AADAT - Aminoadipate Aminotransferase | Elisa - Clia - Antibody - Protein

Background

Aminoadipate Aminotransferase (AADAT) is an enzyme that plays a critical role in the metabolism of lysine, an essential amino acid. It catalyzes the conversion of α-aminoadipate to glutamate, a crucial neurotransmitter, as part of the lysine degradation pathway. This enzyme is involved in the metabolism of amino acids and helps regulate important metabolic processes, including nitrogen balance and the synthesis of neurotransmitters.

AADAT specifically catalyzes the transamination of α-aminoadipate (the result of the lysine degradation pathway) by transferring an amino group to an appropriate acceptor molecule. The overall reaction produces glutamate, a key molecule in cellular metabolism that is central to various processes, including protein synthesis, neurotransmission, and energy production.

AADAT is found in various tissues, including the liver and kidneys, and is particularly important in amino acid metabolism. Given its role in lysine metabolism and its involvement in key cellular functions, AADAT has been implicated in a range of physiological and pathological conditions, including disorders related to amino acid metabolism, neurotransmitter imbalances, and neurodegenerative diseases.

Protein Structure

AADAT is a pyridoxal-5'-phosphate (PLP)-dependent enzyme, meaning it requires the active form of vitamin B6 (PLP) as a cofactor for its activity. The protein structure of AADAT is optimized for the binding of PLP and its interaction with amino acid substrates.

Key features of AADAT's structure include:

1. PLP Binding Site: As a PLP-dependent enzyme, AADAT contains a binding site for pyridoxal phosphate, which is crucial for its activity. PLP serves as a cofactor that facilitates the transamination reaction, where the amino group of α-aminoadipate is transferred to the acceptor molecule, typically 2-oxoglutarate, to produce glutamate.
2. Active Site for Transamination: The active site of AADAT contains residues that facilitate the transamination reaction. This includes a catalytic lysine residue that interacts with the PLP cofactor, enabling the enzyme to perform its function of amino group transfer.
3. Substrate Binding: The enzyme's structure also accommodates the binding of its substrates, including α-aminoadipate and 2-oxoglutarate (or another suitable acceptor molecule). This ensures that the enzyme can efficiently catalyze the conversion of α-aminoadipate into glutamate.
4. Quaternary Structure: AADAT functions as a monomer or dimer, with a quaternary structure that allows for stability and interaction with its substrates and cofactors. Its dimeric or monomeric form can be essential for maintaining its activity under different physiological conditions.
5. Conformational Changes: AADAT undergoes conformational changes during the reaction cycle, facilitating the proper alignment of the substrates and the catalytic center for efficient transamination.

The overall structure of AADAT ensures that it can bind PLP, interact with amino acid substrates, and catalyze the transfer of amino groups with high specificity and efficiency.

Classification and Subtypes

AADAT is classified as a transaminase, specifically an aminotransferase enzyme. Aminotransferases are a subclass of transferases, which are enzymes that catalyze the transfer of functional groups between molecules. AADAT specifically transfers an amino group from α-aminoadipate to an acceptor molecule, producing glutamate.

AADAT is part of the aminotransferase family that includes other enzymes involved in amino acid metabolism, such as:

• Glutamate aminotransferase (GOT/GPT): Involved in the reversible conversion of glutamate to α-ketoglutarate.
• Aspartate aminotransferase (AST): Catalyzes the conversion of aspartate to oxaloacetate.
• Alanine aminotransferase (ALT): Catalyzes the conversion of alanine to pyruvate.

These enzymes share a common mechanism of action, transferring an amino group from one substrate to another, but AADAT is specialized in the conversion of α-aminoadipate to glutamate, linking it specifically to the lysine catabolic pathway.

Function and Biological Significance

AADAT plays an important role in lysine degradation, an essential process for the breakdown of lysine and the production of key metabolites like glutamate. This function is vital for maintaining cellular amino acid homeostasis and supporting neurotransmitter synthesis. Some of its primary functions and biological significance include:

1. Lysine Degradation: AADAT is involved in the lysine catabolic pathway, which is responsible for breaking down lysine into various intermediates, including α-aminoadipate. Through its transamination activity, AADAT converts α-aminoadipate into glutamate, which is a crucial metabolite in several metabolic pathways. The breakdown of lysine provides precursors for the Krebs cycle and other biochemical processes.
2. Glutamate Production: Glutamate is a critical neurotransmitter in the brain, and its proper synthesis and regulation are vital for normal brain function. AADAT’s role in converting α-aminoadipate into glutamate makes it an important enzyme in maintaining neurotransmitter homeostasis. Glutamate is involved in numerous processes, including synaptic plasticity, memory formation, and excitatory neurotransmission.
3. Nitrogen Metabolism: As an aminotransferase, AADAT helps regulate nitrogen metabolism by facilitating the transfer of amino groups. This is important for maintaining nitrogen balance in cells, supporting the synthesis of various amino acids, and detoxifying excess nitrogen.
4. Amino Acid Homeostasis: AADAT’s activity is integral to maintaining the balance of amino acids in the cell. By breaking down lysine and producing glutamate, it helps regulate amino acid levels, which are crucial for protein synthesis, metabolic processes, and cellular function.
5. Regulation of Metabolic Pathways: AADAT links the metabolism of lysine with that of glutamate, two important metabolites involved in energy production and cellular function. The production of glutamate through AADAT also influences the Krebs cycle, where glutamate can be converted into α-ketoglutarate, a key intermediate in cellular energy production.

Clinical Issues

Defects in AADAT activity or regulation can lead to various metabolic disorders, particularly those related to lysine metabolism and glutamate regulation. Some key clinical issues associated with AADAT dysfunction include:

1. Lysine Metabolism Disorders: Defects in AADAT activity can disrupt the normal degradation of lysine, leading to the accumulation of toxic intermediates like α-aminoadipate. This could result in lysine accumulation disorders, potentially causing neurological and developmental issues.
2. Glutamate Imbalance: Since AADAT is involved in glutamate synthesis, any dysfunction of AADAT may lead to an imbalance in glutamate levels in the brain. This imbalance can contribute to several neurological conditions, including neurodegenerative diseases, epilepsy, and neurodevelopmental disorders. Excessive glutamate can cause excitotoxicity, damaging neurons and leading to conditions like Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS).
3. Neurotransmitter Imbalance: AADAT's role in the synthesis of glutamate also implicates it in neurotransmitter regulation. Disruption in AADAT activity may affect synaptic function and neuronal communication, leading to cognitive impairments, mood disorders, and learning disabilities.
4. Cancer: Altered lysine metabolism has been linked to certain cancer types. Since lysine degradation is connected to the regulation of various metabolic pathways, including the synthesis of glutamate and energy production, alterations in AADAT may play a role in cancer cell metabolism and tumorigenesis.

Summary

Aminoadipate Aminotransferase (AADAT) is a crucial enzyme involved in the breakdown of lysine and the production of glutamate, an essential neurotransmitter. By catalyzing the conversion of α-aminoadipate to glutamate, AADAT helps regulate amino acid homeostasis, nitrogen metabolism, and cellular energy pathways. The enzyme is critical for proper lysine degradation, glutamate synthesis, and neurotransmitter regulation. Dysfunction in AADAT activity can lead to metabolic disorders related to lysine and glutamate metabolism, contributing to neurological diseases, cognitive impairments, and possibly cancer. Understanding AADAT's role in metabolic pathways offers potential therapeutic targets for diseases associated with amino acid imbalances and neurodegeneration.