biostudies-literatureZerbini EMinistero dell'Università e della RicercaMinistero dell'Università e della Ricercae70505https://www.ebi.ac.uk/biostudies/studies/S-EPMC12917857biostudies-literatureUnknown35(3)Emerging evidence suggests that sex-specific differences in L-serine (L-Ser) metabolism play a key role in Alzheimer's disease (AD). While disruptions in amino acid balance are well known, recent findings point to a dimorphic regulation of the serine biosynthetic pathway. To explore this, we examined post-translational modifications (PTMs) of D-3-phosphoglycerate dehydrogenase (PHGDH)-the rate-limiting enzyme for de novo L-Ser synthesis-as a potentialmechanism underlying this difference. PHGDH was immunoprecipitated from hippocampal tissue of healthy and AD-affected males and females and analyzed by mass spectrometry. Five phosphorylation sites (S55, T60, T78, S383, and S473) were shared across all groups, but a unique deacetylation at K289 appeared exclusively in AD males. Functional assaProtein science : a publication of the Protein SocietyPost-translational regulation of human D-3-phosphoglycerate dehydrogenase in Alzheimer's disease.PMC12917857PRIN 2017 (2017H4J3AS)Pollegioni LSacchi SMaffioli ERiva DZerbini ETedeschi GfalsePost-translational regulation of human D-3-phosphoglycerate dehydrogenase in Alzheimer's disease.Emerging evidence suggests that sex-specific differences in L-serine (L-Ser) metabolism play a key role in Alzheimer's disease (AD). While disruptions in amino acid balance are well known, recent findings point to a dimorphic regulation of the serine biosynthetic pathway. To explore this, we examined post-translational modifications (PTMs) of D-3-phosphoglycerate dehydrogenase (PHGDH)-the rate-limiting enzyme for de novo L-Ser synthesis-as a potentialmechanism underlying this difference. PHGDH was immunoprecipitated from hippocampal tissue of healthy and AD-affected males and females and analyzed by mass spectrometry. Five phosphorylation sites (S55, T60, T78, S383, and S473) were shared across all groups, but a unique deacetylation at K289 appeared exclusively in AD males. Functional assa2026-01-01T00:00:00Z2026 Mar2026-07-16T09:15:58.907Z2026-07-09T10:46:41.412ZS-EPMC129178574171116010.1002/pro.70505