Ethylmalonic Encephalopathy Is Caused by Mutations in ETHE1, a Gene Encoding a Mitochondrial Matrix Protein

Abstract

Ethylmalonic encephalopathy (EE) is a devastating infantile metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels. High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle. By use of a combination of homozygosity mapping, integration of physical and functional genomic data sets, and mutational screening, we identified GenBank D83198 as the gene responsible for EE. We also demonstrated that the D83198 protein product is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The gene had previously been known as "HSCO" (for hepatoma subtracted clone one). However, given its role in EE, the name of the gene has been changed to "ETHE1." The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism.

Mechanism-based inhibition of human persulfide dioxygenase by γ-glutamyl-homocysteinyl-glycine

“…Binding of GSSH displaces a water molecule as the sulfane sulfur coordinates to the iron [2]. Oxygen binding displaces a second water molecule and gives rise to the Fe(III)-superoxo complex [3], which exists in resonance with structure [4] in which the coordinated sulfur has a radical cation character. Recombination of the iron-coordinated sulfur leads to formation of a cyclic-peroxo intermediate [5].…”

“…Binding of O 2 displaces a second water ligand and results in the formation of a ferric-superoxo complex [3]. The latter, via resonance, gives a radical cation character to the coordinated sulfane sulfur on the substrate [4]. Recombination of the superoxo and sulfur radical species yields a cyclic peroxo intermediate [5], followed by homolytic cleavage of the O-O bond resulting in a sulfoxy-cation intermediate and an Fe(II)-bound activated oxygen [6].…”

“…Mutations in PDO lead to an increase in the levels of thiosulfate and sulfide in EE patients and in ethe1 -/-mice (4,5). The majority of the patient mutations clusters around the iron-coordinating residues and the active site pocket suggesting that they disrupt metal and substrate binding and lead to enzyme destabilization.…”

“…EE is caused by mutations in the ethe1 gene that encodes persulfide dioxygenase (PDO or ETHE1). Over 20 mutations have been described in the ethe1 gene, of which a subset represents missense mutations (3,4,6).…”

“…EE is caused by mutations in the ethe1 gene that encodes persulfide dioxygenase (PDO or ETHE1). Over 20 mutations have been described in the ethe1 gene, of which a subset represents missense mutations (3,4,6).PDO is a mitochondrial matrix protein that participates in the mitochondrial sulfide oxidation pathway, which converts H 2 S to the end products, thiosulfate and sulfate (7,8). In addition to PDO, the other enzymes involved in the mitochondrial sulfur oxidation pathway are sulfide quinone oxidoreductase (9), rhodanese (10), and sulfite oxidase (11).…”