Structural highlights
FunctionPublication Abstract from PubMedThe Ethylmalonic Encephalopathy Protein 1 (ETHE1) catalyzes the oxygen dependent oxidation of glutathione persulfide 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-beta-lactamase fold superfamily. We report crystallographic analysis of hETHE1 in complex with iron to 2.6 A resolution. hETHE1 contains an alphabetabetaalpha MBL-fold, which supports metal-binding by the side-chains of an aspartate- and two histidine- residues; three water molecules complete an octahedral coordination of 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 two histidine-, and aspartate- residues involved in iron-binding in ETHE1, occupy similar positions to those observed by 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 glutathione persulfide 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. Crystal Structure of Human Persulfide Dioxygenase: Structural Basis of Ethylmalonic Encephalopathy.,Pettinati I, Brem J, McDonough MA, Schofield CJ Hum Mol Genet. 2015 Jan 16. pii: ddv007. PMID:25596185[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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