The reference OMIM entry for this protein is 607037

Enoyl-coa hydratase/3-hydroxyacyl coa dehydrogenase; ehhadh
L-bifunctional protein, peroxisomal; lbfp; lbp

DESCRIPTION

The EHHADH gene encodes an enzyme involved in peroxisomal oxidation of fatty acids and is expressed in the proximal renal tubule (summary by Klootwijk et al., 2014).

CLONING

Hoefler et al. (1994) reported the full-length cDNA sequence of the enoyl-CoA-hydratase:3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme. The cDNA sequence spans 3,779 nucleotides with an open reading frame of 2,169 nucleotides. In human kidney tissue, Klootwijk et al. (2014) found strong immunostaining of EHHADH in the terminal segments of the proximal tubule.

GENE FUNCTION

Zhao et al. (2010) showed that lysine acetylation is a prevalent modification in enzymes that catalyze intermediate metabolism in the human liver. Virtually every enzyme in glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, the urea cycle, fatty acid metabolism, and glycogen metabolism was found to be acetylated in human liver tissue. The concentration of metabolic fuels, such as glucose, amino acids, and fatty acids, influenced the acetylation status of metabolic enzymes. Acetylation activated EHHADH in fatty acid oxidation and malate dehydrogenase (see 154200) in the TCA cycle, inhibited argininosuccinate lyase in the urea cycle, and destabilized phosphoenolpyruvate carboxykinase (261680) in gluconeogenesis. Zhao et al. (2010) concluded that acetylation plays a major role in metabolic regulation.

MAPPING

By fluorescence in situ hybridization, Hoefler et al. (1994) localized the EHHADH gene to chromosome 3q26.3-q28.

MOLECULAR GENETICS

In affected members of a family with autosomal dominant Fanconi renotubular syndrome-3 (FRTS3; 615605), originally reported by Tolaymat et al. (1992), Klootwijk et al. (2014) identified a heterozygous mutation in the EHHADH gene (E3K; 607037.0001). The mutation was found by genomewide linkage analysis followed by Sanger sequencing of candidate genes in the region. Transfection of the mutation into several cell lines, including a renal proximal tubular cell line, showed that the mutant protein localized to mitochondria as well as to peroxisomes, whereas wildtype EHHADH localized only to peroxisomes. Transfected renal tubular cells showed a defect in the transepithelial transport of fluids, with an inability to maintain fluid-filled domes in confluent monolayers, as well as a defect in luminal to basolateral transport of a glucose surrogate. These changes were associated with a defect in mitochondrial respiration and impaired ATP production. Mutant EHHADH coimmunoprecipitated with mitochondrial HADHA (600890) and HADHB (143450), which likely impaired mitochondrial function. These findings, combined with the lack of renal or mitochondrial dysfunction in Ehhadh-null mice, were consistent with a dominant-negative toxic effect of the mutant EHHADH protein rather than haploinsufficiency. The patients had onset in early childhood of metabolic acidosis, glucosuria, phosphaturia, aminoaciduria, and proteinuria, but did not develop renal failure. Some patients had rickets and poor growth. Klootwijk et al. (2014) noted that proximal tubular cells use fatty acid oxidation as the predominant energy source, and that proper mitochondrial function is required for renal tubular reabsorption.

HISTORY

A number of patients with presumed L-bifunctional protein deficiency were later found to have D-bifunctional protein deficiency; see 261515.

ANIMAL MODEL

Qi et al. (1999) generated ... More on the omim web site

Subscribe to this protein entry history

June 29, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 607037 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).