Phosphoserine Aminotransferase has Conserved Active Site from Microbes to Higher Eukaryotes with Minor Deviations

Abstract

: Serine is ubiquitously synthesized in all living organisms from the glycolysis intermediate 3-phosphoglycerate (PGA) by phosphoserine biosynthetic pathway, consisting of three different enzymes, namely: 3-phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). Any functional defect or mutation in these enzymes may cause deliberating conditions, such as colon cancer progression and chemoresistance in humans. Phosphoserine aminotransferase (PSAT) is the second enzyme in this pathway that converts phosphohydroxypyruvate (PHP) to O-phospho-L-serine (OPLS). Humans encode two isoforms of this enzyme: PSAT1 and PSAT2. PSAT1 exists as a functional dimer, where each protomer has a large and a small domain; each large domain contains a Lys residue that covalently binds PLP. The PLP-binding site of human PSAT1 and most of its active site residues are highly conserved in all known PSAT structures except for Cys-80. Interestingly, Two PSAT structures from different organisms show halide binding near their active site. While the human PSAT1 shows a water molecule at this site with different interacting residues, suggesting the inability of halide binding in the human enzyme. Analysis of the human PSAT1 structure showed a big patch of positive charge around the active site, in contrast to the bacterial PSATs. Compared to human PSAT1, the PSAT2 isoform lacks 46 residues at its C-terminal tail. This tail region is present at the opening of the active site as observed in the other PSAT structures. Further structural work on human PSAT2 may reveal the functional importance of these 46 residues.

The mitochondrial enzyme FAHD1 regulates complex II activity in breast cancer cells and is indispensable for basal BT‐20 cells in vitro

“…As a substrate of the malate–aspartate shuttle, it enables the transport of OAA (in the form of aspartate) through the mitochondrial membrane. Similarly, glutamate provides the nitrogen for the molecule phosphoserine, a precursor for serine-biosynthesis [ 29 , 30 ]. In this process, the cofactor pyridoxal-5-phosphate plays a crucial role which is synthetized partially from glutamate and pyruvate.…”

Predicting the functional effect of compound heterozygous genotypes from large scale variant effect maps

“…The overall structural organization and active site architecture of PSAT are conserved with other members of the class IV family of aminotransferases [41], and phosphoserine aminotransferases from eukaryotic and prokaryotic organisms [46]. Evolutionary conservation scores for PSAT (pdb 3e77; subunit A) from the ConSurf DataBase [38,39], which are derived from sequence alignments of amino acid homologs with known structure, illustrate that more conserved (negative ConSurf score) regions localize near the active sites ( Figure 4.B ).…”

“…In PSAT, six interfacial residues, G78, G79, C80, Q199, N241*, and T242*(asterisk indicates residues from opposite subunit), bind to the phosphate group ( This residue (C80) is typically found as a serine, threonine (not SNV-accessible in human), or arginine in other organisms (ConSurf DataBase [38,39] profile for 3e77 subunit A). It has been hypothesized that C80 contributes to the higher phosphoserine substrate affinity (Km = 5 μM) observed in PSAT relative to other phosphoserine aminotransferases [46], and possibly the positive charge introduction represented by C80R negatively impacts this binding.…”

De novo serine biosynthesis from glucose predicts sex-specific response to antifolates in non-small cell lung cancer cell lines

“…Serine is an important one-carbon donor to the folate cycle and therefore contributes to nucleotide synthesis, NADPH generation, and methylation reactions ( Locasale, 2013 ; Minton et al., 2018 ; Mullarky et al., 2016 ; Singh et al., 2021 ; Tanaka et al., 2021 ; Tedeschi et al., 2013 ; Ye et al., 2014 ). The folate cycle is a well-studied target of multiple antifolate therapeutics.…”