Biochemical and cellular studies of three human 3 ‐phosphoglycerate dehydrogenase variants responsible for pathological reduced L‐serine levels

In the brain, L-serine is produced through the phosphorylated pathway (PP). hPHGDH catalyzes the first and rate-limiting step in the PP. Three variants related to hPHGDH deficiency and Neu-Laxova syndrome have been studied. V261M, V425M, and V490M substitutions alter the kinetic and structural properties of hPHGDH. Variants ectopic expression results in protein aggregation and reduced L-serine level. AbstractIn the brain, the non-essential amino acid L-serine is produced through the phosphorylated pathway (PP) starting from the glycolytic intermediate 3-phosphoglycerate: among the different roles played by this amino acid, it can be converted into D-serine and glycine, the two main co-agonists of NMDA receptors. In humans, the enzymes of the PP, namely phosphoglycerate dehydrogenase (hPHGDH, which catalyzes the first and rate-limiting step of this pathway), 3-phosphoserine aminotransferase, and 3-phosphoserine phosphatase are likely organized in the cytosol as a metabolic assembly (a “serinosome”). The hPHGDH deficiency is a pathological condition biochemically characterized by reduced levels of L-serine in plasma and cerebrospinal fluid and clinically identified by severe neurological impairment. Here, three single-point variants responsible for hPHGDH deficiency and Neu-La xova syndrome have been studied. Their biochemical characterization shows that V261M, V425M, and V490M substitutions alter either the kinetic (both maximal activity andKm for 3-phosphoglycerate in the...
Source: BioFactors - Category: Biochemistry Authors: Tags: RESEARCH ARTICLE Source Type: research