Structure of GTP cyclohydrolase I fromListeria monocytogenes, a potential anti-infective drug target

Abstract

A putative open reading frame encoding GTP cyclohydrolase I from Listeria monocytogenes was expressed in a recombinant Escherichia coli strain. The recombinant protein was purified and was confirmed to convert GTP to dihydroneopterin triphosphate (K m = 53 µM; v max = 180 nmol mg−1 min−1). The protein was crystallized from 1.3 M sodium citrate pH 7.3 and the crystal structure was solved at a resolution of 2.4 Å (R free = 0.226) by molecular replacement using human GTP cyclohydrolase I as a template. The protein is a D 5-symmetric decamer with ten topologically equivalent active sites. Screening a small library of about 9000 compounds afforded several inhibitors with IC50 values in the low-micromolar range. Several inhibitors had significant selectivity with regard to human GTP cyclohydrolase I. Hence, GTP cyclohydrolase I may be a potential target for novel drugs directed at microbial infections, including listeriosis, a rare disease with high mortality.

A Putative Guanosine Triphosphate Cyclohydrolase I Named CaGCH1 Is Involved in Hyphal Branching and Fruiting Development in Cyclocybe aegerita

“…A study reported that the disruption of GCH1 in S. cerevisiae leads to conditional lethality due to the obstruction of folinic acid synthesis ( Nardese et al, 1996 ). Another study reported that the important role of GCH1 in various physiological processes renders it suitable as a potential anti-infective drug target ( Schüssler et al, 2019 ), which was confirmed when the inhibitors of tetrahydrofolate biosynthesis were successfully able to control a wide variety of microbial and protozoan infections ( Swarbrick et al, 2008 ). However, the function of GCH1 in basidiomycetes has not been investigated so far.…”

Comprehensive analysis of GTP cyclohydrolase I activity in Mycobacterium tuberculosis H37Rv via in silico studies

“…In literature, through experiments, it has been proved in H. sapiens , the zinc ion binding residues (Cys‐141, His‐143, and Cys‐212) and residues present near active sites in GTPCH‐I protein [10]. L. monocytogenes has also used H. sapiens GTPCH‐I protein as a template for its structure analysis [37]. So, here we have aligned GTPCH‐I protein of human with GTPCH‐I protein of M. tuberculosis H 37 Rv.…”

“…In Listeria monocytogenes , which causes listeriosis (food borne disease) in humans, its folE gene ortholog has been used for drug target. Inhibitor with IC 50 of 13 μM has been used, which is less effective against human GTPCH‐I (IC > 500 μM) [37]. Even in humans, this GTPCH‐I protein is targeted for pain relief [25].…”