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更新于：2025-05-07

GOAT

更新于：2025-05-07

基本信息

别名

FKSG89、Ghrelin O-acyltransferase、GOAT

+ [6]

简介

Catalyzes ghrelin acylation at 'Ser-3' using preferentially octanoyl-CoA, hexanoyl-CoA and decanoyl-CoA as acyl-CoA donors leading to ghrelin activity (PubMed:18443287, PubMed:24045953, PubMed:25562443, PubMed:28134508). In vitro uses also acyl-CoA donors of different lengths from short-chain (C2) to long-chain fatty acids (C16) knowing that acyl-CoA donors from butanoyl-CoA (C4) to dodecanoyl-CoA (C12) are more efficient compared to longer acyl-CoA donors, such as myristoyl-CoA (C14) and palmitoyl-CoA (C16) that are not efficient (PubMed:18443287).

关联

项与 GOAT 相关的药物

RM-853

靶点

GOAT

作用机制

GOAT抑制剂

在研机构

Takeda Pharmaceutical Co., Ltd. [+1]

原研机构

Takeda Pharmaceutical Co., Ltd.

在研适应症

普拉德-威利综合症

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

GLWL-01

靶点

GOAT

作用机制

GOAT抑制剂

在研机构-

原研机构

Eli Lilly & Co.

在研适应症-

非在研适应症

2型糖尿病 [+1]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

LY-3073034

靶点

GOAT

作用机制

GOAT抑制剂

在研机构-

原研机构

Eli Lilly & Co.

在研适应症-

非在研适应症

2型糖尿病 [+1]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 GOAT 相关的临床试验

NCT03896516

/ Completed临床1/2期IIT

Manipulating Ghrelin Signaling Via GOAT Inhibition in Alcohol Use Disorder

Background:
People with alcohol use disorder (AUD) have trouble controlling their drinking. Medications can help some people with AUD but are not effective for many others. Researchers want to test new drugs to better treat the disease.
Objective:
To see if the investigational drug GLWL-01 is safe to use in people with alcohol problems. Also, to find out if the drug reduces the urge to drink alcohol.
Eligibility:
People ages 18-70 with Alcohol Use Disorder (AUD)
Design:
Participants will be screened under protocol 06-DA-N415.
Participants will be admitted to the inpatient facility, Clinical Research Unit (CRU) on the Johns Hopkins Bayview Medical Center for up to 21 days. They may leave the CRU on specified days pending approval. All their meals will be provided. They cannot drink alcohol.
Participants will take either the study drug or a placebo by mouth twice daily. They will not know which they are receiving.
Participants will complete many questionnaires.
Participants may have urine tests.
Participants will complete tasks on a computer.
Participants will have blood samples obtained on some study days.
Participants will taste and indicate their preference for sweet liquids.
Participants' blood pressure, pulse, respiratory rate, body temperature and weight, heart rate and rhythm will be measured.
Participants will have breath testing to obtain information about smoking.
Participants will be exposed to alcohol cues, water, and food cues in a bar-like room. Cues are things that might make them feel the urge to eat or drink alcohol.
Participants will take part in a virtual buffet experiment - They will wear a virtual reality headset, walk around a virtual room, and select virtual food and drink.

开始日期2021-06-22

申办/合作机构

National Institute on Drug Abuse

NCT03641417

/ CompletedN/AIIT

BARI-INSIGHT: A Double-blind, Placebo-controlled, Within-subject, Cross-over Mechanistic Study Investigating the Role of Ghrelin in Regulating Appetite and Energy Intake in Patients Following Bariatric Surgery

Bariatric surgery helps patients with severe obesity to lose weight, cures and prevents diseases linked to obesity and reduces the risk of death. Unfortunately, 1 in 5 patients do not respond well to surgery in terms of weight loss and health gains. Thus, maximising weight loss and health benefits after surgery is critical. This study aims to gain insight into the role that the appetite-stimulating hormone, ghrelin, plays in driving appetite and energy intake in patients with poor weight loss (≤ 20% total body weight) following bariatric surgery. This will guide future work to develop pharmacological treatments for obesity, both as standalone treatments and adjuncts to bariatric surgery.
Participants will be invited to attend the Clinical Research Facility at University College London Hospital for a screening visit and six study visits. Active ghrelin levels will be reduced by inhibiting ghrelin-o-acyl-transferase (GOAT), the enzyme needed to generate active ghrelin (acyl ghrelin, AG). Participants will be randomised to receive GLWL-01 (GOAT inhibitor) 300mg BD or placebo for a 10 day study cycle. The effect of AG reduction on appetite and energy intake will be evaluated through both fixed-energy and ad libitum meal tests on day 7 and 10, respectively. Measures of body weight and composition, appetite and food cravings will be performed in addition to biochemical profiling of circulating gut hormone, adipokine and cytokine levels. Targeted physical examinations and assessment of adverse events will be performed. Safety monitoring calls will be conducted 2 and 7 days after the last dose. Following a 6-10 week washout period, participants will cross over to receive either placebo or GLWL-01 300mg BD and undergo a second study cycle, with all measures repeated.

开始日期2019-02-15

申办/合作机构

University College London

NCT03274856

/ Completed临床2期

A Phase 2 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of GLWL-01 in the Treatment of Patients With Prader-Willi Syndrome

The aim of this study is to evaluate efficacy, safety, and pharmacokinetics of GLWL-01 in the treatment of patients with Prader-Willi Syndrome (PWS).

开始日期2018-02-20

申办/合作机构

GLWL Research, Inc.

100 项与 GOAT 相关的临床结果

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100 项与 GOAT 相关的转化医学

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0 项与 GOAT 相关的专利（医药）

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304

项与 GOAT 相关的文献（医药）

2025-03-01·Journal of Animal Physiology and Animal Nutrition

Regulatory Effects of Copper on Ghrelin Secretion in Rat Fundic Glands

Article

作者: Jia, Shuang ; Wang, Zhongshen ; Li, Meng ; Yang, Wenyan ; Yang, Lianyu ; Du, Tianyang ; Sun, Rui

ABSTRACTCopper (Cu) is an effective additive in feed for promoting growth. Growth dan axis comprising growth hormone (GH), somatostatin (SS) and GH‐releasing hormone (GHRH), with ghrelin regulating their release. The growth‐promoting effects of Cu are closely related to ghrelin, but the specific mechanism behind the relationship remains unknown. We investigated the adjustment of ghrelin synthesis and secretion by Cu. Sprague–Dawley rats were fed basal diets with an addition of 0, 120 or 240 mg/kg Cu sulfate for 28 day to establish a growth‐promoting model. Signalling molecules relevant to ghrelin synthesis and secretion were detected and mechanistically explored using enzyme‐linked immunosorbent assay, quantitative reverse‐transcription polymerase chain reaction and Western blot analysis. The 120 mg/kg supplement improved growth performance; significantly increased the serum levels of ghrelin, ghrelin O‐acyltransferase (GOAT), acylated ghrelin (AG), GH, and reactive oxygen species (ROS) and decreased those of SS; significantly increased the mRNA and protein expression of ghrelin, GOAT, ghrelin receptor (GHS‐R1α), and activator protein 1 (AP‐1); increased the phosphorylation ratio of JNK and p38 MAPK; and inhibited the mRNA and protein expression of SS and SS receptor subtype 2 (SSTR2) in gastric fundic gland tissues. Thus, Cu may affect gastric ghrelin synthesis at the transcriptional level by activating the JNK/p38 MAPK pathway through increased ROS levels and regulating the activation of the downstream redox‐sensitive transcription factor AP‐1. SS plays a crucial determinant role in ghrelin regulation via intragastric Cu. Cu promotes GOAT activity and ghrelin secretion by inhibiting SS secretion, affecting AG levels, and promoting ghrelin acylation through ghrelin/GOAT/GHS‐R1α system, modulating ghrelin secretion.

2024-12-16·Journal of Biomolecular Structure and Dynamics

Genetic insights into obesity: in silico identification of pathogenic SNPs in MBOAT4 gene and their structural molecular dynamics consequences

Article

作者: Asif, Uzma ; Sehgal, Sheikh Arslan ; Azmi, Muhammad Bilal ; Suri, Azeema ; Abedin, Mariam Farhan Essa ; Qureshi, Shamim Akhtar ; Musani, Sarah ; Ahmed, Syed Danish Haseen

Membrane Bound O-Acyltransferase Domain-Containing 4 (MBOAT4) protein catalyzes ghrelin acylation, leading to prominent ghrelin activity, hence characterizing its role as an anti-obesity target. We extracted 625 exonic SNPs from the ENSEMBL database and one phenotype-based missense mutation associated with obesity (A46T) from the HGMD (Human Gene Mutation Database). These were differentiated on deleterious missense SNPs of the MBOAT4 gene through MAF (minor allele frequency: <0.01) cut-off criteria in relation to some bioinformatics-based supervised machine learning tools. We found 8 rare-coding and harmful missense SNPs. The consensus classifier (PredictSNP) tool predicted that the SNP (G57S, C: rs561065025) was the most pathogenic. Several trained in silico algorithms have predicted decreased protein stability [ΔΔG (kcal/mol)] function in the presence of these rare-coding pathogenic mutations in the MBOAT4 gene. Then, a stereochemical quality check (i.e. validation and assessment) of the 3D model was performed, followed by a blind cavity docking approach, used to search for druggable cavities and molecular interactions with citrus flavonoids of the Rutaceae family, ranked with energetic estimations. Significant interactions with Phloretin 3',5'-Di-C-Glucoside were also observed at R304, W306, N307, A311, L314 and H338 with (iGEMDOCK: -95.82 kcal/mol and AutoDock: -7.80 kcal/mol). The RMSD values and other variables of MD simulation analyses on this protein further validated its significant interactions with the above flavonoids. The MBOAT4 gene and its molecular interactions could serve as an interventional future anti-obesity target. The current study's findings will benefit future prospects for large population-based studies and drug development, particularly for generating personalized medicine.Communicated by Ramaswamy H. Sarma.

2024-12-01·Neuropeptides

Physiologically relevant lactate accumulation from exercise or peripheral injection does not alter central or peripheral appetite signaling in mice

Article

作者: Finch, Michael S ; McCarthy, Seth F ; MacPherson, Rebecca E K ; MacPherson, Rebecca E.K. ; Hazell, Tom J. ; McCarthy, Seth F. ; Finch, Michael S. ; Hazell, Tom J

Lactate has been implicated in exercise-induced appetite suppression though little work has explored the mechanisms underpinning its role. Recent work suggests lactate accumulation via exercise and intracerebroventricular injection can alter central appetite regulating pathways, though a supraphysiological dose of lactate was administered centrally and there was no assessment of peripheral appetite markers. Therefore, we examined how physiologically relevant lactate accumulation via exercise or intraperitoneal injection altered central and peripheral appetite signaling pathways and whether the lactate dehydrogenase inhibitor oxamate could blunt any exercise effect. Forty 10-week-old C57BL/6 J male mice (n = 10/group) were assigned to either: 1) sedentary (SED + SAL; saline); 2) exercise (EX+SAL; saline); 3) exercise with oxamate (EX+OX; 750 mg‧kg^-1 body mass); or 4) lactate (SED + LAC; 1.0 g‧kg^-1 body mass). Blood, stomach, and hypothalamus samples were collected ∼2 h post-exercise/injection. Though oxamate blunted exercise-induced lactate accumulation compared to the EX+SAL condition (P = 0.044, d = 0.73), there were no differences in circulating acylated ghrelin or stomach ghrelin O-acyltransferase content between groups (P > 0.213, η_p²<0.125). There were also no differences in hypothalamic content for neuropeptide Y, proopiomelanocortin, agouti-related peptide, and alpha melanocyte-stimulating hormone (P > 0.150, η_p²<0.170). Exercise did increase phosphorylated-total signal transducer and activator of transcription 3 (pSTAT3) compared to EX+OX (p = 0.065, d = 1.23) but there were no differences in other markers of lactate signaling: phosphorylated-total adenosine monophosphate activated protein kinase, and protein kinase b (P > 0.121, η_p²<0.160). Our results suggest that lactate accumulation due to exercise or peripheral injection does not alter central or peripheral appetite signaling when measured 2 h post-exercise/injection, though pSTAT3 was blunted with oxamate.