ACY1

The ACY1 gene encodes aminoacylase 1, a cytosolic, homodimeric, zinc-binding enzyme that catalyzes the hydrolysis of N-acylated L-amino acids into free L-amino acids and an acyl group: its primary function is the catabolism and salvage of acylated amino acids. 

These acylated amino acids protect and stabilize proteins, regulate their activity, and influence cellular interactions. 

Mutations in ACY1 cause aminoacylase 1 deficiency, an extremely rare metabolic disorder marked by central nervous system defects and increased urinary excretion of N-acetylated amino acids. 

This gene's mutations, such as IVS5-1G→A, 1105^1106insAC, 699A→C (E233D), and 1057C→T (R353C), result in a variety of clinical manifestations, ranging from intellectual disability to muscular hypotonia, underscoring its importance in neurological and metabolic health.

What is ACY1? [1., 2., 4.]

The ACY1 gene encodes aminoacylase 1, a cytosolic, homodimeric, zinc-binding enzyme that catalyzes the hydrolysis of N-acylated L-amino acids into free L-amino acids and an acyl group. 

By catalyzing the catabolism and salvage of acylated amino acids, ACY1 allows them to be recycled and used for new protein synthesis.

Acylated amino acids are amino acids that have undergone a chemical modification called acylation. This process involves the attachment of an acyl group (a group derived from an organic acid by removal of a hydroxyl group) to the amino acid molecule. 

This modification can help protect and stabilize proteins, regulate their activity, and influence their interactions and localization within the cell.

Aminoacylase 1, the enzyme encoded by the ACY1 gene, specifically catalyzes the hydrolysis (breakdown) of these N-acetylated amino acids, removing the acetyl group and generating free amino acids that can then be reused by the body for protein synthesis and other metabolic processes.

Located on chromosome 3p21.1, ACY1 is often reduced to homozygosity in small-cell lung cancer (SCLC), where its expression is notably decreased or undetectable in SCLC cell lines and tumors. [4.] 

Mutations in ACY1 cause aminoacylase 1 deficiency, a metabolic disorder characterized by central nervous system defects and increased urinary excretion of N-acetylated amino acids. 

ACY1 in Health and Disease

Aminoacylase 1 Deficiency (ACY1D) [3., 4., 5.]  

Aminoacylase 1 Deficiency (ACY1D) is an extremely rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-acetylated amino acids.  To date, only 21 cases have been noted. [5.] 

The condition is caused by mutations in the ACY1 gene located on chromosome 3p21.2, which encodes the aminoacylase 1 enzyme responsible for catalyzing the formation of free amino acids from N-acetylated precursors.

Symptoms and signs of Aminoacylase 1 Deficiency (ACY1D) are highly variable, encompassing a range of neurological and developmental issues. 

Common manifestations include intellectual disability, seizures, hypotonia, and motor delay. Some patients, particularly infants, may experience acute episodes of encephalopathy. 

Psychomotor retardation, ranging from mild to moderate, is frequently observed. In certain cases, cerebral and cerebellar atrophy have been reported. 

Speech and language delays, as well as muscular hypotonia, are also characteristic of the condition. 

There is significant phenotypic variability among affected individuals, with some remaining asymptomatic despite having the genetic mutation.

Diagnosis of ACY1D typically involves a combination of biochemical and genetic analyses. Gas chromatography-mass spectrometry (GC-MS) analysis of urinary organic acids is a primary diagnostic tool, revealing increased levels of N-acetylated amino acids, including derivatives of methionine, glutamine, alanine, leucine, glycine, valine, and isoleucine. 

NMR spectroscopy of urine can also be employed for detection. 

Genetic testing to identify mutations in the ACY1 gene provides definitive diagnosis. 

Additionally, reduced ACY1 enzyme activity can be detected in Epstein-Barr virus (EBV)-transformed lymphoblasts or fibroblasts, further confirming the diagnosis. [6.] 

Genetic Alterations in the ACY1 Gene

The gene for the ACY1 protein may contain alterations or mutations that cause increase or decrease of function of the ACY1 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 the ACY1 Gene [7.] 

IVS5-1G→A

A homozygous obligatory splice-site mutation predicting malfunction of the acceptor splice-site from exon 6.

1105^1106insAC

A homozygous 2-bp insertion predicting a frame shift starting from amino acid residue 369, leading to a longer, mutated protein.

699A→C (E233D) and 1057C→T (R353C)

Compound heterozygous missense mutations in one individual, predicting substitutions in evolutionary conserved amino acid residues.

1057C→T (R353C)

A homozygous missense mutation found in another individual, also predicting a substitution in an evolutionary conserved amino acid residue.

These mutations lead to the excretion of distinct N-acetylated amino acids and were associated with a range of clinical features, although the significance of ACY1 deficiency in terms of disease pathology remains to be fully understood. [7.] 

Laboratory Testing for ACY1

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.

Frequently Asked Questions (FAQs) About ACY1

What Is ACY1?

ACY1, or aminoacylase 1, is an enzyme involved in the metabolism of amino acids. It is responsible for hydrolyzing N-acylated amino acids into free amino acids and acyl groups, which are important for various physiological processes.

Why Is ACY1 Important?

ACY1 is important because it plays a crucial role in amino acid metabolism and the urea cycle. It helps maintain the balance of amino acids in the body, which is essential for protein synthesis, detoxification, and overall metabolic function.

What Is the Function of ACY1?

The primary function of ACY1 is to catalyze the hydrolysis of N-acylated amino acids into free amino acids and their respective acyl groups. This process is vital for the proper utilization and recycling of amino acids within the body.

How Is ACY1 Measured?

ACY1 activity can be measured through blood tests or urine tests. These tests typically involve analyzing the enzyme's activity levels or the concentration of its substrates and products in biological samples.

What Are Normal Levels of ACY1?

Normal levels of ACY1 activity can vary based on factors such as age, sex, and overall health. Reference ranges are provided by the testing laboratory and should be interpreted by a healthcare provider within the context of the patient's health status and medical history.

What Can Cause Low Levels of ACY1?

Low levels of ACY1 activity may indicate genetic mutations or deficiencies in the enzyme. Such deficiencies can lead to metabolic disorders where the body cannot efficiently process N-acylated amino acids, potentially causing a buildup of these compounds.

What Are the Symptoms of Abnormal ACY1 Levels?

Elevated levels of ACY1 are not typically seen. Low levels of ACY1 activity can lead to symptoms related to amino acid metabolism disorders such as developmental delays, intellectual disability, and other metabolic complications.

How Are Abnormal Levels of ACY1 Treated?

Management may involve dietary modifications to reduce the intake of specific amino acids that cannot be adequately metabolized. It is important to consult with a healthcare provider for an accurate diagnosis and appropriate treatment plan.

Why Might a Doctor Order an ACY1 Test?

A doctor might order an ACY1 test to evaluate a patient's amino acid metabolism, particularly if there are symptoms or family history suggestive of a metabolic disorder. The test can also help in diagnosing liver function abnormalities and monitoring certain metabolic conditions.

Is the ACY1 Test Safe?

Yes, the ACY1 test is safe. Blood tests involve a minor risk of discomfort or bruising at the site where blood is drawn. Urine and cheek swab tests are non-invasive and generally risk-free.

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