Helicobacter pylori FabX contains a [4Fe-4S] cluster essential for unsaturated fatty acid synthesis

Jiashen Zhou, Lin Zhang, Liping Zeng, Lu Yu, Yuanyuan Duan, Siqi Shen, Jingyan Hu, Pan Zhang, Wenyan Song, Xiaoxue Ruan, Jing Jiang, Yinan Zhang, Lu Zhou, Jia Jia, Xudong Hang, Changlin Tian, Houwen Lin, Hong Zhuan Chen, John E. Cronan, Hongkai BiLiang Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Unsaturated fatty acids (UFAs) are essential for functional membrane phospholipids in most bacteria. The bifunctional dehydrogenase/isomerase FabX is an essential UFA biosynthesis enzyme in the widespread human pathogen Helicobacter pylori, a bacterium etiologically related to 95% of gastric cancers. Here, we present the crystal structures of FabX alone and in complexes with an octanoyl-acyl carrier protein (ACP) substrate or with holo-ACP. FabX belongs to the nitronate monooxygenase (NMO) flavoprotein family but contains an atypical [4Fe-4S] cluster absent in all other family members characterized to date. FabX binds ACP via its positively charged α7 helix that interacts with the negatively charged α2 and α3 helices of ACP. We demonstrate that the [4Fe-4S] cluster potentiates FMN oxidation during dehydrogenase catalysis, generating superoxide from an oxygen molecule that is locked in an oxyanion hole between the FMN and the active site residue His182. Both the [4Fe-4S] and FMN cofactors are essential for UFA synthesis, and the superoxide is subsequently excreted by H. pylori as a major resource of peroxide which may contribute to its pathogenic function in the corrosion of gastric mucosa.

Original languageEnglish (US)
Article number6932
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'Helicobacter pylori FabX contains a [4Fe-4S] cluster essential for unsaturated fatty acid synthesis'. Together they form a unique fingerprint.

Cite this