Structural basis of fumarate hydratase deficiency

Abstract

Fumarate hydratase catalyzes the stereospecific hydration across the olefinic double bond in fumarate leading to L-malate. The enzyme is expressed in mitochondrial and cytosolic compartments, and participates in the Krebs cycle in mitochondria, as well as in regulation of cytosolic fumarate levels. Fumarate hydratase deficiency is an autosomal recessive trait presenting as metabolic disorder with severe encephalopathy, seizures and poor neurological outcome. Heterozygous mutations are associated with a predisposition to cutaneous and uterine leiomyomas and to renal cancer. The crystal structure of human fumarate hydratase shows that mutations can be grouped into two distinct classes either affecting structural integrity of the core enzyme architecture, or are localized around the enzyme active site. An interactive version of this manuscript (which may contain additional mutations appended after acceptance of this manuscript) may be found on the SSIEM website at: http://www.ssiem.org/resources/structures/FH .

Fig. 1

Ribbon/surface diagram of human fumarate hydratase illustrating the tetrameric assembly of class II fumarases. Molecular surface representation is used to convey the overall shape of each monomer as well as the tetrameric assembly. Each monomer has been coloured distinctively, to facilitate visualization. Two monomers are represented using semi-transparent surfaces, to highlight the fold (represented as ribbons). One of the active sites is highlighted in red, showing contribution of three distinct subunits. The figures were generated using the program ICM (www.molsoft.com)

Fig. 2

Clustering of human fumarase missense mutations observed in FHD, MCUL1 and HLRCC. The active site is highlighted in cyan. Positions of amino acid mutations are indicated as small spheres and numbered according to Table 2. The positions around the active site are indicated in red, mutations affecting inter- or intrasubunit interactions are indicated in dark yellow. For clarity, one monomeric subunit is omitted