Details for: NAALADL1

Gene ID: 10004

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: NAALADL1

Ensembl ID: ENSG00000168060

Description: N-acetylated alpha-linked acidic dipeptidase like 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • glutamatergic neuron CL0000679
    CSI 13.27
    rCSI 27.27%
    PRS 93.94
  • glial cell CL0000125
    CSI 8.98
    rCSI 34.19%
    PRS 96.42
  • neural progenitor cell CL0011020
    CSI 8.72
    rCSI 38.37%
    PRS 94.1
  • colonocyte CL1000347
    CSI 8.63
    rCSI 12.36%
    PRS 98.56
  • GABAergic neuron CL0000617
    CSI 7.85
    rCSI 26.29%
    PRS 93.65
  • colon epithelial cell CL0011108
    CSI 6.43
    rCSI 6.74%
    PRS 98.61
  • hematopoietic stem cell CL0000037
    CSI 6.13
    rCSI 4.07%
    PRS 99.21
  • goblet cell CL0000160
    CSI 5.69
    rCSI 5.37%
    PRS 98.43
  • common myeloid progenitor CL0000049
    CSI 4.66
    rCSI 3.77%
    PRS 99.48
  • enterocyte CL0000584
    CSI 4.29
    rCSI 6.92%
    PRS 97.71
  • hematopoietic multipotent progenitor cell CL0000837
    CSI 4.28
    rCSI 10.31%
    PRS 99.52
  • activated type II NK T cell CL0000931
    CSI 3.67
    rCSI 4.13%
    PRS 99.47
  • intestinal tuft cell CL0019032
    CSI 3.17
    rCSI 4.85%
    PRS 98.49
  • group 3 innate lymphoid cell CL0001071
    CSI 3.17
    rCSI 2.38%
    PRS 99.22
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 2.95
    rCSI 3.56%
    PRS 99.64
  • brush cell CL0002204
    CSI 2.78
    rCSI 5.5%
    PRS 98.47
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.65
    rCSI 2.39%
    PRS 98.89
  • enterocyte of epithelium of small intestine CL1000334
    CSI 0.48
    rCSI 7.44%
    PRS 98.95

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

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • 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 N-acetylated alpha-linked acidic dipeptidase like 1, or **[NAALADL1](/details-gene/10004)**, is a protein-coding gene located on chromosome 11q13.1. Functionally, it is characterized as a zinc-dependent metallopeptidase with both aminopeptidase and carboxypeptidase activities, playing a role in peptide catabolism. Expression data from the **Overall** context reveals that **[NAALADL1](/details-gene/10004)** is a highly significant gene in the central nervous system, with prominent expression in [glutamatergic neuron](/details-cell/CL0000679)s and [glial cell](/details-cell/CL0000125)s. It is also a key marker for epithelial cells of the gastrointestinal tract, including [colonocyte](/details-cell/CL1000347)s and [enterocyte](/details-cell/CL0000584), suggesting a dual role in both neural function and intestinal biology. ## Cellular Roles and Expression Landscape The expression profile of **[NAALADL1](/details-gene/10004)** highlights its specific and significant roles in two primary biological systems: the nervous system and the gastrointestinal tract. **Overall**, the gene shows its highest significance in the nervous system. It is most prominent in [glutamatergic neuron](/details-cell/CL0000679) (CSI: 13.27), followed by [glial cell](/details-cell/CL0000125) (CSI: 8.98) and [GABAergic neuron](/details-cell/CL0000617) (CSI: 7.85). Its strong presence in [neural progenitor cell](/details-cell/CL0011020)s (CSI: 8.72) further suggests a potential involvement during neural development or differentiation. This pattern indicates a fundamental role for **[NAALADL1](/details-gene/10004)** in neuronal and glial cell function, possibly related to neuropeptide processing or metabolism in the neural microenvironment. Concurrently, **[NAALADL1](/details-gene/10004)** is a key marker for the intestinal epithelium. It is highly significant in [colonocyte](/details-cell/CL1000347)s (CSI: 8.63), [colon epithelial cell](/details-cell/CL0011108)s (CSI: 6.43), and [enterocyte](/details-cell/CL0000584)s (CSI: 4.29). This expression is consistent with early research that first characterized the peptidase from the ileum, highlighting its role in the gut [Link](https://doi.org/10.1074/jbc.272.49.31006). Its presence is also noted in secretory cells like [goblet cell](/details-cell/CL0000160)s, supporting a broad function in intestinal homeostasis. A less prominent, yet notable, expression is observed in the hematopoietic system, particularly in primitive cell types like [hematopoietic stem cell](/details-cell/CL0000037) (CSI: 6.13) and [common myeloid progenitor](/details-cell/CL0000049)s (CSI: 4.66), hinting at a potential role in the early stages of blood cell development. ## Pathways and Molecular Function **[NAALADL1](/details-gene/10004)** encodes a membrane-bound peptidase with a well-defined molecular function. Based on Gene Ontology annotations, it is an active metallopeptidase ([GO:0008237](https://www.ebi.ac.uk/QuickGO/term/GO:0008237)) that relies on both zinc ([GO:0008270](https://www.ebi.ac.uk/QuickGO/term/GO:0008270)) and calcium ([GO:0005509](https://www.ebi.ac.uk/QuickGO/term/GO:0005509)) ions for its activity. The enzyme exhibits dual substrate specificity, with both aminopeptidase ([GO:0004177](https://www.ebi.ac.uk/QuickGO/term/GO:0004177)) and carboxypeptidase ([GO:0004180](https://www.ebi.ac.uk/QuickGO/term/GO:0004180)) activities, allowing it to cleave peptides from both the N- and C-termini. This enzymatic function contributes to the broader biological processes of proteolysis ([GO:0006508](https://www.ebi.ac.uk/QuickGO/term/GO:0006508)) and peptide catabolism ([GO:0043171](https://www.ebi.ac.uk/QuickGO/term/GO:0043171)). Structurally, the protein functions as a homodimer ([GO:0042803](https://www.ebi.ac.uk/QuickGO/term/GO:0042803)) and is localized to the membrane ([GO:0016020](https://www.ebi.ac.uk/QuickGO/term/GO:0016020)), specifically the apical plasma membrane ([GO:0016324](https://www.ebi.ac.uk/QuickGO/term/GO:0016324)). This localization is highly consistent with its expression in polarized cells like [enterocyte](/details-cell/CL0000584)s, where it would be positioned to process luminal peptides, and in [glutamatergic neuron](/details-cell/CL0000679)s, where it could modulate signals in the synaptic cleft. Research has confirmed its dipeptidyl peptidase IV activity and its identity as a glutamate carboxypeptidase [Link](https://doi.org/10.1074/jbc.274.13.8470), while further studies have elucidated its structural basis for activity [Link](https://doi.org/10.1074/jbc.m114.628149). ## Research Directions The specific, high-level expression of **[NAALADL1](/details-gene/10004)** in both the gut and the brain, combined with its defined enzymatic function, opens several avenues for future investigation. **Proposed Hypotheses:** 1. **Neuromodulatory Role:** Given its high expression in [glutamatergic neuron](/details-cell/CL0000679)s and its classification as a glutamate carboxypeptidase, **[NAALADL1](/details-gene/10004)** may play a critical role in regulating synaptic signaling by processing neuropeptides or other peptide-based neurotransmitters in the synaptic cleft. Its dysfunction could potentially contribute to imbalances in neuronal excitability or signaling pathways implicated in neurodegenerative diseases. 2. **Gut-Brain Axis Signaling:** The dual expression in intestinal epithelial cells and neurons suggests **[NAALADL1](/details-gene/10004)** could be a molecular link in the gut-brain axis. It may be involved in processing dietary or microbial peptides in the gut, generating metabolites or signaling molecules that subsequently influence neuronal function, either directly or indirectly. **Key Experimental Approach:** To test the hypothesis of its neuromodulatory role (Hypothesis 1), a compelling experiment would be to use a conditional knockout mouse model where **[NAALADL1](/details-gene/10004)** is specifically deleted in forebrain glutamatergic neurons. Researchers could then perform *ex vivo* electrophysiological recordings on hippocampal slices from these mice to measure alterations in synaptic transmission and plasticity, such as long-term potentiation (LTP). In parallel, mass spectrometry-based peptidomics could be used on synaptosome preparations from these animals to identify specific neuropeptide substrates that accumulate in the absence of **[NAALADL1](/details-gene/10004)** activity. **Therapeutic Potential:** As an extracellular, membrane-bound peptidase, **[NAALADL1](/details-gene/10004)** represents a highly accessible drug target. If its enzymatic activity is found to contribute to neurological disorders by generating excitotoxic molecules or degrading beneficial neuropeptides, developing specific small-molecule **inhibitors** could be a viable neuroprotective strategy. Conversely, if its role in the gut is critical for nutrient absorption or maintaining mucosal barrier integrity, **activation** could be explored for gastrointestinal disorders. However, its dual expression profile necessitates the development of highly targeted therapies (e.g., non-brain-penetrant drugs for gut indications) to avoid undesirable off-target effects.

Genular Protein ID: 2661529335

Symbol: NALDL_HUMAN

Name: Ileal dipeptidylpeptidase

UniProtKB Accession Codes:

Q9UQQ1 C9J8A1 C9J964 C9JL35 C9JSN0 O43176

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CTD 1 ChEBI 11 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 3 Ensembl 3 EvolutionaryTrace 1 ExpressionAtlas 1 GO 11 Gene3D 3 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 8 RNAct 1 RefSeq 2 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 10085079

Title: Isolation and expression of novel human glutamate carboxypeptidases with N-acetylated alpha-linked acidic dipeptidase and dipeptidyl peptidase IV activity.

PubMed ID: 10085079

DOI: 10.1074/jbc.274.13.8470

PubMed ID: 16554811

Title: Human chromosome 11 DNA sequence and analysis including novel gene identification.

PubMed ID: 16554811

DOI: 10.1038/nature04632

PubMed ID: 9388249

Title: Cloning and characterization of a novel peptidase from rat and human ileum.

PubMed ID: 9388249

DOI: 10.1074/jbc.272.49.31006

PubMed ID: 25752612

Title: Structural and biochemical characterization of a novel aminopeptidase from human intestine.

PubMed ID: 25752612

DOI: 10.1074/jbc.m114.628149

Sequence Information:

  • Length: 740
  • Mass: 80558
  • Checksum: 018D59835F2C48AC
  • Sequence:
    • MQWTKVLGLG LGAAALLGLG IILGHFAIPK KANSLAPQDL DLEILETVMG QLDAHRIREN 
LRELSREPHL ASSPRDEDLV QLLLQRWKDP ESGLDSAEAS TYEVLLSFPS QEQPNVVDIV 
GPTGGIIHSC HRTEENVTGE QGGPDVVQPY AAYAPSGTPQ GLLVYANRGA EEDFKELQTQ 
GIKLEGTIAL TRYGGVGRGA KAVNAAKHGV AGVLVYTDPA DINDGLSSPD ETFPNSWYLP 
PSGVERGSYY EYFGDPLTPY LPAVPSSFRV DLANVSGFPP IPTQPIGFQD ARDLLCNLNG 
TLAPATWQGA LGCHYRLGPG FRPDGDFPAD SQVNVSVYNR LELRNSSNVL GIIRGAVEPD 
RYVLYGNHRD SWVHGAVDPS SGTAVLLELS RVLGTLLKKG TWRPRRSIVF ASWGAEEFGL 
IGSTEFTEEF FNKLQERTVA YINVDISVFA NATLRVQGTP PVQSVVFSAT KEIRSPGPGD 
LSIYDNWIRY FNRSSPVYGL VPSLGSLGAG SDYAPFVHFL GISSMDIAYT YDRSKTSARI 
YPTYHTAFDT FDYVDKFLDP GFSSHQAVAR TAGSVILRLS DSFFLPLKVS DYSETLRSFL 
QAAQQDLGAL LEQHSISLGP LVTAVEKFEA EAAALGQRIS TLQKGSPDPL QVRMLNDQLM 
LLERTFLNPR AFPEERYYSH VLWAPRTGSV VTFPGLSNAC SRARDTASGS EAWAEVQRQL 
SIVVTALEGA AATLRPVADL