ACAA1 Human
Description
Introduction to ACAA1 Human
ACAA1 (Acetyl-CoA Acyltransferase 1) is a peroxisomal enzyme encoded by the ACAA1 gene in humans. It plays a critical role in lipid metabolism by catalyzing the thiolytic cleavage of 3-ketoacyl-CoA substrates during fatty acid β-oxidation . This process generates acetyl-CoA and acyl-CoA, which are essential for energy production and metabolic regulation . ACAA1 is ubiquitously expressed, with high activity observed in the liver, kidney, and adipose tissue . Dysregulation of ACAA1 has been linked to neurodegenerative disorders, metabolic diseases, and cancer .
Gene and Protein Structure
The ACAA1 gene is located on chromosome 3 (3p22.1) and spans 18 exons . The encoded protein comprises 419 amino acids with a molecular mass of ~43.8 kDa . Key structural and functional features include:
-
Catalytic Domain: Responsible for acetyl-CoA C-acyltransferase activity .
-
Peroxisomal Targeting Signal: Directs the enzyme to peroxisomes for fatty acid oxidation .
-
Post-Translational Modifications: Interacts with proteins involved in lipid metabolism, such as PPAR signaling pathway components .
Table 1: Biochemical Functions of ACAA1
Tissue-Specific Expression
ACAA1 is expressed in multiple tissues, with the highest levels observed in the liver and kidney . In pigs, its expression in the longissimus dorsi muscle decreases with age, correlating with fat deposition patterns . Human studies highlight its role in lipid-rich organs, influencing adipogenesis and fatty acid oxidation .
Genetic Variants and Disease Associations
-
Neurodegenerative Disorders: The missense variant ACAA1 p.N299S disrupts lysosomal function, exacerbates amyloid-β pathology, and is linked to early-onset Alzheimer’s disease .
-
Metabolic Dysregulation: Synonymous mutations (e.g., rs343060194, rs333279910) alter mRNA splicing and are associated with obesity-related traits in animal models .
-
Cancer: Downregulated in hepatocellular carcinoma but upregulated in triple-negative breast cancer, suggesting context-dependent roles in tumorigenesis .
Table 2: Clinical Implications of ACAA1 Dysfunction
Recombinant ACAA1 in Research
Recombinant human ACAA1 (produced in E. coli) is utilized to study its enzymatic activity and therapeutic potential . Key properties include:
Future Directions
Current research focuses on:
Product Specs
Q&A
What is the primary function of ACAA1 in human cells?
ACAA1 is an enzyme that catalyzes reactions in the beta-oxidation system of peroxisomes. It plays a crucial role in metabolizing very long-chain fatty acids and branched-chain fatty acids. The enzyme facilitates the thiolytic cleavage of 3-ketoacyl-CoA to produce acetyl-CoA and a shortened acyl-CoA molecule, representing a critical step in peroxisomal fatty acid metabolism. Deficiency of this enzyme has been linked to pseudo-Zellweger syndrome, highlighting its essential role in cellular metabolism .
Where is ACAA1 predominantly expressed in human tissues?
ACAA1 expression varies across tissues and developmental stages. According to datasets like the Allen Brain Atlas, ACAA1 shows distinct expression patterns in various brain regions. The Harmonizome database indicates that ACAA1 has over 5,000 functional associations with biological entities spanning 8 categories extracted from 97 datasets. Researchers can assess tissue-specific expression through these resources to identify high and low expression patterns relative to other tissues . Expression analysis methods include RNA-seq, microarray analysis, and immunohistochemistry with specific antibodies like the ACAA1 Monoclonal Antibody [PAT9E5AT].
How is ACAA1 gene expression regulated?
Research indicates that ACAA1 expression can be regulated through the MAPK signaling pathway. Studies in non-small cell lung cancer have shown that oncogenic KRAS may downregulate ACAA1 through MAPK signaling, as evidenced by increased ACAA1 mRNA levels following knockdown of mutant KRAS or treatment with the MAPK pathway inhibitor sorafenib . This regulatory mechanism may have implications for metabolic processes and disease states where KRAS mutations are prevalent. Researchers can investigate this regulation using pathway inhibitors, gene silencing techniques, and transcriptomic analyses under various cellular conditions.
What role does ACAA1 play in neurodegenerative disorders?
Recent studies have identified a novel missense variant in ACAA1 (rs117916664, p.Asn299Ser [p.N299S]) that contributes to early-onset Alzheimer's disease (EOFAD). This loss-of-function variant impairs lysosomal function, disturbs global gene expression patterns, and facilitates amyloid-β pathology and cognitive decline . The variant was significantly enriched in EOFAD patients (MAF = 0.0525) compared to controls (MAF = 0.0204), with an odds ratio of 2.662. Interestingly, this variant appears to have a population-specific effect, being extremely rare in European populations (MAF < 0.01%), suggesting genetic background may influence its impact .
How does ACAA1 expression correlate with cancer progression?
ACAA1 expression is typically lower in tumor tissues compared to adjacent normal tissues across various cancer types . In non-small cell lung cancer (NSCLC), decreased ACAA1 expression correlates with poor prognosis. ACAA1 has been identified as a predictive factor for survival in several cancer types. The mechanism may involve the KRAS/ACAA1 axis, as oncogenic KRAS mutations can downregulate ACAA1 expression. Additionally, ACAA1 expression negatively correlates with biomarkers of tumor mutation burden, including BRCA1, ATM, ATR, CDK1, PMS2, MSH2, and MDH6, suggesting a potential role in genomic stability .
What is the relationship between ACAA1 and immune infiltration in cancer?
ACAA1 expression positively correlates with infiltrating CD4+ T cells in the lung tumor microenvironment, including associations with Th1, Th2, and Treg cell subsets . This suggests that ACAA1 may influence immune surveillance and anti-tumor responses. In NSCLC, ACAA1 also predicts T cell exhaustion, particularly in lung squamous cell carcinoma (LUSC). These findings indicate that ACAA1 could serve as a biomarker for immunotherapy response or potentially be targeted to enhance anti-tumor immunity. Research methods to study these associations include correlation analyses of gene expression data, flow cytometry, and immunohistochemistry to assess immune cell populations in relation to ACAA1 expression.
What tools are available for detecting ACAA1 in experimental settings?
Researchers can utilize several tools for ACAA1 detection and analysis:
-
Antibodies: The ACAA1 Monoclonal Antibody [PAT9E5AT] (CPAB0245) is a validated tool for Western blot applications in human samples . This antibody facilitates precise detection and analysis of ACAA1 expression in various cell types.
-
Gene expression databases: Resources like the Harmonizome database and Allen Brain Atlas provide extensive data on ACAA1 expression patterns across different tissues and conditions .
-
Genetic databases: The LOVD (Leiden Open Variation Database) contains information on ACAA1 variants, including 20 public variants with 18 unique DNA variants reported .
These tools enable comprehensive investigation of ACAA1 at protein and genetic levels for both basic and translational research applications.
How can ACAA1 function be modulated in experimental models?
Experimental modulation of ACAA1 can be achieved through several approaches:
-
Gene silencing: siRNA targeting ACAA1 can effectively reduce its expression to study loss-of-function effects. This approach has been used in cancer cell lines to investigate ACAA1's role in tumor progression .
-
Pharmacological inhibition: MAPK pathway inhibitors like sorafenib can indirectly modulate ACAA1 expression by interfering with its regulatory pathways .
-
Overexpression systems: Transfection with wild-type or mutant ACAA1 constructs allows for gain-of-function studies or investigation of specific variants like p.N299S.
-
CRISPR-Cas9 gene editing: This technique enables precise modification of the ACAA1 gene to create knockout models or introduce specific mutations of interest.
Each method offers distinct advantages depending on the research question and experimental system.
How does the ACAA1 p.N299S variant mechanistically impair lysosomal function?
The ACAA1 p.N299S variant (c.896T>C, rs117916664) has been identified as a loss-of-function mutation that impairs lysosomal function and contributes to Alzheimer's disease pathogenesis . Research on the mechanistic link between this peroxisomal enzyme variant and lysosomal dysfunction reveals an important interface between different cellular organelles. Investigating this connection requires:
-
Biochemical characterization of wild-type and mutant ACAA1 enzymatic activity
-
Lysosomal function assays (pH measurement, cathepsin activity, lysosomal membrane integrity)
-
Examination of lipid accumulation patterns in cells expressing the variant
-
Assessment of autophagy and mitophagy processes that depend on lysosomal function
-
Analysis of peroxisome-lysosome membrane contact sites and lipid transfer
The variant has a high CADD score of 19.72, indicating predicted pathogenicity, which supports its functional significance in cellular processes .
What metabolomic signatures are associated with altered ACAA1 function?
Given ACAA1's role in fatty acid metabolism, alterations in its function likely produce distinct metabolomic signatures. Advanced research approaches should include:
-
Untargeted and targeted metabolomics to identify altered metabolites in biological samples from models with ACAA1 dysfunction
-
Lipidomic profiling to characterize changes in very long-chain fatty acids, branched-chain fatty acids, and their derivatives
-
Flux analysis using isotope-labeled substrates to track metabolic pathway alterations
-
Integration of metabolomic data with transcriptomic and proteomic profiles to identify compensatory mechanisms
-
Comparison of metabolite profiles between different tissues to identify tissue-specific responses to ACAA1 dysfunction
These approaches would provide insights into how ACAA1 alterations affect cellular metabolism in different disease contexts.
How does the KRAS/ACAA1 axis influence tumor immunology?
The inverse relationship between oncogenic KRAS and ACAA1 expression has significant implications for tumor immunology. Research has shown that ACAA1 expression positively correlates with CD4+ T cell infiltration in lung cancer . Advanced investigation of this axis requires:
-
Single-cell RNA sequencing of tumor and immune cells to characterize the relationship between KRAS mutations, ACAA1 expression, and immune cell phenotypes
-
Spatial transcriptomics to analyze the physical relationship between ACAA1-expressing cells and infiltrating immune cells
-
In vivo models with conditional KRAS and ACAA1 expression to assess causal relationships with immune infiltration
-
Examination of metabolic crosstalk between tumor cells with altered ACAA1 expression and immune cells
-
Analysis of cytokine and chemokine production in relation to ACAA1 expression levels
Understanding this axis could reveal new therapeutic targets for enhancing anti-tumor immunity, particularly in KRAS-mutant cancers.
What is the evolutionary conservation of ACAA1 and its implications for model organism studies?
The evolutionary conservation of ACAA1 has important implications for selecting appropriate model organisms for research. Advanced comparative genomics approaches include:
-
Phylogenetic analysis of ACAA1 sequence and function across species, from simple eukaryotes to mammals
-
Structural comparison of ACAA1 enzymes from different species to identify conserved functional domains
-
Cross-species validation of disease-associated variants in corresponding positions
-
Comparative analysis of peroxisomal beta-oxidation pathways across evolutionary diverse organisms
-
Assessment of tissue-specific expression patterns of ACAA1 orthologs in different model organisms
This information helps researchers select the most appropriate models for studying specific aspects of ACAA1 biology and ensures that findings can be meaningfully translated to human health and disease.
Product Science Overview
Acetyl-CoA Acyltransferase, also known as thiolase, is an enzyme that plays a crucial role in the metabolism of fatty acids and the biosynthesis of ketone bodies. This enzyme catalyzes the thiolytic cleavage of 3-ketoacyl-CoA into acetyl-CoA and a shortened acyl-CoA molecule. The human recombinant form of Acetyl-CoA Acyltransferase is produced using recombinant DNA technology, allowing for the study and application of this enzyme in various biochemical and medical research fields.
Acetyl-CoA Acyltransferase is a homotetrameric enzyme, meaning it consists of four identical subunits. Each subunit contains an active site where the catalytic reaction occurs. The enzyme’s primary function is to facilitate the breakdown of fatty acids through β-oxidation, a process that generates acetyl-CoA, which can then enter the citric acid cycle to produce energy.
In addition to its role in fatty acid metabolism, Acetyl-CoA Acyltransferase is involved in the synthesis of ketone bodies, which are important energy sources during periods of fasting or low carbohydrate intake. The enzyme’s activity is regulated by various factors, including substrate availability and post-translational modifications.
The production of human recombinant Acetyl-CoA Acyltransferase involves the insertion of the human gene encoding the enzyme into a suitable expression vector. This vector is then introduced into a host organism, such as Escherichia coli or yeast, which expresses the enzyme. The recombinant enzyme is subsequently purified using techniques such as affinity chromatography, ensuring high purity and activity.
Recombinant production offers several advantages, including the ability to produce large quantities of the enzyme, consistency in enzyme activity, and the elimination of potential contaminants found in enzymes extracted from natural sources.
Human recombinant Acetyl-CoA Acyltransferase has numerous applications in research and medicine. It is used to study the mechanisms of fatty acid metabolism and ketogenesis, providing insights into metabolic disorders such as diabetes and obesity. The enzyme is also employed in drug discovery and development, where it serves as a target for potential therapeutic agents aimed at modulating its activity.
Furthermore, Acetyl-CoA Acyltransferase is utilized in the production of biofuels and bioplastics, where its ability to catalyze the formation of acetyl-CoA is harnessed to generate renewable energy sources and environmentally friendly materials.
