Publication

Article Metrics

Citations


Online attention

Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy

DOI: 10.1093/hmg/ddv007 DOI Help
PMID: 25596185 PMID Help

Authors: I. Pettinati (University of Oxford) , J. Brem (University of Oxford) , M. A. Mcdonough (University of Oxford) , C. J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Human Molecular Genetics , VOL 24 (9) , PAGES 2458 - 2469

State: Published (Approved)
Published: April 2015

Open Access Open Access

Abstract: The ethylmalonic encephalopathy protein 1 (ETHE1) catalyses the oxygen-dependent oxidation of glutathione persulfide (GSSH) to give persulfite and glutathione. Mutations to the hETHE1 gene compromise sulfide metabolism leading to the genetic disease ethylmalonic encephalopathy. hETHE1 is a mono-iron binding member of the metallo-β-lactamase (MBL) fold superfamily. We report crystallographic analysis of hETHE1 in complex with iron to 2.6 Å resolution. hETHE1 contains an αββα MBL-fold, which supports metal-binding by the side chains of an aspartate and two histidine residues; three water molecules complete octahedral coordination of the iron. The iron binding hETHE1 enzyme is related to the ‘classical’ di-zinc binding MBL hydrolases involved in antibiotic resistance, but has distinctive features. The histidine and aspartate residues involved in iron-binding in ETHE1, occupy similar positions to those observed across both the zinc 1 and zinc 2 binding sites in classical MBLs. The active site of hETHE1 is very similar to an ETHE1-like enzyme from Arabidopsis thaliana (60% sequence identity). A channel leading to the active site is sufficiently large to accommodate a GSSH substrate. Some of the observed hETHE1 clinical mutations cluster in the active site region. The structure will serve as a basis for detailed functional and mechanistic studies on ETHE1 and will be useful in the development of selective MBL inhibitors.

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography