Crystal structure of mitochondrial quinol-fumarate reductase from the parasitic nematode Ascaris suum

Abstract

In the anaerobic respiratory chain of the parasitic nematode Ascaris suum, complex II couples the reduction of fumarate to the oxidation of rhodoquinol, a reverse reaction catalyzed by mammalian complex II. In this study, the first structure of anaerobic complex II of mitochondria was determined. The structure, composed of four subunits and five co-factors, is similar to that of aerobic complex II, except for an extra peptide found in the smallest anchor subunit of the A. suum enzyme. We discuss herein the structure-function relationship of the enzyme and the critical role of the low redox potential of rhodoquinol in the fumarate reduction of A. suum complex II.

Catalytic mechanisms of complex II enzymes: A structural perspective

“…To date, the X-ray crystal structures of six complex II superfamily enzymes have been determined [5-10]. These structures represent three subfamilies: subfamily B (one membrane-spanning polypeptide with five helices and two b -type hemes, exemplified by the Wolinella succinogenes QFR [6]), type C (two membrane spanning polypeptides that each have three membrane-spanning helices, exemplified by the E. coli [7], porcine [8], and avian [9] SQRs, and the Ascaris suum QFR [10]), and subfamily D (two membrane spanning polypeptides each containing three helices and no b -type heme, exemplified by the E. coli QFR [5]).…”

“…Intriguingly, X-ray crystal structures have demonstrated that the oligomerization state of complex II proteins differs both across the superfamily and across subfamilies with “monomers” [5, 8-10] (where a monomer is defined as the SdhA/B/C/D or FrdA/B/C/(D)), dimers [6], and trimers [7] all observed to date. The impact of the differences in oligomerization is not yet understood, however it is clear that the chemical reaction proceeds through the monomer.…”

“…1) and W. succinogenes [6] provided the first high-resolution information about the complex II superfamily and represent subfamilies D and B, respectively. The crystal structure of the QFR from the eukaryotic parasite A. suum has only recently been determined [10] and belongs to subfamily C. As anticipated, these three enzymes each have similar folds in the soluble domains. Interestingly, the membrane spanning domains, where menaquinol oxidation takes place, are all arranged around a four-helix bundle [12, 13].…”

The competition between chemistry and biology in assembling iron–sulfur derivatives. Molecular structures and electrochemistry. Part II. {[Fe2S2](SγCys)4} proteins

“…The crystal structure of quinol fumarate reductase (QFR) of A. suum is available [258]. As discussed in Sections 2.…”

The Open Form Inducer Approach for Structure-Based Drug Design

“…Previously, we reported the crystal structures of TAO in complex with ascofuranone derivatives (3VVA and 3W54)[27] as well as A . suum QFR in complex with flutolanil (3VR9 and 3VRB)[28] , [29] , [30], its derivatives (4YSZ, 4YT0, 4YTM, 4YSX and 4YSY) and the substrate rhodoquinone (5C2T)[31], providing structural insights into their inhibition mechanisms. Both type of inhibitors bind to the quinol binding site of each target.…”