The dipeptide W-acetylaspartylglutamate (NAAG) was first identified in bovine brain in 1965.1 NAAG is present in high millimolar concentrations in mammalian brain and peripheral nervous system.2 Its role was largely unknown until the early 1980s when the concept of its potential function as a neurotransmitter was postulated.3 As neurotransmitters generally undergo inactivation via re-uptake or by enzymatic degradation, the enzyme for the catabolism of NAAG was sought, identified, purified and characterized from the brains and kidneys of rodents.4 Glutamate carboxypeptidase (GCPII) is a zinc peptidase that hydrolyzes the neuropeptide NAAG to glutamate (G) and W-acetyl aspartate (NAA) (Fig. 1).


Figure 1. Hydrolysis of NAAG catalyzed by GCP II.


Figure 1. Hydrolysis of NAAG catalyzed by GCP II.

Rat GCP II was cloned in 1996 and found to be homologous to human prostate-specific membrane antigen (PSMA).5 GCP II has been found in new vasculature of

* Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, Maryland 21224 USA; phone, 410-6316804, email, [email protected]

several solid tumors.6 Additionally, GCP II catalyzes the hydrolysis of folate polyglutamate to folate and several molecules of glutamate in the membrane brush border of the small intestine.7 It is localized on the plasma membrane of glial cells and positioned with its catalytic region facing the synapse.8 Depending on localization and function, GCP II has been referred to as NAALADase (w-acetylated-a-linked acidic dipeptidase) when studying NAAG hydrolysis in the brain9, as PSMA when studying the role of the enzyme in prostate cancer10 or as folate hydrolase when focusing on the potential function of this enzyme in human nutrition.7 However, the preferred official name for the enzyme is GCP II (EC

Excessive glutamate has been implicated in a variety of neurodegenerative disorders including stroke, ALS, and chronic pain. Conventional therapies have focused on blockade of post-synaptic glutamate receptors with small molecules. To this end, several glutamate receptors have been evaluated and exploited as therapeutic targets for neurological disorders associated with excess glutamate toxicity. Of these, the NMDA receptors have received the most attention culminating in several antagonists in clinical trials.11 However, this class of compounds has been historically associated with major side effects thought to be associated with blockade of normal physiological neurotransmission, such as learning and memory.11

An alternative therapeutic approach to blocking postsynaptic glutamate receptors would be upstream reduction of presynaptic glutamate. If NAAG were functioning as a storage form of glutamate, then inhibition of GCP II would, in theory, prevent the release of excess glutamate and thereby be neuroprotective. In addition, NAAG has been shown to have other functions including acting as an mgluR3 agonist and a partial antagonist of postsynaptic NMDA receptors.12 Activation of mGluR3 by NAAG has been shown to inhibit glutamate release13 and increase transforming growth factor P (TGFP) release, both of which have been shown to provide neuroprotection.14 Consequently, elevation of NAAG would be beneficial in its own right via its interaction at the mGluR3. Therefore, inhibition of GCP II should be neuroprotective via a dual mechanism involving both a direct reduction of glutamate and an elevation of NAAG.

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