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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\u2010translational modifications (PTMs) of D\u20103\u2010phosphoglycerate dehydrogenase (PHGDH)\u2014the rate\u2010limiting enzyme for de novo L\u2010Ser synthesis\u2014as a potentialmechanism underlying this difference. PHGDH was immunoprecipitated from hippocampal tissue of healthy and AD\u2010affected 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 assays using recombinant PHGDH variants revealed that changes at solvent\u2010exposed sites (K289, S383, and S473) reduced solubility, while phosphomimetic substitutions at S55 and T78 within the catalytic cleft strongly impaired activity. Notably, mimicking acetylation at K289 improved protein stability. Overall, these PTMs act both as subtle modulators and as on\/off switches, fine\u2010tuning PHGDH function and potentially contributing to sex\u2010dependent metabolic vulnerability in AD.<\/jats:p>","DOI":"10.1002\/pro.70505","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T11:36:51Z","timestamp":1771501011000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Post\u2010translational regulation of human D\u20103\u2010phosphoglycerate dehydrogenase in Alzheimer's disease"],"prefix":"10.1002","volume":"35","author":[{"given":"Elena","family":"Zerbini","sequence":"first","affiliation":[{"name":"Department of Biotechnology and Life Sciences University of Insubria  Varese Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Riva","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Life Sciences University of Insubria  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