Phosphoserine aminotransferase

Phosphoserine aminotransferase (PSAT1) is a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the second step of L-serine biosynthesis, converting 3-phosphohydroxypyruvate and L-glutamate to O-phosphoserine and alpha-ketoglutarate (UniProt: Q9Y617). Beyond its role in amino acid metabolism, PSAT1 acts as a ferroptosis inhibitor by stabilizing GPX4 through interaction and delivery of 2-oxoglutarate to EGLN3, following phosphorylation by CAMK2A.

Mutations in PSAT1 cause two rare genetic disorders: phosphoserine aminotransferase deficiency (PSATD), characterized by seizures, microcephaly, and developmental delay; and Neu-Laxova syndrome 2 (NLS2), a severe lethal malformation syndrome affecting multiple organ systems and involving CNS anomalies. These conditions highlight the critical importance of serine biosynthesis in neurological development and function.

In Alzheimer's disease, PSAT1 is significantly upregulated in human post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics: mean log2 fold-change +0.75 across 3 subcellular fractions from TMT-labeled proteomics). This elevation may reflect altered amino acid metabolism or ferroptosis regulation in the AD brain microenvironment.