Details for: ORM1

Gene ID: 5004

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: ORM1

Ensembl ID: ENSG00000229314

Description: orosomucoid 1

Cell Significance Landscape

Associated with

Significant Cells

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

  • hepatocyte CL0000182
    CSI 7.99
    rCSI 14.31%
    PRS 95.46
  • midzonal region hepatocyte CL0019028
    CSI 5.64
    rCSI 13.24%
    PRS 94.62
  • intrahepatic cholangiocyte CL0002538
    CSI 4.32
    rCSI 10.36%
    PRS 96.52
  • centrilobular region hepatocyte CL0019029
    CSI 3.44
    rCSI 8.99%
    PRS 93.79
  • hepatic stellate cell CL0000632
    CSI 3.1
    rCSI 11.61%
    PRS 95.59
  • foveolar cell of stomach CL0002179
    CSI 3.09
    rCSI 6.57%
    PRS 97.32
  • Kupffer cell CL0000091
    CSI 2.79
    rCSI 6.39%
    PRS 97.42
  • neutrophil CL0000775
    CSI 2.73
    rCSI 15.28%
    PRS 94.61
  • periportal region hepatocyte CL0019026
    CSI 2.6
    rCSI 10.13%
    PRS 94.22
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 1.88
    rCSI 5.8%
    PRS 97.25

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.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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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 [ORM1](/details-gene/5004) encodes orosomucoid 1, also known as alpha-1-acid glycoprotein 1, a heavily glycosylated plasma protein primarily synthesized in the liver. As a major acute-phase reactant, its circulating levels increase significantly in response to inflammation, infection, and tissue injury. Functional annotations highlight its role in modulating the immune system, particularly in the [acute-phase response](/details-go/GO:0006953) and the regulation of cytokine production. **Overall**, expression data reveals that [ORM1](/details-gene/5004) is most significantly and abundantly expressed in [hepatocytes](/details-cell/CL0000182), underscoring the liver's central role in its synthesis and secretion into the bloodstream. Its clinical relevance is noted under OMIM entry [153245](https://omim.org/entry/138600). ## Cellular Roles and Expression Landscape The expression profile of [ORM1](/details-gene/5004) points to a highly specialized function centered on the liver and its interaction with the innate immune system. **Overall**, the gene's significance is highest in liver parenchymal cells. It is the top marker for [hepatocytes](/details-cell/CL0000182) (CSI: 7.99), with strong significance also observed in specific zonal hepatocytes like [midzonal](/details-cell/CL0019028) and [centrilobular region hepatocytes](/details-cell/CL0019029), as well as [intrahepatic cholangiocytes](/details-cell/CL0002538). This pattern is consistent with its established role as a major protein secreted by the liver into circulation [Link](https://pubmed.ncbi.nlm.nih.gov/2822385/). Beyond its primary site of synthesis, [ORM1](/details-gene/5004) also shows significant expression in key immune and stromal cells within the liver microenvironment, including [Kupffer cells](/details-cell/CL0000091) (the resident macrophages of the liver) and [hepatic stellate cells](/details-cell/CL0000632). Furthermore, its notable significance in circulating [neutrophils](/details-cell/CL0000775) suggests a secondary role where it may be stored in granules and released locally at sites of inflammation. This dual expression pattern in both liver and immune cells highlights its function as a systemic modulator synthesized centrally and a potential local effector deployed by immune cells. ## Pathways and Molecular Function The molecular functions of [ORM1](/details-gene/5004) are tightly linked to the regulation of systemic inflammation and hemostasis. As an extracellular protein found in blood plasma and exosomes ([GO:0070062](/details-go/GO:0070062)), its primary activities are executed outside the cell. Its involvement in the [acute-phase response](/details-go/GO:0006953) and [inflammatory response](/details-go/GO:0006954) is its most prominent annotated function. This is further specified by its role in regulating cytokine production, where it can exert both positive and negative control, for instance, through the [negative regulation of interleukin-6 production](/details-go/GO:0032715) and the [positive regulation of tumor necrosis factor production](/details-go/GO:0032760). This immunomodulatory capacity aligns with its expression in both cytokine-producing [hepatocytes](/details-cell/CL0000182) and immune-responsive [Kupffer cells](/details-cell/CL0000091). Reactome pathway analysis reinforces this immunological role, placing [ORM1](/details-gene/5004) within the [Innate immune system](/details-reactome/R-HSA-168249) and, more specifically, in [Neutrophil degranulation](/details-reactome/R-HSA-6798695). Its presence in pathways like [Hemostasis](/details-reactome/R-HSA-109582) and [Platelet activation, signaling and aggregation](/details-reactome/R-HSA-76002) is consistent with its annotation to platelet granules ([GO:0031093](/details-go/GO:0031093)), suggesting it may also modulate coagulation and wound healing processes during inflammatory events. ## Research Directions The dual-expression profile of [ORM1](/details-gene/5004) in both the liver and in immune cell granules presents intriguing questions about its specific local versus systemic functions. Future research could focus on dissecting these distinct roles. ### Proposed Hypotheses 1. **Paracrine Regulation within the Liver:** Given its expression in [hepatocytes](/details-cell/CL0000182) and [Kupffer cells](/details-cell/CL0000091), [ORM1](/details-gene/5004) secreted by hepatocytes may act locally as a paracrine signal to modulate the inflammatory activation state of neighboring Kupffer cells, thereby fine-tuning the liver's innate immune response. 2. **Local Immunomodulation by Neutrophils:** The presence of [ORM1](/details-gene/5004) in [neutrophil](/details-cell/CL0000775) granules suggests that its rapid degranulation at sites of infection or injury provides a high local concentration that acts to directly modulate the activity of adjacent immune cells, a function distinct from the more slowly regulated systemic levels produced by the liver. ### Key Experiment To test the hypothesis of paracrine regulation within the liver (Hypothesis 1), a co-culture experiment could be designed. Primary human [hepatocytes](/details-cell/CL0000182) would be stimulated with an inflammatory agent like IL-1β to induce [ORM1](/details-gene/5004) secretion. The conditioned medium from these hepatocytes would then be transferred to a culture of primary human [Kupffer cells](/details-cell/CL0000091) that have been activated with LPS. The effect of the hepatocyte-secreted factors on Kupffer cell cytokine production (e.g., TNF-alpha, IL-6) would be measured by ELISA or multiplex assay. The specific contribution of [ORM1](/details-gene/5004) could be confirmed by repeating the experiment with conditioned medium that has been depleted of [ORM1](/details-gene/5004) using an immunoaffinity column or neutralized with a specific antibody. ### Therapeutic Potential As a natural immunomodulatory protein, [ORM1](/details-gene/5004) has potential as a biologic therapeutic. Its documented ability to negatively regulate the production of pro-inflammatory cytokines like IL-6 and TNF-alpha suggests that administration of recombinant human [ORM1](/details-gene/5004) could be a strategy for treating conditions characterized by excessive inflammation or cytokine storms. Rather than being a target for inhibition, its activation or supplementation represents a more plausible therapeutic avenue. The main challenge would be to achieve and maintain therapeutic concentrations for a protein with a relatively short plasma half-life.

Genular Protein ID: 3445804824

Symbol: A1AG1_HUMAN

Name: Alpha-1-acid glycoprotein 1

UniProtKB Accession Codes:

P02763 B7ZKQ5 Q5T539 Q5U067 Q8TC16

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 CarbonylDB 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 147 DrugCentral 1 EMBL 19 Ensembl 1 EvolutionaryTrace 1 GO 16 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PIR 1 PIRSF 1 PRIDE 1 PRINTS 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 SASBDB 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2409529

Title: Structure of the human alpha 1-acid glycoprotein gene: sequence homology with other human acute phase protein genes.

PubMed ID: 2409529

DOI: 10.1093/nar/13.11.3941

PubMed ID: 3770479

Title: Molecular cloning and nucleotide sequence of human alpha 1 acid glycoprotein cDNA.

PubMed ID: 3770479

DOI: 10.1016/0378-1119(86)90051-x

PubMed ID: 2822385

Title: Structure and expression of the genes coding for human alpha 1-acid glycoprotein.

PubMed ID: 2822385

DOI: 10.1002/j.1460-2075.1987.tb02503.x

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15164053

Title: DNA sequence and analysis of human chromosome 9.

PubMed ID: 15164053

DOI: 10.1038/nature02465

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 4711474

Title: Structure of alpha 1-acid glycoprotein. The complete amino acid sequence, multiple amino acid substitutions, and homology with the immunoglobulins.

PubMed ID: 4711474

DOI: 10.1021/bi00738a026

PubMed ID: 4561179

Title: Isolation and partial characterization of the cyanogen bromide fragments of alpha 1-acid glycoprotein and the elucidation of the amino acid sequence of the carboxyl-terminal cyanogen bromide fragment.

PubMed ID: 4561179

DOI: 10.1021/bi00770a022

PubMed ID: 4603214

Title: The disulfide bonds of alpha1-acid glycoprotein.

PubMed ID: 4603214

DOI: 10.1021/bi00710a006

PubMed ID: 1567356

Title: Analysis of the five glycosylation sites of human alpha 1-acid glycoprotein.

PubMed ID: 1567356

DOI: 10.1042/bj2830105

PubMed ID: 12754519

Title: Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry.

PubMed ID: 12754519

DOI: 10.1038/nbt827

PubMed ID: 15253437

Title: A new strategy for identification of N-glycosylated proteins and unambiguous assignment of their glycosylation sites using HILIC enrichment and partial deglycosylation.

PubMed ID: 15253437

DOI: 10.1021/pr034112b

PubMed ID: 15084671

Title: A proteomic analysis of human bile.

PubMed ID: 15084671

DOI: 10.1074/mcp.m400015-mcp200

PubMed ID: 14760718

Title: Screening for N-glycosylated proteins by liquid chromatography mass spectrometry.

PubMed ID: 14760718

DOI: 10.1002/pmic.200300556

PubMed ID: 16335952

Title: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.

PubMed ID: 16335952

DOI: 10.1021/pr0502065

PubMed ID: 17008009

Title: Selective binding of imatinib to the genetic variants of human alpha1-acid glycoprotein.

PubMed ID: 17008009

DOI: 10.1016/j.bbagen.2006.08.015

PubMed ID: 16740002

Title: Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry.

PubMed ID: 16740002

DOI: 10.1021/pr050492k

PubMed ID: 17321687

Title: The drug binding site of human alpha1-acid glycoprotein: insight from induced circular dichroism and electronic absorption spectra.

PubMed ID: 17321687

DOI: 10.1016/j.bbagen.2007.01.009

PubMed ID: 19159218

Title: Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.

PubMed ID: 19159218

DOI: 10.1021/pr8008012

PubMed ID: 19838169

Title: Enrichment of glycopeptides for glycan structure and attachment site identification.

PubMed ID: 19838169

DOI: 10.1038/nmeth.1392

PubMed ID: 22171320

Title: Human urinary glycoproteomics; attachment site specific analysis of N- and O-linked glycosylations by CID and ECD.

PubMed ID: 22171320

DOI: 10.1074/mcp.m111.013649

PubMed ID: 18823996

Title: The 1.8-A crystal structure of alpha1-acid glycoprotein (Orosomucoid) solved by UV RIP reveals the broad drug-binding activity of this human plasma lipocalin.

PubMed ID: 18823996

DOI: 10.1016/j.jmb.2008.09.020

PubMed ID: 9050929

Title: Human orosomucoid polymorphism: molecular basis of the three common ORM1 alleles, ORM1*F1, ORM1*F2, and ORM1*S.

PubMed ID: 9050929

DOI: 10.1007/s004390050378

Sequence Information:

  • Length: 201
  • Mass: 23540
  • Checksum: CC2AD1FD9C8CBFA4
  • Sequence:
    • MALSWVLTVL SLLPLLEAQI PLCANLVPVP ITNATLDRIT GKWFYIASAF RNEEYNKSVQ 
EIQATFFYFT PNKTEDTIFL REYQTRQDQC IYNTTYLNVQ RENGTISRYV GGQEHFAHLL 
ILRDTKTYML AFDVNDEKNW GLSVYADKPE TTKEQLGEFY EALDCLRIPK SDVVYTDWKK 
DKCEPLEKQH EKERKQEEGE S