ALDOB

The ALDOB gene encodes the enzyme fructose-1,6-bisphosphate aldolase, also known as aldolase B, essential for fructose metabolism in the liver, kidneys, and intestines. 

This enzyme catalyzes the conversion of fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde, a crucial step in fructose and glycolytic metabolism. 

Mutations in the ALDOB gene lead to hereditary fructose intolerance (HFI), a condition causing severe discomfort upon fructose ingestion due to the toxic buildup of fructose-1-phosphate in liver cells. This accumulation disrupts energy production and glucose regulation, leading to symptoms such as nausea, abdominal pain, and hypoglycemia. 

The A149P mutation is the most common, accounting for 57% of HFI alleles, and has been found in diverse populations worldwide. 

Understanding ALDOB's role is critical, as it also plays a significant part in various diseases, including diabetes and several cancers, where its expression levels can affect disease progression and prognosis.

What is ALDOB? [1., 4., 6.]

The ALDOB gene encodes the enzyme fructose-1,6-bisphosphate aldolase, also known as aldolase B, which is crucial for the metabolism of fructose in the liver, kidney, and intestines. 

This enzyme catalyzes the conversion of fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde, a vital step in fructose and glycolytic metabolism. 

Mutations in the ALDOB gene lead to hereditary fructose intolerance (HFI), a condition marked by nausea and discomfort upon ingestion of fructose. 

These mutations often result in a dysfunctional enzyme that cannot form the necessary tetramer structure, causing a toxic buildup of fructose-1-phosphate in liver cells. This accumulation disrupts energy production and glucose regulation, leading to the symptoms of HFI.

ALDOB in Health and Disease

Hereditary Fructose Intolerance [5., 8., 10.]

Mutations in the ALDOB gene are primarily associated with Hereditary Fructose Intolerance (HFI), a condition characterized by nausea, bloating, abdominal pain, diarrhea, and vomiting following the ingestion of foods containing fructose. 

This autosomal recessive disorder is caused by mutations in the ALDOB gene, which encodes the aldolase B enzyme crucial for fructose metabolism in the liver. 

Over 50 different mutations have been identified, all of which impair the enzyme's ability to break down fructose-1-phosphate. This impairment leads to the accumulation of fructose-1-phosphate in liver cells, which is toxic and can result in liver cell death over time. It also causes decreased cellular energy production.

Symptoms typically appear in infancy when fructose is introduced to the diet. 

When individuals with HFI consume fructose, sucrose, or sorbitol, they experience severe metabolic disturbances such as hypoglycemia, lactic acidemia, and hyperuricemia, along with symptoms like nausea, vomiting, and abdominal pain. 

If untreated, HFI can lead to serious complications, including liver and kidney failure. 

Diagnosis is confirmed through genetic testing or, less commonly, liver biopsy. 

Management involves strict dietary restrictions to avoid fructose, sucrose, and sorbitol, and in acute cases, symptomatic treatment in a hospital setting. Early diagnosis and adherence to a fructose-free diet can lead to a normal quality of life and life expectancy. Genetic counseling is recommended for at-risk families to prevent life-threatening complications.

Diabetes [7.] 

ALDOB expression is significantly elevated in beta cells from pancreatic islets in hyperglycemic individuals, and this increase correlates negatively with insulin secretion while being associated with higher HbA1c levels. 

Hyperglycemia induces ALDOB expression in β-cells, and chronic exposure to high glucose levels further increases ALDOB protein in human islets. 

This suggests that hyperglycemia triggers ALDOB upregulation, potentially shifting glucose metabolism away from ATP production and impairing glucose-induced insulin secretion.

A genetic variation in ALDOB, specifically the rs550915 SNP, is associated with higher levels of C-peptide and insulin during oral glucose tolerance tests (OGTT) and hyperglycemic clamp studies. 

This SNP is an expression quantitative trait locus affecting ALDOB expression in multiple tissues, thereby influencing insulin secretion. Increased ALDOB expression in β-cells due to hyperglycemia contributes to impaired insulin secretion, underscoring its role in the development of type 2 diabetes. 

The impaired glucose-induced insulin secretion linked to ALDOB may involve reduced ATP production and increased methylglyoxal production, which negatively impacts mitochondrial function and insulin secretion.

Gastric Cancer [11.] 

The ALDOB gene encodes fructose-1,6-bisphosphate aldolase, a glycolytic enzyme critical for energy production through the breakdown of fructose. In the context of gastric cancer (GC), ALDOB exhibits a tumor-suppressive role by inhibiting the activation of the AKT signaling pathway. 

Research indicates that ALDOB expression is significantly reduced in GC tissues and is associated with larger tumor size, deeper invasion, lymph node metastasis, advanced TNM staging, and poor prognosis. [11.]

Functional studies demonstrate that ALDOB suppresses GC cell proliferation and migration. [11.]

Mechanistically, the reduction of ALDOB leads to increased AKT activation, promoting tumor growth and metastasis. Thus, ALDOB's regulation of the AKT pathway presents a novel therapeutic target for GC treatment.

Hepatocellular Carcinoma [8.]

Aldolase B (ALDOB), a key enzyme in glucose and fructose metabolism, is significantly downregulated in HCC compared to normal liver tissue. This downregulation is associated with aggressive cancer features and poor prognosis. 

ALDOB inhibits hepatocellular carcinogenesis by downregulating the pentose phosphate pathway and through interactions with other cellular components. Reduced ALDOB expression correlates with larger tumor size, higher tumor stage, and shorter overall survival (OS).

Overall, ALDOB downregulation in HCC contributes to metabolic dysregulation, tumor growth, and invasiveness, making it a potential prognostic biomarker and therapeutic target.

Colorectal Cancer [3.]

Aldolase B (ALDOB) plays a significant role in colorectal cancer (CRC) by regulating bioenergy metabolism through the Warburg effect. 

The Warburg effect is a phenomenon where cancer cells preferentially use glycolysis to produce energy, even in the presence of ample oxygen. 

Instead of relying on the more efficient mitochondrial oxidative phosphorylation, cancer cells convert glucose to lactate, which allows them to generate the energy and metabolic intermediates needed for rapid growth and proliferation. 

This shift supports tumor progression and survival under various conditions, despite being less efficient in terms of ATP production.

Higher ALDOB expression in CRC is linked to poor prognosis, increased carcinoembryonic antigen (CEA) levels, and altered bioenergetics. 

ALDOB promotes cell proliferation, chemoresistance, and CEA expression in CRC cells by inducing lactagenesis and activating pyruvate dehydrogenase kinase-1 (PDK1). [3.] 

Secreted lactate enhances lactate dehydrogenase B (LDHB) expression in adjacent cells, driving metabolic changes and supporting cancer cell renewal and resistance to chemotherapy. 

CEACAM6, a downstream effector of ALDOB, further controls CRC cell proliferation and chemoresistance, stabilized through lysine lactylation. 

Thus, the ALDOB/PDK1/lactate/CEACAM6 axis is crucial for CRC progression, offering insights into potential therapeutic targets.

Big Picture: ALDOB in Cancer [12.] 

ALDOB serves as a potential prognostic biomarker for various cancers. Its expression levels can help predict overall survival and disease-free survival in different cancer types, although its mechanism of action and meaning may differ among cancer types.

Depending on the cancer type, ALDOB can act either as a tumor suppressor or an oncogene. Its downregulation is often associated with poor prognosis and increased tumor aggressiveness, while its upregulation can also be linked to poor outcomes in specific cancers like colorectal cancer.

What is known is that ALDOB is crucial for metabolic regulation in cancer cells, impacting glycolysis and other metabolic pathways critical for tumor growth and survival.

Also, the correlation between ALDOB expression and immune cell infiltration highlights its role in modulating the tumor microenvironment and potentially affecting tumor immune evasion mechanisms.

Genetic Alterations in the ALDOB Gene

The gene for the ALDOB protein may contain alterations or mutations that cause increase or decrease of function of the ALDOB protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in Function of ALDOB

Over 50 different missense mutations in the ALDOB gene have been identified as causing HFI.

Most of these mutations replace single amino acids in the aldolase B enzyme, resulting in reduced function.

These mutations impair the enzyme's ability to break down fructose-1-phosphate, leading to its accumulation in liver cells.

rs550915 [7.]

The minor allele of the ALDOB variant rs550915 is associated with significantly higher levels of C-peptide and insulin during oral glucose tolerance tests (OGTT) and hyperglycemic clamp studies.

This SNP is suggested to modulate insulin secretion.

A149P [2.] 

Hereditary fructose intolerance (HFI) is a severe autosomal recessive disorder caused by a deficiency in aldolase B, an enzyme essential for metabolizing fructose. The A149P mutation is the most common mutation associated with HFI, accounting for 57% of HFI alleles.

The presence of the A149P mutation in diverse populations across Europe, North America, the Dominican Republic, Britain, France, Switzerland, Italy, Yugoslavia, Australia, Israel, and Turkey suggests its widespread distribution through genetic drift rather than recurrent mutations at this site. 

Laboratory Testing for ALDOB

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

FAQ: ALDOB (Aldolase B)

What is ALDOB?

ALDOB (Aldolase B) is an enzyme that plays a crucial role in the metabolism of fructose. It is primarily found in the liver, kidneys, and intestines. 

ALDOB helps break down fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate, which are further used in energy production and other metabolic processes.

What is the Function of ALDOB in the Body?

ALDOB is involved in:

• Fructose metabolism: the ALDOB enzyme breaks down fructose-1-phosphate into products that enter glycolysis and gluconeogenesis pathways, essential for energy production.

• Energy production: ALDOB contributes to the body's ability to generate energy from dietary sugars.

What is ALDOB Deficiency?

ALDOB deficiency, also known as Hereditary Fructose Intolerance (HFI), is a genetic disorder caused by mutations in the ALDOB gene. This deficiency leads to the accumulation of fructose-1-phosphate in the liver, kidneys, and intestines, causing toxic effects and metabolic disturbances.

What are the Symptoms of ALDOB Deficiency?

Symptoms of ALDOB deficiency can include:

• Severe hypoglycemia (low blood sugar) after consuming fructose, sucrose, or sorbitol

• Abdominal pain and vomiting

• Jaundice (yellowing of the skin and eyes)

• Enlarged liver (hepatomegaly)

• Failure to thrive in infants

• Aversion to sweet foods

How is ALDOB Deficiency Diagnosed?

ALDOB deficiency is diagnosed through:

• Genetic testing: To identify mutations in the ALDOB gene.

• Biochemical tests: Measuring levels of fructose-1-phosphate and related metabolites in blood and urine.

• Clinical history: Observing symptoms and dietary responses.

What are the Health Implications of ALDOB Deficiency?

ALDOB deficiency can lead to several health issues, including:

• Liver damage, due to the accumulation of toxic metabolites.

• Kidney dysfunction, which results from prolonged exposure to high levels of fructose-1-phosphate.

• Growth and developmental delays, particularly in infants and young children due to metabolic disturbances.

How is ALDOB Deficiency Managed?

Management of ALDOB deficiency involves:

• Strict dietary restriction: avoiding foods that contain fructose, sucrose, and sorbitol to prevent symptoms and metabolic complications.

• Nutritional support: ensuring adequate intake of other nutrients to support overall health and development.

• Regular monitoring: Regular check-ups with healthcare providers to monitor liver and kidney function and overall health.

What Foods Should Be Avoided with ALDOB Deficiency?

Individuals with ALDOB deficiency should avoid:

• Fruits, such as apples, pears, and grapes.

• Sweeteners, including sucrose (table sugar), high-fructose corn syrup, and honey.

• Processed foods that contain hidden sources of fructose, sucrose, or sorbitol.

• Certain vegetables such as sweet corn and sweet potatoes.

Can Lifestyle Changes Help Manage ALDOB Deficiency?

Yes, lifestyle changes can significantly help manage ALDOB deficiency:

• Dietary management: Strictly avoiding foods containing fructose, sucrose, and sorbitol.
  

• Reading labels: Carefully reading food labels to identify and avoid hidden sources of problematic sugars.

• Education and support: Working with dietitians and support groups to maintain a safe and balanced diet.

Where Can I Find More Information About ALDOB and Related Conditions?

For more information about ALDOB and related conditions, consider consulting:

• Healthcare providers: Medical professionals can provide personalized advice and diagnosis.

• Scientific literature: Research articles and reviews on ALDOB and its role in metabolism and health.

• Reputable health organizations: Websites of organizations such as the National Institutes of Health (NIH), Genetic and Rare Diseases Information Center (GARD), and the American Liver Foundation (ALF).

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