sex hormones may be important. Traditionally, estrogen exerts its biological activities by activating two classical nuclear estrogen receptors, ESR1 and ESR2. However, the roles of estrogen in the regulation of physiological functions and the pathogenesis of diseases become more complicated with the identification of the G protein-coupled estrogen receptor (GPER1). Although many GPER1-specific ligands have been developed, the therapeutic mechanisms of exclusively targeting GPER1 are not yet well understood. Translational applications and clinical trial efforts for the identified GPER1 ligands have been focused primarily on the reproductive, cardiovascular, nervous, endocrine, and immune systems. More recently, research found that GPER1 may play an important role in regulating the digestive system. Cholesterol gallstone disease, a major biliary disease, has a higher prevalence in women than in men worldwide. Emerging evidence implies that GPER1 could play an important role, independent of the classical ESR1, in the pathophysiology of cholesterol gallstones in women. This review discusses the complex signaling pathways of three estrogen receptors, highlights the development of GPER1-specific ligands, and summarizes the latest advances in the role of GPER1 in the pathogenesis of gallstone formation.
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6.
Cellular mechanisms governing glucose-dependent insulinotropic polypeptide secretion.
Reimann, F, Diakogiannaki, E, Hodge, D, Gribble, FM
Peptides. 2020;:170206
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted from the upper small intestine, which plays an important physiological role in the control of glucose metabolism through its incretin action to enhance glucose-dependent insulin secretion. GIP has also been implicated in postprandial lipid homeostasis. GIP is secreted from enteroendocrine K-cells residing in the intestinal epithelium. K-cells sense a variety of components found in the gut lumen following food consumption, resulting in an increase in plasma GIP signal dependent on the nature and quantity of ingested nutrients. We review the evidence for an important role of sodium-coupled glucose uptake through SGLT1 for carbohydrate sensing, of free-fatty acid receptors FFAR1/FFAR4 and the monoacyl-glycerol sensing receptor GPR119 for lipid detection, of the calcium-sensing receptor CASR and GPR142 for protein sensing, and additional modulation by neurotransmitters such as somatostatin and galanin. These pathways have been identified through combinations of in vivo, in vitro and molecular approaches.
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7.
RhoA/C inhibits proliferation by inducing the synthesis of GPRC5A.
Richter, L, Oberländer, V, Schmidt, G
Scientific reports. 2020;(1):12532
Abstract
Rho GTPases are important regulators of many cellular functions like cell migration, adhesion and polarity. The molecular switches are often dysregulated in cancer. We detected Rho-dependent upregulation of the orphan seven-transmembrane receptor G-protein-coupled receptor family C group 5 member A (GPRC5A). GPRC5A is highly expressed in breast cancer whereas in lung cancer, it is often downregulated. Here, we analyzed the function of GPRC5A in breast epithelial and breast cancer cells. Activation or expression of RhoA/C led to GPRC5A-dependent inhibition of proliferation and reduction of the colony forming capacity of benign breast epithelial cells. This effect is based on an inhibition of EGFR signalling. Knockout of retinoic acid induced 3 (RAI3, the gene for GPRC5A) in breast cancer cells increased cell division, whereas Rho activation had no effect on proliferation. Knockout of RAI3 in benign breast epithelial cells led to decrease of EGFR expression and diminished proliferation.
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8.
An in-silico layer-by-layer adsorption study of the interaction between Rebaudioside A and the T1R2 human sweet taste receptor: modelling and biosensing perspectives.
Arodola, OA, Kanchi, S, Hloma, P, Bisetty, K, Asiri, AM, Inamuddin,
Scientific reports. 2020;(1):18391
Abstract
The human sweet taste receptor (T1R2) monomer-a member of the G-protein coupled receptor family that detects a wide variety of chemically and structurally diverse sweet tasting molecules, is known to pose a significant threat to human health. Protein that lack crystal structure is a challenge in structure-based protein design. This study focused on the interaction of the T1R2 monomer with rebaudioside A (Reb-A), a steviol glycoside with potential use as a natural sweetener using in-silico and biosensing methods. Herein, homology modelling, docking studies, and molecular dynamics simulations were applied to elucidate the interaction between Reb-A and the T1R2 monomer. In addition, the electrochemical sensing of the immobilised T1R2-Reb-A complex with zinc oxide nanoparticles (ZnONPs) and graphene oxide (GO) were assessed by testing the performance of multiwalled carbon nanotube (MWCNT) as an adsorbent experimentally. Results indicate a strong interaction between Reb-A and the T1R2 receptor, revealing the stabilizing interaction of the amino acids with the Reb-A by hydrogen bonds with the hydroxyl groups of the glucose moieties, along with a significant amount of hydrophobic interactions. Moreover, the presence of the MWCNT as an anchor confirms the adsorption strength of the T1R2-Reb-A complex onto the GO nanocomposite and supported with electrochemical measurements. Overall, this study could serve as a cornerstone in the development of electrochemical immunosensor for the detection of Reb-A, with applications in the food industry.
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9.
Oral Microbiota Profile Associates with Sugar Intake and Taste Preference Genes.
Esberg, A, Haworth, S, Hasslöf, P, Lif Holgerson, P, Johansson, I
Nutrients. 2020;(3)
Abstract
Oral microbiota ecology is influenced by environmental and host conditions, but few studies have evaluated associations between untargeted measures of the entire oral microbiome and potentially relevant environmental and host factors. This study aimed to identify salivary microbiota cluster groups using hierarchical cluster analyses (Wards method) based on 16S rRNA gene amplicon sequencing, and identify lifestyle and host factors which were associated with these groups. Group members (n = 175) were distinctly separated by microbiota profiles and differed in reported sucrose intake and allelic variation in the taste-preference-associated genes TAS1R1 (rs731024) and GNAT3 (rs2074673). Groups with higher sucrose intake were either characterized by a wide panel of species or phylotypes with fewer aciduric species, or by a narrower profile that included documented aciduric- and caries-associated species. The inferred functional profiles of the latter type were dominated by metabolic pathways associated with the carbohydrate metabolism with enrichment of glycosidase functions. In conclusion, this study supported in vivo associations between sugar intake and oral microbiota ecology, but it also found evidence for a variable microbiota response to sugar, highlighting the importance of modifying host factors and microbes beyond the commonly targeted acidogenic and acid-tolerant species. The results should be confirmed under controlled settings with comprehensive phenotypic and genotypic data.
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10.
The energetics of protein-lipid interactions as viewed by molecular simulations.
Corey, RA, Stansfeld, PJ, Sansom, MSP
Biochemical Society transactions. 2020;(1):25-37
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Abstract
Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Integral, membrane proteins are embedded in this bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is, therefore, important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe many computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular, we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bis-phosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation.