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.
Highlights
Ethylmalonic encephalopathy (EE; OMIM: 602473) is an inborn autosomal-recessive disorder that has severe gastrointestinal and neurological effects in infants [1,2,3]
Structure-based topology diagrams show conserved structural organization with the exception of the addition of the β11–β12 hairpin in the region linking β10 and β13 of the core fold of hETHE1 compared with the A. thaliana encephalopathy protein 1 (ETHE1) (Supplementary Material, Figs S2A and B)
The results reveal that there are clearly specific differences in the active site metal binding of hETHE1 compared with both other eukaryotic MBL-fold enzymes [19] and the classical bacterial MBLs [12]; the degree of conservation is striking
Summary
Ethylmalonic encephalopathy (EE; OMIM: 602473) is an inborn autosomal-recessive disorder that has severe gastrointestinal and neurological effects in infants [1,2,3]. EE is caused by mutations to the gene (HGNC: 23287) encoding for the ethylmalonic encephalopathy protein 1 (ETHE1, known as sulphur dioxygenase, SDO) [4,5,6] and correlates with increased cellular levels of hydrogen sulfide. Hydrogen sulfide is highly toxic above low threshold levels, it is proposed as a gaseous redox signalling molecule. Abnormally increased hydrogen sulfide levels have the potential to result in highly pleiotropic and toxic effects consistent with the lethal phenotype observed in infants with EE [7]. A deficiency of hydrogen sulfide is proposed to be of pathophysiological relevance, arising perhaps as a consequence of cross-talk with nitric oxide or other reactive oxygen species involved in signalling [10]. ETHE1 is a non-heme iron-dependent oxygenase that catalyses the biochemically interesting oxidation of glutathione persulfide (GSSH) to give glutathione and persulfite [11] [Eq [1]]
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