Murine serine racemase (SR), the enzyme responsible for the biosynthesis of the neuromodulator D-serine, was reported to form a complex with glyceraldehyde 3-phosphate dehydrogenase (GAPDH), resulting in SR inhibition. In this work, we investigated the interaction between the two human orthologues. We were not able to observe neither the inhibition nor the formation of the SR-GAPDH complex. Rather, hSR is inhibited by the hGAPDH substrate glyceraldehyde 3-phosphate (G3P) in a time- and concentration-dependent fashion, likely through a covalent reaction of the aldehyde functional group. The inhibition was similar for the two G3P enantiomers but it was not observed for structurally similar aldehydes. We ruled out a mechanism of inhibition based on the competition with either pyridoxal phosphate (PLP) – described for other PLP-dependent enzymes when incubated with small aldehydes – or ATP. Nevertheless, the inhibition time course was affected by the presence of hSR allosteric and orthosteric ligands, suggesting a conformation-dependence of the reaction.

Human serine racemase is inhibited by glyceraldehyde 3-phosphate, but not by glyceraldehyde 3-phosphate dehydrogenase / Michielon, A.; Marchesani, F.; Faggiano, S.; Giaccari, R.; Campanini, B.; Bettati, S.; Mozzarelli, A.; Bruno, S.. - In: BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS. - ISSN 1570-9639. - 1869:1(2021), pp. 140544.1-140544.7. [10.1016/j.bbapap.2020.140544]

Human serine racemase is inhibited by glyceraldehyde 3-phosphate, but not by glyceraldehyde 3-phosphate dehydrogenase

Michielon A.;Marchesani F.;Faggiano S.;Giaccari R.;Campanini B.;Bettati S.;Mozzarelli A.;Bruno S.
2021-01-01

Abstract

Murine serine racemase (SR), the enzyme responsible for the biosynthesis of the neuromodulator D-serine, was reported to form a complex with glyceraldehyde 3-phosphate dehydrogenase (GAPDH), resulting in SR inhibition. In this work, we investigated the interaction between the two human orthologues. We were not able to observe neither the inhibition nor the formation of the SR-GAPDH complex. Rather, hSR is inhibited by the hGAPDH substrate glyceraldehyde 3-phosphate (G3P) in a time- and concentration-dependent fashion, likely through a covalent reaction of the aldehyde functional group. The inhibition was similar for the two G3P enantiomers but it was not observed for structurally similar aldehydes. We ruled out a mechanism of inhibition based on the competition with either pyridoxal phosphate (PLP) – described for other PLP-dependent enzymes when incubated with small aldehydes – or ATP. Nevertheless, the inhibition time course was affected by the presence of hSR allosteric and orthosteric ligands, suggesting a conformation-dependence of the reaction.
2021
Human serine racemase is inhibited by glyceraldehyde 3-phosphate, but not by glyceraldehyde 3-phosphate dehydrogenase / Michielon, A.; Marchesani, F.; Faggiano, S.; Giaccari, R.; Campanini, B.; Bettati, S.; Mozzarelli, A.; Bruno, S.. - In: BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS. - ISSN 1570-9639. - 1869:1(2021), pp. 140544.1-140544.7. [10.1016/j.bbapap.2020.140544]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2882081
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