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  • br GSNOR activity and functions

    2021-09-18


    GSNOR activity and functions The identification of the enzyme responsible for GSNO decomposition dates back to 1998, when Jensen and colleagues described an NAD(P)H-dependent GSNO catabolizing activity in cytosolic fractions obtained from rat liver [16]. Upon purification, they identified this enzyme being, actually, the class III alcohol dehydrogenase (ADH III), also known as GSH-dependent formaldehyde dehydrogenase (GSH-FDH) [16], [17]. ADHIII catalyzes the second step of formaldehyde oxidation to formate. In particular, it participates to NAD(P)+-dependent oxidation of S-hydroxymethylglutathione (GSCH2OH), which is an intermediate generated by the spontaneous and reversible interaction between GSH and formaldehyde. Identified in the early 70s together with the other members of the ADH family [17], it became clear that GSH-FDH was identical to ADH III only in the late 80s [18] and, almost ten years afterwards, the same enzyme was identified as also being involved in GSNO metabolism.
    Class III ADHs are enzymes ubiquitously present in all mammals [10], [35]. Coding sequence is evolutionarily conserved, underscoring a crucial role for GSNOR as formaldehyde detoxifier and redox tuner. In humans, GSNOR is encoded by the gene ADH5[36]. Unlike other ADHs, whose expression is mostly tissue-specific, GSNOR is copiously expressed in all tissues [37], [38], in particular in liver, LGX818 and kidney, and it represents the only ADH present in brain, placenta, and testis [39], [40], [41].
    GSNOR in cell development and physiopathology
    Discussion and future directions In the last fifteen years, S-nitrosylation has been rapidly established as the major redox posttranslational modification of reactive cysteines. Many proteins have been discovered being subjected to S-nitrosylation and, thus modified, found out to change activity, localization, function and stability, this deeply impacting on cellular process and contributing to human diseases. The discovery of Trx, and mostly GSNOR, as enzymes committed to remove NO moiety from proteins was a milestone of redox biology, as denitrosylation was demonstrated to occur via enzymatic catalysis, meaning that it could be regulated. Since then, a great amount of papers aimed at showing the plethora of cellular processes in which GSNOR was involved, or phenotypes caused by its genetic ablation, accumulated. However, many pieces of the puzzle are still missing. Indeed, notwithstanding the great amount of information supporting the importance of GSNOR in physiological process, we still do not know how GSNOR mediate selective denitrosylation of PSNOs. We have still no idea about the mechanisms able to transform GSNOR from an indirect (hence intrinsically non-specific) denitrosylase – which actually acts by GSNO-mediated trans-nitrosylation – into a very selective enzyme. Future studies will be directed to fill this gap; however, some indications, arguing for localization being the determinant of GSNOR selectivity, are emerging. In a way resembling S-nitrosylase complexes conveying NO on target proteins [113], in cardiomyocytes GSNOR has been found to co-localize with eNOS just underneath the sarcolemma where RyR2 is also placed [108]. This suggests that RyR2 cycles of nitrosylation and denitrosylation can be sustained by GSNO and maintained by close proximity of different modules of a unique system. In particular, i) signal generator (NOS), ii) protein target and iii) signal modulators (GSNOR/GSNO) could functionally interact in a very specific manner, in order to maximize selectivity and temporality of S-nitrosylation. This aspect, as well as figuring out potential posttranslational modifications that are involved in GSNOR localization, or in modulating its interaction with other proteins, deserves to be investigated in order to provide in the future a detailed understanding of S-nitrosylation dynamics and signaling pathways depending on it.
    Acknowledgements The authors gratefully acknowledge M. Francesca Allega for valuable help she provided in making Fig. 1, Fig. 5, and Laila Fisher for secretarial work. This work has been supported by grants from the Danish Cancer Society (R72-A4647; R146-A9414); the Italian Association for Cancer Research, (AIRC-MFAG 2011 n.1145). We are also grateful to the Bjarne Saxhof Foundation to have sustained this research. Moreover, lab in Copenhagen is part of the newly established Center of Excellence in Autophagy, Recycling and Disease (CARD), funded by the Danish National Research Foundation.