In addition for the function of

In addition, for the function of GSNOR in brain, since GSNOR is the sole alcohol dehydrogenase isozyme in brain, the failure to detect ethanol dehydrogenase activity poses a problem if it is assumed that this enzyme has evolved and developed as a protective mechanism for ethanol detoxification in that organ [46]. Our findings that GSNOR participates in the regulation of learning and memory may provide an answer to this dilemma: control of NO metabolism and GSNO/SNO Narciclasine receptor as demonstrated in the present study suggested a novel theory for understanding the presence of GSNOR in the brain. In conclusion, the present study demonstrated that fdh-controlled NO metabolism plays a key role in visual pattern memory of Drosophila. This mechanism may be involved in protein S-nitrosation modification and the NO-cGMP-PKG signaling pathway. GSNOR and NOS composed a double-control of NO bioactivity during synthesis and metabolism. GSNOR could be a potential novel target for curing dysfunctions related to NO bioactivity. Further studies are needed to determine how GSNOR regulates S-nitrosated proteins and thereby influences learning and memory.
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Introduction Nitric oxide has been recognized as a gaseous signalling molecule with important regulatory role across all types of organisms. Similarly to animals, a broad spectrum of NO functions been demonstrated also in plants, involving seed germination, plant growth, flowering, root development stomata movements and plant responses to various abiotic and biotic stress factors [1]. Post-translational modifications (PTMs) of proteins represent important features of NO-dependent signalling pathways. NO can bind to transition metals in their ionic forms such as iron (Fe2+ or Fe3+), copper (Cu2+) or zinc (Zn2+) to form metal-nitrosyl complexes in a process referred to as metal-nitrosylation [2]. Further, interaction of proteins with NO or derived reactive nitrogen species can result in protein nitration, a covalent attachment of a nitro-group (-NO2) to tyrosine or histidine residues [3]. However, protein S-nitrosation as the covalent attachment of a nitroso group (-NO) to protein cysteine thiols, has emerged as a crucial mechanism of NO biological activity [4]. An increasing number of S-nitrosation targets have been identified among proteins involved in crucial cellular processes like apoptosis, gene transcription or iron homeostasis [5], and disturbances in the control of S-nitrosothiol formation and catabolism are related with a series of pathological states [6]. S-nitrosoglutathione (GSNO) represents the major low molecular weight S-nitrosothiol, capable under specific conditions to release NO radical to participate in NO transport or in transnitrosation reactions, when a nitroso group is transferred from GSNO to another protein thiol group [7]. S-nitrosoglutathione reductase (GSNOR, EC 1.1.1.284) has been identified as a key enzyme in the regulation of S-nitrosation and formaldehyde detoxification [8]. GSNORs belong Zn-dependent class III alcohol dehydrogenases family (ADH3; EC 1.1.1.1), distinct from class I ADH family by a high affinity towards long-chain alcohols [9], [10]. ADH3 is considered the most effective formaldehyde-metabolising enzyme in vivo both in plant and animals [11], [12], [13]. NAD+-dependent oxidation of S-(hydroxymethyl)glutathione (HMGSH), a spontaneous adduct of formaldehyde with glutathione (GSH) catalysed by ADH3 represents a key step in the detoxification of exo- and endogenous formaldehyde, whereas NADH-dependent reduction of GSNO catalysed by ADH3/GSNOR is considered as an irreversible degradation step within NO and S-nitrosothiol metabolism. The reaction mechanism of GSNO reduction proceeds via an unstable intermediate N-hydroxysulfinamide (GSNHOH), which under physiological GSH levels in milimolar range is further converted to oxidised glutathione (GSSG) and N-hydroxylamine. However at low GSH level, when cells are exposed to stress factors such as toxic xenobiotics or oxidative stress, GSNHOH can spontaneously rearrange to glutathione sulfinamide (GSONH2), which is further hydrolysed to glutathione sulfinic acid (GSO2H) and NH3[14], [15].