Structural Analyses of <i>Helicobacter</i> <i>Pylori</i> FolC Conducting Glutamation in Folate Metabolism

• Main Authors: Joon Sung Park, Hyoun Sook Kim, Sang Ho Park, Mi Seul Park, Sung-Min Kang, Hyun-Jung Kim, Byung Woo Han
• Format: Article
• Language: English
• Published: MDPI AG 2019-08-01
• Series: Crystals
• Subjects: bifunctional FolC; dihydrofolate synthetase (DHFS); folate metabolism; folylpolyglutamate synthetase (FPGS); <i>Helicobacter</i> <i>pylori</i>
• Online Access: https://www.mdpi.com/2073-4352/9/8/429

FolC plays important roles in the folate metabolism of cells by attaching <span style="font-variant: small-caps;">l</span>-Glu to dihydropteroate (DHP) and folate, which are known activities of dihydrofolate synthetase (DHFS) and folylpolyglutamate synthetase (FPGS), respectively. Here, we determined the crystal structure of <i>Helicobacter</i> <i>pylori</i> FolC (<i>Hp</i>FolC) at 1.95 &#197; resolution using the single-wavelength anomalous diffraction method. <i>Hp</i>FolC has globular N- and C-terminal domains connected by a single loop, and a binding site for ATP is located between the two domains. Apo-<i>Hp</i>FolC was crystallized in the presence of citrate in a crystallization solution, which was held in the ATP-binding site. Structural motifs such as the P-loop and &#937;-loop of <i>Hp</i>FolC for binding of ATP and two magnesium ions are well conserved in spite of the low overall sequence similarity to other FolC/FPGSs. The &#937;-loop would also recognize a folate molecule, and the DHP-binding loop of <i>Hp</i>FolC is expected to exhibit a unique recognition mode on DHP, compared with other FolCs. Because human FolC is known to only exhibit FPGS activity, the DHFS activity of bacterial FolC is an attractive target for the eradication of pathogenic bacteria. Consequently, our structural analyses of <i>Hp</i>FolC provide a valuable foundation for a universal antibacterial strategy against <i>H.</i> <i>pylori</i> as well as other pathogenic bacteria.