Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer

Abstract

Glutamate carboxypeptidase II (GCPII) is a membrane-bound binuclear zinc metallopeptidase with the highest expression levels found in the nervous and prostatic tissue. Throughout the nervous system, glia-bound GCPII is intimately involved in the neuron-neuron and neuron-glia signaling via the hydrolysis of N-acetylaspartylglutamate (NAAG), the most abundant mammalian peptidic neurotransmitter. The inhibition of the GCPII-controlled NAAG catabolism has been shown to attenuate neurotoxicity associated with enhanced glutamate transmission and GCPII-specific inhibitors demonstrate efficacy in multiple preclinical models including traumatic brain injury, stroke, neuropathic and inflammatory pain, amyotrophic lateral sclerosis, and schizophrenia. The second major area of pharmacological interventions targeting GCPII focuses on prostate carcinoma; GCPII expression levels are highly increased in androgen-independent and metastatic disease. Consequently, the enzyme serves as a potential target for imaging and therapy. This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies. The review also outlines the development of GCPII-specific small-molecule compounds and their use in preclinical and clinical settings.

Fig. (1)

Homodimer of human GCPII (crystal structure) tethered to the biological membrane. One monomer shown in semitransparent surface representation with individual domains of the extracellular part colored green (protease domain; amino acids 57 – 116 and 352 – 590), blue (apical domain; amino acids 117 – 351), and yellow (C-terminal; amino acids 591 – 750); the second monomer is colored gray. N-linked sugar moieties are colored cyan, and the active-site Zn²⁺ ions are shown as red spheres. Left panel – residing at the plasma membrane of astrocytes /schwann cells, GCPII catabolizes NAAG, the most prevalent peptidic neurotransmitter in the mammalian nervous system. N-acetylaspartate and glutamate, the reaction products, are selectively transported into glial cells, metabolized and reused for NAAG synthesis in neurons. Right panel– GCPII (or folate hydrolase) at the plasma membrane of enterocytes in the proximal jejunum sequentially hydrolyzes the C-terminal γ-glutamate tail of dietary folates, finally leaving folate-monoglutamate, which can be then transported transcellularly into the blood stream.

Fig. (2)

Human PET imaging with [¹⁸F]DCFBC. (A) Coronal view. Note increased radiopharmaceutical uptake in an enlarged right external iliac lymph node (short arrow), a small right external iliac node (long arrow) and a small left periaortic node (dashed arrow). [¹⁸F]DCFBC, like all of the hydrophilic GCPII inhibitors of the urea class, is excreted almost exclusively through the urine. The large pelvic focus of uptake in the midline is due to radiotracer in the bladder. (B) Axial view. Clockwise from upper left: PET, CT and fused PET/CT images depicting the right external iliac lymph node (arrow). These foci of increased radiopharmaceutical uptake are most likely due to metastases from prostate cancer. R = right, L = left.