Details for: ALDH4A1

Gene ID: 8659

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: ALDH4A1

Ensembl ID: ENSG00000159423

Description: aldehyde dehydrogenase 4 family member A1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • midzonal region hepatocyte CL0019028
    CSI 4.56
    rCSI 10.7%
    PRS 97.04
  • choroid plexus epithelial cell CL0000706
    CSI 3.39
    rCSI 5.54%
    PRS 97.02
  • epithelial cell of proximal tubule CL0002306
    CSI 3.22
    rCSI 7.86%
    PRS 96.28
  • placental villous trophoblast CL2000060
    CSI 3.21
    rCSI 4.97%
    PRS 98.09
  • periportal region hepatocyte CL0019026
    CSI 3.1
    rCSI 12.05%
    PRS 96.84
  • hepatocyte CL0000182
    CSI 3.03
    rCSI 5.42%
    PRS 97.42
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.57
    rCSI 5.77%
    PRS 95.67
  • centrilobular region hepatocyte CL0019029
    CSI 2.33
    rCSI 6.09%
    PRS 96.56
  • kidney connecting tubule epithelial cell CL1000768
    CSI 1.44
    rCSI 3.65%
    PRS 97.64
  • parietal epithelial cell CL1000452
    CSI 1.36
    rCSI 3.64%
    PRS 97.6
  • kidney proximal convoluted tubule epithelial cell CL1000838
    CSI 0.98
    rCSI 10.36%
    PRS 95.79

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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  • 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 [ALDH4A1](/details-gene/8659) (aldehyde dehydrogenase 4 family member A1) encodes a mitochondrial enzyme, delta-1-pyrroline-5-carboxylate dehydrogenase, which is a critical component of the proline catabolic pathway. Its primary function is to catalyze the NAD-dependent oxidation of delta-1-pyrroline-5-carboxylate (P5C) to glutamate. Reflecting its central role in amino acid metabolism, [ALDH4A1](/details-gene/8659) shows the highest significance in metabolically active cells, particularly [midzonal region hepatocytes](/details-cell/CL0019028), [choroid plexus epithelial cells](/details-cell/CL0000706), and [epithelial cells of the proximal tubule](/details-cell/CL0002306). Clinically, loss-of-function mutations in this gene are the cause of type II hyperprolinemia, an autosomal recessive metabolic disorder ([239510](https://omim.org/entry/239510)) [Link](https://doi.org/10.1093/hmg/7.9.1411). ## Cellular Roles and Expression Landscape The expression profile of [ALDH4A1](/details-gene/8659) underscores its essential role in tissues responsible for systemic metabolism, filtration, and barrier function. **Overall**, the gene's significance is most pronounced in the liver, as evidenced by its high Cell Significance Index (CSI) across all major hepatocyte subtypes, including [midzonal region hepatocyte](/details-cell/CL0019028) (CSI: 4.56), [periportal region hepatocyte](/details-cell/CL0019026) (CSI: 3.10), and [centrilobular region hepatocyte](/details-cell/CL0019029) (CSI: 2.33). This is consistent with the liver's central role in amino acid processing. High significance is also observed in key epithelial cell types involved in transport and filtration. These include [choroid plexus epithelial cell](/details-cell/CL0000706) (CSI: 3.39), which forms the blood-cerebrospinal fluid barrier, and multiple epithelial cell types of the kidney nephron, such as [epithelial cell of proximal tubule](/details-cell/CL0002306) (CSI: 3.22) and [kidney connecting tubule epithelial cell](/details-cell/CL1000768) (CSI: 1.44). This pattern suggests a crucial function for [ALDH4A1](/details-gene/8659) in managing metabolic loads and maintaining homeostasis in these specialized tissues. Additionally, its notable expression in [astrocytes of the cerebral cortex](/details-cell/CL0002605) (CSI: 2.57) points towards a role in neurotransmitter precursor synthesis and metabolic support within the central nervous system. ## Pathways and Molecular Function The function of [ALDH4A1](/details-gene/8659) is tightly linked to amino acid metabolism, primarily through the '[Proline catabolism](/details-reactome/R-HSA-70688)' pathway ([R-HSA-70688](https://reactome.org/content/detail/R-HSA-70688)). According to Gene Ontology annotations, the encoded protein is localized to the '[mitochondrial matrix](/details-go/GO:0005759)' ([GO:0005759](https://www.ebi.ac.uk/QuickGO/term/GO:0005759)), where it executes its key molecular function of '[1-pyrroline-5-carboxylate dehydrogenase activity](/details-go/GO:0003842)' ([GO:0003842](https://www.ebi.ac.uk/QuickGO/term/GO:0003842)). This enzymatic step is the final reaction in the '[proline catabolic process to glutamate](/details-go/GO:0010133)' ([GO:0010133](https://www.ebi.ac.uk/QuickGO/term/GO:0010133)), converting the intermediate P5C into glutamate. This reaction not only disposes of excess proline but also links proline metabolism directly to the Krebs cycle and the synthesis of other amino acids and neurotransmitters. The enzyme's broader classification under '[aldehyde dehydrogenase (nad+) activity](/details-go/GO:0004029)' ([GO:0004029](https://www.ebi.ac.uk/QuickGO/term/GO:0004029)) highlights its role in cellular redox balance by reducing NAD+ to NADH. ## Research Directions The well-defined role of [ALDH4A1](/details-gene/8659) in proline metabolism and its high expression in specific cell types provide a foundation for several testable hypotheses regarding its role in health and disease. **Proposed Hypotheses:** 1. **Role in Neuro-metabolism:** Given its high significance in [astrocytes](/details-cell/CL0002605) and [choroid plexus epithelial cells](/details-cell/CL0000706), it is hypothesized that [ALDH4A1](/details-gene/8659) plays a critical role in regulating the glutamate-glutamine cycle in the brain. Its dysfunction may lead to an accumulation of its substrate, P5C, a known pro-oxidant, thereby contributing to neuronal stress and neurodegeneration in certain metabolic or age-related pathologies. 2. **Function in Renal Protection:** The high expression of [ALDH4A1](/details-gene/8659) in the [epithelial cell of the proximal tubule](/details-cell/CL0002306) suggests a role in protecting the kidney from metabolic stress. It is hypothesized that [ALDH4A1](/details-gene/8659) activity is essential for managing the metabolic byproducts of proline-rich collagen turnover and that its deficiency could sensitize proximal tubule cells to damage during acute kidney injury or in chronic fibrotic diseases. **Key Experimental Approach:** To test the second hypothesis regarding the protective role of [ALDH4A1](/details-gene/8659) in the kidney, a conditional knockout mouse model could be generated with [ALDH4A1](/details-gene/8659) specifically deleted in proximal tubule cells (using a Cre-Lox system with a proximal tubule-specific promoter). These knockout mice and their wild-type littermates would be subjected to an ischemia-reperfusion model of acute kidney injury. The extent of renal damage would be assessed by measuring serum creatinine and blood urea nitrogen (BUN), quantifying tubular necrosis and apoptosis through histology (e.g., TUNEL staining), and analyzing markers of oxidative stress in kidney tissue lysates. An exacerbation of kidney injury in the knockout mice would support the hypothesis that [ALDH4A1](/details-gene/8659) has a renoprotective function. **Therapeutic Potential:** As [ALDH4A1](/details-gene/8659) deficiency is the direct cause of a monogenic metabolic disease (Type II hyperprolinemia), its therapeutic potential lies in restoration of function. Strategies would involve **activation** or **replacement**, not inhibition. Gene therapy to deliver a functional copy of [ALDH4A1](/details-gene/8659) to affected tissues, particularly the liver, represents a potential long-term cure. Alternatively, the development of small-molecule chaperones to stabilize misfolded mutant protein or pharmacological activators to boost residual enzyme activity could offer another therapeutic avenue for patients with specific mutation types.

Genular Protein ID: 2007207744

Symbol: AL4A1_HUMAN

Name: Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial

UniProtKB Accession Codes:

P30038 A8K1Q7 B4DGE4 D2D4A3 Q16882 Q53HU4 Q5JNV6 Q8IZ38 Q96IF0 Q9UDI6

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 1 CPTAC 2 CTD 1 CarbonylDB 1 ChEBI 10 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 EC 2 EMBL 12 Ensembl 4 EvolutionaryTrace 1 ExpressionAtlas 1 GO 11 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 7 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OGP 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 6 PDBsum 6 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 Pumba 1 RNAct 1 Reactome 2 RefSeq 4 Rhea 1 SABIO-RK 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 8621661

Title: Cloning, characterization, and expression of cDNAs encoding human delta 1-pyrroline-5-carboxylate dehydrogenase.

PubMed ID: 8621661

DOI: 10.1074/jbc.271.16.9795

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

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: 1395511

Title: Human liver glutamic gamma-semialdehyde dehydrogenase: structural relationship to the yeast enzyme.

PubMed ID: 1395511

DOI: 10.1016/0305-0491(92)90081-2

PubMed ID: 1286669

Title: Human liver protein map: a reference database established by microsequencing and gel comparison.

PubMed ID: 1286669

DOI: 10.1002/elps.11501301201

PubMed ID: 8493898

Title: Human liver high Km aldehyde dehydrogenase (ALDH4): properties and structural relationship to the glutamic gamma-semialdehyde dehydrogenase.

PubMed ID: 8493898

DOI: 10.1007/978-1-4615-2904-0_21

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 25944712

Title: N-terminome analysis of the human mitochondrial proteome.

PubMed ID: 25944712

DOI: 10.1002/pmic.201400617

PubMed ID: 22516612

Title: The three-dimensional structural basis of type II hyperprolinemia.

PubMed ID: 22516612

DOI: 10.1016/j.jmb.2012.04.010

PubMed ID: 9700195

Title: Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia.

PubMed ID: 9700195

DOI: 10.1093/hmg/7.9.1411

Sequence Information:

  • Length: 563
  • Mass: 61719
  • Checksum: 4D964771B7DB5FFD
  • Sequence:
    • MLLPAPALRR ALLSRPWTGA GLRWKHTSSL KVANEPVLAF TQGSPERDAL QKALKDLKGR 
MEAIPCVVGD EEVWTSDVQY QVSPFNHGHK VAKFCYADKS LLNKAIEAAL AARKEWDLKP 
IADRAQIFLK AADMLSGPRR AEILAKTMVG QGKTVIQAEI DAAAELIDFF RFNAKYAVEL 
EGQQPISVPP STNSTVYRGL EGFVAAISPF NFTAIGGNLA GAPALMGNVV LWKPSDTAML 
ASYAVYRILR EAGLPPNIIQ FVPADGPLFG DTVTSSEHLC GINFTGSVPT FKHLWKQVAQ 
NLDRFHTFPR LAGECGGKNF HFVHRSADVE SVVSGTLRSA FEYGGQKCSA CSRLYVPHSL 
WPQIKGRLLE EHSRIKVGDP AEDFGTFFSA VIDAKSFARI KKWLEHARSS PSLTILAGGK 
CDDSVGYFVE PCIVESKDPQ EPIMKEEIFG PVLSVYVYPD DKYKETLQLV DSTTSYGLTG 
AVFSQDKDVV QEATKVLRNA AGNFYINDKS TGSIVGQQPF GGARASGTND KPGGPHYILR 
WTSPQVIKET HKPLGDWSYA YMQ