Glutamate carboxypeptidase

Glutamate Carboxypeptidase (GCPII), also known as N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) or prostate-specific membrane antigen (PSMA), is an enzyme that in humans is encoded by the FOLH1 gene on chromosome 11. This membrane-bound protein is involved in various processes, including the metabolism of glutamate, the most abundant excitatory neurotransmitter in the central nervous system (CNS), and the absorption of folate. GCPII has gained attention for its role in neurological disorders and its potential as a target for cancer therapy, particularly in prostate cancer.

Function

Glutamate Carboxypeptidase II plays a critical role in the hydrolysis of N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-aspartate (NAA) and glutamate. This reaction is significant in the CNS, where glutamate acts as a key neurotransmitter involved in synaptic transmission and plasticity. By regulating the availability of glutamate, GCPII can influence various neural processes and has been implicated in the pathophysiology of several neurological conditions, including schizophrenia, neuropathic pain, and neurodegenerative diseases.

In addition to its enzymatic function, GCPII is involved in the absorption of folate, a vitamin essential for numerous bodily functions, including DNA synthesis and repair, methylation reactions, and the synthesis of neurotransmitters. The enzyme's role in folate metabolism underscores its importance in maintaining cellular health and proper neurological function.

Clinical Significance

GCPII has been extensively studied for its role in prostate cancer, where it is known as prostate-specific membrane antigen (PSMA). PSMA is highly expressed in prostate cancer cells, making it a valuable biomarker for the diagnosis and prognosis of prostate cancer. Furthermore, its expression on the surface of cancer cells has led to the development of PSMA-targeted therapies, including radioligand therapy and antibody-drug conjugates, which show promise in treating advanced prostate cancer.

The enzyme's involvement in glutamate metabolism also makes it a potential target for the treatment of neurological disorders. Inhibitors of GCPII, such as 2-PMPA, have been explored for their therapeutic potential in conditions characterized by excessive glutamate activity, such as neuropathic pain, schizophrenia, and neurodegenerative diseases.

Genetics

The FOLH1 gene encodes the Glutamate Carboxypeptidase II enzyme. Variants and mutations within this gene have been studied for their association with disease susceptibility, particularly in the context of prostate cancer and neurological disorders. Understanding the genetic regulation of GCPII is crucial for developing targeted therapies and personalized medicine approaches.

See Also

• Neurotransmitter
• Prostate cancer
• Folate metabolism
• Neurodegenerative diseases
• Synaptic transmission