Details for: MBOAT4

Gene ID: 619373

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: MBOAT4

Ensembl ID: ENSG00000177669

Description: membrane bound O-acyltransferase domain containing 4

Selected Context(s):  Overall

Cell Significance Landscape

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Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • P/D1 enteroendocrine cell CL0002268
    CSI 1
    rCSI 5.46%
    PRS 99.96

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [MBOAT4](/details-gene/619373) (Membrane Bound O-Acyltransferase Domain Containing 4) is a protein-coding gene located on chromosome 8. It encodes a multipass membrane protein that functions as the enzyme ghrelin O-acyltransferase (GOAT). This enzyme is critically responsible for the post-translational modification of the peptide hormone ghrelin, a key regulator of appetite, energy homeostasis, and growth hormone release. [MBOAT4](/details-gene/619373) catalyzes the attachment of an eight-carbon fatty acid (octanoylation) to a serine residue on proghrelin, a step that is essential for ghrelin's biological activity ([Link](https://doi.org/10.1073/pnas.0800708105)). Consistent with this highly specialized function, its expression is almost exclusively restricted to ghrelin-producing cells, most notably the [P/D1 enteroendocrine cell](/details-cell/CL0002268) of the gastric fundus. ## Cellular Roles and Expression Landscape The expression of [MBOAT4](/details-gene/619373) is remarkably specific, highlighting its specialized biological role. **Overall**, the gene's expression profile shows it to be a definitive and highly significant marker for the [P/D1 enteroendocrine cell](/details-cell/CL0002268) (CSI: 1.00). These specialized endocrine cells, located primarily in the lining of the stomach, are the main source of circulating ghrelin. The exceptionally high significance of [MBOAT4](/details-gene/619373) in this cell type underscores its indispensable role in the synthesis of active ghrelin. This restricted expression pattern is consistent with its dedicated function in ghrelin acylation, suggesting its activity is tightly controlled and confined to the site of hormone production. The lack of significant expression in other cell types implies a very narrow physiological function, centered on metabolic and endocrine regulation mediated by ghrelin. ## Pathways and Molecular Function The molecular function of [MBOAT4](/details-gene/619373) is well-defined and centered on protein and lipid metabolism within the [endoplasmic reticulum](/details-go/GO:0005783). - **Enzymatic Activity:** As a member of the membrane-bound O-acyltransferase family, [MBOAT4](/details-gene/619373) exhibits [O-acyltransferase activity](/details-go/GO:0008374), specifically [serine o-acyltransferase activity](/details-go/GO:0016412). It utilizes medium-chain fatty acyl-CoAs as substrates to modify target proteins. - **Ghrelin Activation:** Its primary and most well-characterized role is in the [Synthesis, secretion, and deacylation of ghrelin](/details-reactome/R-HSA-422085) pathway. Within the [endoplasmic reticulum membrane](/details-go/GO:0005789), the GOAT enzyme, encoded by [MBOAT4](/details-gene/619373), catalyzes the transfer of an octanoyl group to the serine-3 residue of the ghrelin peptide ([Link](https://doi.org/10.1073/pnas.0800708105)). This [peptidyl-serine octanoylation](/details-go/GO:0018191) is a unique and essential post-translational modification that enables ghrelin to bind and activate its receptor, the growth hormone secretagogue receptor (GHSR). - **Broader Context:** More generally, this function places [MBOAT4](/details-gene/619373) within the biological processes of [lipid modification](/details-go/GO:0030258) and [peptide hormone processing](/details-go/GO:0016486), highlighting a key mechanism by which lipid metabolism is directly integrated with endocrine signaling. ## Research Directions The highly specific and critical function of [MBOAT4](/details-gene/619373) in metabolism makes it a compelling subject for further investigation and a promising therapeutic target. ### Proposed Hypotheses: 1. **Role in Metabolic Heterogeneity:** Given its singular role in activating the "hunger hormone," naturally occurring genetic variants in [MBOAT4](/details-gene/619373) that alter its enzymatic efficiency or expression levels are likely significant contributors to the inter-individual variability observed in appetite, body weight regulation, and susceptibility to metabolic diseases such as obesity and anorexia. 2. **Novel Peptide Substrates:** While ghrelin is the only confirmed substrate, the existence of other MBOAT family members with diverse substrates suggests that [MBOAT4](/details-gene/619373) may acylate other, as-yet-unidentified peptide hormones or proteins, potentially within the same or different endocrine cell types, thereby modulating other physiological pathways. ### Key Experiments: To test the hypothesis that [MBOAT4](/details-gene/619373) variants contribute to metabolic heterogeneity (Hypothesis 1), a multi-pronged approach could be employed. First, targeted sequencing of the [MBOAT4](/details-gene/619373) gene in large human cohorts with extreme metabolic phenotypes (e.g., morbid obesity, constitutional thinness) could identify rare or common variants associated with these traits. Subsequently, the functional impact of any identified non-synonymous variants could be directly assessed using an *in vitro* cell-based assay. This would involve co-transfecting cells with a specific [MBOAT4](/details-gene/619373) variant and a ghrelin expression vector, followed by mass spectrometry analysis of the secreted ghrelin to quantify the ratio of acylated (active) to unacylated (inactive) hormone, thereby measuring the variant's enzymatic capacity. ### Therapeutic Potential: [MBOAT4](/details-gene/619373) represents a highly attractive therapeutic target for metabolic disorders due to its "gatekeeper" role in ghrelin activation. - **Inhibition:** Development of specific [MBOAT4](/details-gene/619373) inhibitors is a promising strategy for treating obesity and type 2 diabetes. By blocking ghrelin acylation, such a drug would decrease levels of the active, orexigenic hormone, leading to reduced appetite and potentially improved glycemic control. The high tissue specificity of [MBOAT4](/details-gene/619373) is a major advantage, suggesting that a targeted inhibitor could have minimal off-target effects. Studies have already explored the development of such inhibitors ([Link](https://doi.org/10.1021/acs.biochem.6b01008)). - **Activation:** Conversely, strategies to enhance [MBOAT4](/details-gene/619373) activity or develop enzyme activators could be beneficial in conditions characterized by pathological weight loss and anorexia, such as cancer-associated cachexia or sarcopenia, by increasing appetite and promoting an anabolic state.

Genular Protein ID: 742261518

Symbol: MBOA4_HUMAN

Name: Membrane-bound O-acyltransferase domain-containing protein 4

UniProtKB Accession Codes:

Q96T53 B1Q003

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEBI 44 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 3 Ensembl 1 GO 8 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 InterPro 2 KEGG 1 MANE-Select 1 MIM 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 1 RefSeq 2 Rhea 44 SMR 1 STRING 1 SwissLipids 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 18443287

Title: Ghrelin octanoylation mediated by an orphan lipid transferase.

PubMed ID: 18443287

DOI: 10.1073/pnas.0800708105

PubMed ID: 16421571

Title: DNA sequence and analysis of human chromosome 8.

PubMed ID: 16421571

DOI: 10.1038/nature04406

PubMed ID: 24045953

Title: Architectural organization of the metabolic regulatory enzyme ghrelin O-acyltransferase.

PubMed ID: 24045953

DOI: 10.1074/jbc.m113.510313

PubMed ID: 25562443

Title: Structure-activity analysis of human ghrelin O-acyltransferase reveals chemical determinants of ghrelin selectivity and acyl group recognition.

PubMed ID: 25562443

DOI: 10.1021/bi5010359

PubMed ID: 28134508

Title: Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation.

PubMed ID: 28134508

DOI: 10.1021/acs.biochem.6b01008

Sequence Information:

  • Length: 435
  • Mass: 49716
  • Checksum: 0CF97AAE734F24A7
  • Sequence:
    • MEWLWLFFLH PISFYQGAAF PFALLFNYLC IMDSFSTRAR YLFLLTGGGA LAVAAMGSYA 
VLVFTPAVCA VALLCSLAPQ QVHRWTFCFQ MSWQTLCHLG LHYTEYYLHE PPSVRFCITL 
SSLMLLTQRV TSLSLDICEG KVKAASGGFR SRSSLSEHVC KALPYFSYLL FFPALLGGSL 
CSFQRFQARV QGSSALHPRH SFWALSWRGL QILGLECLNV AVSRVVDAGA GLTDCQQFEC 
IYVVWTTAGL FKLTYYSHWI LDDSLLHAAG FGPELGQSPG EEGYVPDADI WTLERTHRIS 
VFSRKWNQST ARWLRRLVFQ HSRAWPLLQT FAFSAWWHGL HPGQVFGFVC WAVMVEADYL 
IHSFANEFIR SWPMRLFYRT LTWAHTQLII AYIMLAVEVR SLSSLWLLCN SYNSVFPMVY 
CILLLLLAKR KHKCN