**3. Transformations of amino acids in the cell metabolic network**

As mentioned above, any example of metabolic transformation in brain tissue is tightly connected with glycolysis Therefore, glutamate/glycine participation in metabolic pathways seems to be considered correctly including the main neighbor reactions of glucose oxidation. The primary source of energy for the brain is glucose. This sugar is almost entirely oxidized under basal physiological conditions, providing nearly all the energy necessary to support brain function. However, when supplemental energy is needed, necessary energy demands may be provided by other metabolites, such as ketones, fatty acids, acetate, lactate, and certain amino acids [19]. Pyruvate, the end product of aerobic glycolysis, can enter the tricarboxylic acid (TCA) cycle by two different routes: (1) via acetyl-CoA formation, catalyzed by the pyruvate dehydrogenase complex, and (2) by the formation of oxaloacetate, catalyzed by PC [24]. However, the end metabolite of anaerobic glycolysis, lactate, also participates in the energy supply of neurons (**Figure 2**). Pellerin and Magistretti originally proposed the astrocyte-neuron lactate shuttle (ANLS) model, wherein lactate released from astrocytes serves as a buffer compound in response to a glutamate-induced glycolysis stimulus [25]. Then, lactate is exported to neurons, where it is converted to pyruvate to fuel oxidative phosphorylation.

Thus, the ANLS model suggests that lactate, not glucose, provides energetic support for firing neurons [26]. Glutamate and glycine are active participants in these metabolic processes. Exclusion of most blood-borne glutamate at the bloodbrain barrier (BBB) and a net removal of glutamine from the brain indicate that the cerebral pools of glutamate are largely produced within the brain [27]. The stability of glutamate concentration is maintained by two main reactions. Glutamine synthetase (GS), which is found in astrocytes, is the only known enzyme to date that is capable of a reversible conversion between glutamine and glutamate and

*Amino Acids as Neurotransmitters. The Balance between Excitation and Inhibition… DOI: http://dx.doi.org/10.5772/intechopen.103760*

#### **Figure 2.**

*A scheme of the metabolic pathways involved in general glutamate/glycine transformations. The reactions occur in various intracellular localizations and can be duplicated in different compartments. The main metabolic pathways (glycolysis and the tricarboxylic acid (TCA) cycle) are labeled. The enzyme abbreviations are as follows: GM: glutaminase; GS: glutamine synthetase; GDH: glutamate dehydrogenase; GL: glutamylcysteine ligase; GTS: glutathione synthetase; AG: asparaginase; AT: aminotransferase; PPC: phosphoenolpyruvate carboxykinase; PC: pyruvate carboxylase; PDC: pyruvate dehydrogenase complex; PK: pyruvate kinase; LDH: lactate dehydrogenase; SDH: serine dehydrogenase; STM: serine transhydroxymethylase; and GCS: the glycine cleavage system. Other abbreviations are as follows: NAD+: Nicotinamide adenine dinucleotide (oxidized); NADH: Nicotinamide adenine dinucleotide (reduced); ATP: Adenosine triphosphate; ADP: Adenosine diphosphate; and THF:Tetrahydrofolate.*

ammonia in the mammalian brain [28]. Furthermore, cells can convert glutamate to glutamine in an ATP-dependent process catalyzed by glutamine synthetase. Astrocytic uptake of glutamate and release of glutamine, together with neuronal uptake of glutamine and release of glutamate, constitute the glutamate-glutamine cycle [29]. However, much of the glutamate taken up by astrocytes is destined for oxidative degradation, which first requires conversion to the TCA cycle intermediate 2-oxoglutarate. This can take place via transamination by aminotransferase (AT) or via oxidative deamination by glutamate dehydrogenase (GDH) [30].

Once glycine passes into a cell by uptake by GlyTs, the intracellular glycine concentration can be regulated via synthesis from L-serine within the cell, which itself can be synthesized from glycolysis intermediates and L-glutamate [24]. The major pathway for the glycine catabolism involves the oxidative cleavage of glycine to CO2, NH4+, and a methylene group (–CH2–), which is accepted by tetrahydrofolate (H4 folate) in a reversible reaction catalyzed by the glycine cleavage system (also called glycine synthase) [31]. The glycine cleavage system is essentially reversible but catalyzes glycine synthesis significantly only under anaerobic conditions, such as in anaerobic bacteria or anaerobic systems in vitro supplemented with NADH+H+ [32].

Taken together, all known information about the metabolic pathways suggests that glutamate and glycine self-regulate the processes of their concentration restoration and mutual transformation. Additionally, oxidative phosphorylation in the mitochondria also plays a key role in the balance of these AAs.
