Distinct biochemical properties of human serine hydroxymethyltransferase compared with the Plasmodium enzyme: implications for selective inhibition.

摘要: Serine hydroxymethyltransferase (SHMT) catalyzes the transfer of a hydroxymethyl group from l-serine to tetrahydrofolate yield glycine and 5,10-methylenetetrahydrofolate. Our previous investigations have shown that SHMTs Plasmodium spp. (P. falciparum, Pf; P. vivax, Pv) are different enzyme rabbit liver in Plasmodium SHMT can use d-serine as substrate. In this report, biochemical biophysical properties human cytosolic form (hcSHMT) enzymes including ligand binding kinetics were investigated. The data indicate that, similar enzymes, hcSHMT However, displays many those enzymes. molar absorption coefficient hcSHMT-bound pyridoxal-5′-phosphate (PLP) is much greater than PvSHMT-bound or PfSHMT-bound PLP. interactions with different, only undergoes formation quinonoid-like species upon d-serine. Furthermore, it has been noted strong substrate inhibition by (THF) (at THF > 40 μm), compared other species. pH–activity profile shows higher activities at lower pH values corresponding pKa value 7.8 ± 0.1. Thiosemicarbazide reacts following one-step model [k1 12 ± 0.6 m−1·s−1 k−1 (1.0 ± 0.6) × 10−3 s−1], while same reaction PfSHMT involves least three steps. All indicated environment SHMT indicating should be possible develop species-selective inhibitors future studies. Database serine hydroxymethyltransferase, EC 2.1.2.1; 5,10-methylenetetrahydrofolate dehydrogenase, 1.5.1.5