Abstract
Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF). In vivo, 5,10-meTHF is the main carrier of one-carbon (1C) units, which are utilized for nucleotide biosynthesis and other processes crucial for every living cell, but hyperactivated in overproliferating cells (e.g. cancer tissues). SHMTs are emerging as a promising target for development of new drugs because it appears possible to inhibit growth of cancer cells by cutting off the supply of 5,10-meTHF. Methotrexate (MTX) and pemetrexed (PTX) are two examples of antifolates that have cured many patients over the years but target different enzymes from the folate cycle (mainly dihydrofolate reductase and thymidylate synthase, respectively). Here we show crystal structures of MTX and PTX bound to plant SHMT isozymes from cytosol and mitochondria—human isozymes exist in the same subcellular compartments. We verify inhibition of the studied isozymes by a thorough kinetic analysis. We propose to further exploit antifolate scaffold in development of SHMT inhibitors because it seems likely that especially polyglutamylated PTX inhibits SHMTs in vivo. Structure-based optimization is expected to yield novel antifolates that could potentially be used as chemotherapeutics.
Highlights
Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF)
The THF substrate inhibition constant (Ki) with human and plant mitochondrial SHMTs stays more or less constant as pH is varied, whereas this parameter is greatly increased as pH increases with human and plant cytosolic isoforms
Dependence of KM for THF is similar between human and A. thaliana SHMT isoforms: this parameter stays constant with the mitochondrial isoforms and increases as pH is increased with the cytosolic isoforms
Summary
Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF). Increased activity of the glycine cleavage system (GCS) in the mitochondrial matrix results in high 5,10-meTHF/THF ratio[10,11,12]. This way, the SHMT-catalyzed reaction is one of the three pathways used by plants for serine biosynthesis[13]. Due to its very poor ability to cross the blood-brain barrier, MTX is administered at remarkably high doses to obtain therapeutic concentrations in the tumor tissue and in lymphoma-surrounding neural tissue[18] Such toxic levels of the drug impact non-cancer cells. To the MTX therapy, patients taking PTX are usually supported with folate
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