ACMSD - 2-Amino-3-Carboxymuconate-6-Semialdehyde Decarboxylase | Elisa - Clia - Antibody - Protein

Background

2-Amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD) is an enzyme involved in the tryptophan catabolic pathway, specifically in the kynurenine pathway. This pathway degrades tryptophan into several bioactive metabolites, some of which are precursors for NAD+ biosynthesis. ACMSD catalyzes the conversion of 2-amino-3-carboxymuconate-6-semialdehyde (ACMS) to 2-aminomuconate-6-semialdehyde (AMS), a step that diverts the pathway away from the production of quinolinic acid, a neuroactive compound. By regulating the flux of metabolites in the kynurenine pathway, ACMSD influences the balance between neurotoxic and neuroprotective metabolites. This enzyme is expressed in various tissues, including the brain, liver, and kidney, suggesting its importance in systemic metabolism and neuronal function. Dysregulation of ACMSD activity has been implicated in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, as well as psychiatric disorders like schizophrenia. Research into the molecular mechanisms and regulation of ACMSD holds promise for understanding the pathogenesis of these disorders and developing therapeutic interventions targeting the kynurenine pathway. Further investigation is needed to explore the potential of ACMSD modulation as a strategy for neuroprotection and the treatment of neurological and psychiatric conditions.

Protein Structure

The structural details of ACMSD include:

• Active Site: Contains residues crucial for binding the substrate (ACMS) and catalyzing its decarboxylation.
• Metal Cofactor: Often requires a metal ion (such as zinc) for its enzymatic activity, which stabilizes the substrate and the transition state.
• Substrate Binding Domain: Specific regions within the enzyme that interact with ACMS, ensuring proper positioning for the decarboxylation reaction.

Classification and Subtypes

ACMSD is a member of the amidohydrolase superfamily and is classified based on its function in the kynurenine pathway. There are no known subtypes of ACMSD, but it shares structural and functional similarities with other enzymes in the amidohydrolase family.

Function and Biological Significance

ACMSD serves several critical roles in tryptophan metabolism:

1. Regulation of NAD+ Synthesis: By catalyzing the conversion of ACMS, ACMSD controls the availability of substrates for NAD+ biosynthesis, thereby influencing cellular NAD+ levels.
2. Tryptophan Metabolism: Modulates the flux through the kynurenine pathway, affecting the production of downstream metabolites with various physiological functions.
3. Neuroprotection: Metabolites of the kynurenine pathway have neuroactive properties; ACMSD activity can influence the balance of neuroprotective and neurotoxic metabolites, impacting neurodegenerative diseases.
4. Immune Regulation: Tryptophan metabolites have immunomodulatory effects, and ACMSD can affect immune responses by regulating these metabolites.

Interactions

ACMSD interacts with various molecules and pathways:

1. ACMS: The primary substrate for ACMSD, derived from the oxidation of kynurenine.
2. Kynurenine Pathway Enzymes: Works in concert with other enzymes in the kynurenine pathway, such as kynurenine-3-monooxygenase (KMO) and kynureninase, to regulate tryptophan catabolism.
3. Metal Ions: Requires metal ions (like zinc) for its enzymatic activity.
4. NAD+ Biosynthesis Pathway: Interacts indirectly with enzymes involved in NAD+ synthesis, as it regulates the availability of precursors for this pathway.

Clinical Significance

Alterations in ACMSD activity or expression can be linked to several pathological conditions:

1. Neurodegenerative Diseases: Dysregulation of the kynurenine pathway, including ACMSD activity, has been implicated in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The balance of neurotoxic and neuroprotective metabolites influenced by ACMSD is crucial in these conditions.
2. Inflammatory Disorders: Changes in tryptophan metabolism and the kynurenine pathway can affect immune responses, potentially contributing to inflammatory diseases.
3. NAD+ Deficiency: Insufficient activity of ACMSD can impact NAD+ synthesis, leading to metabolic and age-related disorders.
4. Psychiatric Disorders: Abnormal tryptophan metabolism has been associated with psychiatric conditions such as depression and schizophrenia, where ACMSD may play a role.

Summary

2-Amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD) is a key enzyme in the kynurenine pathway of tryptophan catabolism. It regulates the production of NAD+ by catalyzing the decarboxylation of ACMS. ACMSD influences neuroprotection, immune responses, and overall tryptophan metabolism. Dysregulation of ACMSD activity is associated with various diseases, including neurodegenerative and inflammatory disorders, NAD+ deficiency, and psychiatric conditions. Understanding the structure, function, and clinical implications of ACMSD is vital for exploring therapeutic strategies targeting the kynurenine pathway and related metabolic processes.