Functional group and stereochemical requirements for substrate binding by ghrelin O-acyltransferase revealed by unnatural amino acid incorporation

Cleverdon, Elizabeth R.; Davis, Tasha R.; Hougland, James L.

doi:10.1016/j.bioorg.2018.04.009

Cited by 11 publications

(30 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because ghrelin is the only predicted substrate for GOAT, GOAT inhibitors mimicking ghrelin have the potential for high selectivity for GOAT, leading to reduced off‐target effects. Various peptides with GOAT inhibiting activity were designed and the most recent study proposed a comprehensive catalogue of the interactions responsible for ghrelin recognition and acylation by GOAT with respect to designing and optimising ghrelin‐competitive GOAT inhibitors. Indeed, inhibiting GOAT activity will result in decreased AG and increased UAG.…”

Section: Ghrelin Levels In Patients With Pwsmentioning

confidence: 99%

Prader‐Willi syndrome: A model for understanding the ghrelin system

Tauber

Coupaye

Diene

et al. 2019

J Neuroendocrinology

View full text Add to dashboard Cite

Subsequent to the discovery of ghrelin as the endogenous ligand of growth hormone secretagogue receptor 1a, this unique gut peptide has been found to exert numerous physiological effects, such as appetite stimulation and lipid accumulation via the central regulating mechanisms in the hypothalamus, stimulation of gastric motility, regulation of glucose metabolism and brown fat thermogenesis, and modulation of stress, anxiety, taste sensation, reward‐seeking behaviour and the sleep/wake cycle. Prader‐Willi syndrome (PWS) has been described as a unique pathological state characterised by severe obesity and high circulating levels of ghrelin. It was hypothesised that hyperghrelinaemia would explain at least a part of the feeding behaviour and body composition of PWS patients, who are characterised by hyperphagia, an obsession with food and food‐seeking, and increased adiposity. Initially, the link between hyperghrelinaemia and growth hormone deficiency, which is observed in 90% of the children with PWS, was not fully understood. Over the years, however, the increasing knowledge on ghrelin, PWS features and the natural history of the disease has led to a more comprehensive description of the abnormal ghrelin system and its role in the pathophysiology of this rare and complex neurodevelopmental genetic disease. In the present study, we (a) present the current view of PWS; (b) explain its natural history, including recent data on the ghrelin system in PWS patients; and (c) discuss the therapeutic approach of modulating the ghrelin system in these patients and the first promising results.

show abstract

Section: Ghrelin Levels In Patients With Pwsmentioning

confidence: 99%

Prader‐Willi syndrome: A model for understanding the ghrelin system

Tauber

Coupaye

Diene

et al. 2019

J Neuroendocrinology

View full text Add to dashboard Cite

show abstract

“…We explored substitutions at glutamate 8 (E8) and phenylalanine 4 (F4) within the ghrelin-derived ligand based on previous studies demonstrating the involvement of these amino acids in ghrelin recognition by GOAT and GHS-R1a. (9,22,24,25) Incorporation of a threonine residue at E8 strengthens ligand binding to the GHS-R1a, and we found this substitution similarly increases ligand binding to GOAT (ligand 11) much more than either tyrosine or asparagine at this position. Both GOAT and GHS-R1a recognize the F4 residue, (22,26) with GOAT exhibiting a preference for large hydrophobic/aromatic amino acids at this position.…”

Section: Development Of a Specific High-affinity Peptide Ligand For Goatmentioning

confidence: 57%

“…Both GOAT and GHS-R1a recognize the F4 residue, (22,26) with GOAT exhibiting a preference for large hydrophobic/aromatic amino acids at this position. (9,24) Exploiting this preference using unnatural amino acids, we found incorporation of 1-naphthylalanine (Nal-1, compound 12) or 2-naphthylalanine (Nal-2, compound 13) at the F4 position substantially increased ligand binding to GOAT in the context of unacylated ligands, which exhibited no detectible binding to the GHS-R1a (Table 1).…”

Section: Development Of a Specific High-affinity Peptide Ligand For Goatmentioning

confidence: 99%

A remarkably specific ligand reveals ghrelinO-acyltransferase interacts with extracellular peptides and exhibits unexpected cellular localization for a secretory pathway enzyme

Campana

Davis

Cleverdon

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Ghrelin O-acyltransferase (GOAT) plays a central role in the maturation and activation of the peptide hormone ghrelin, which performs a wide range of endocrinological signaling roles. Using a tight-binding fluorescent ghrelin-derived peptide designed for high selectivity for GOAT over the ghrelin receptor GHS-R1a, we demonstrate that GOAT interacts with extracellular ghrelin and facilitates ligand cell internalization in both transfected cells and prostate cancer cells endogenously expressing GOAT. Coupled with enzyme mutagenesis, ligand uptake studies provide the first direct evidence supporting interaction of the putative histidine general base within GOAT with the ghrelin peptide acylation site. Our work provides a new understanding of GOAT's catalytic mechanism, establishes a key step required for autocrine/paracrine ghrelin signaling involving local reacylation by GOAT, and raises the possibility that other peptide hormones may exhibit similar complexity in their intercellular and organismal-level signaling pathways.

show abstract

“…As such, modulation of ghrelin signalling through GOAT inhibition presents a potential therapeutic avenue for treating obesity and T2DM . Structure‐activity analyses of ghrelin binding to GOAT have facilitated the development and optimization of GOAT inhibitors . In animal models of Siberian hamsters and rats, treatment with GOAT inhibitor induced reductions in food intake .…”

Section: Resultsmentioning

confidence: 99%

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

et al. 2019

View full text Add to dashboard Cite

Summary In early childhood, individuals with Prader‐Willi syndrome (PWS) experience excess weight gain and severe hyperphagia with food compulsivity, which often leads to early onset morbid obesity. Effective treatments for appetite suppression and weight control are currently unavailable for PWS. Our aim to further understand the pathogenesis of PWS led us to carry out a comprehensive search of the current and emerging therapies for managing hyperphagia and extreme weight gain in PWS. A literature search was performed using PubMed and the following keywords: “PWS” AND “therapy” OR “[drug name]”; reference lists, pharmaceutical websites, and the ClinicalTrials.gov registry were also reviewed. Articles presenting data from current standard treatments in PWS and also clinical trials of pharmacological agents in the pipeline were selected. Current standard treatments include dietary restriction/modifications, exercise, and growth hormone replacement, which appear to have limited efficacy for appetite and weight control in patients with PWS. The long‐term safety and effectiveness of bariatric surgery in PWS remains unknown. However, many promising pharmacotherapies are in development and, if approved, will bring much needed choices into the PWS pharmacological armamentarium. With the progress that is currently being made in our understanding of PWS, an effective treatment may not be far off.

show abstract

Functional group and stereochemical requirements for substrate binding by ghrelin O-acyltransferase revealed by unnatural amino acid incorporation

Cited by 11 publications

References 74 publications

Prader‐Willi syndrome: A model for understanding the ghrelin system

Prader‐Willi syndrome: A model for understanding the ghrelin system

A remarkably specific ligand reveals ghrelinO-acyltransferase interacts with extracellular peptides and exhibits unexpected cellular localization for a secretory pathway enzyme

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

Contact Info

Product

Resources

About