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Significance of redox-active cysteines in human FAD synthase isoform 2. | LitMetric

Significance of redox-active cysteines in human FAD synthase isoform 2.

Biochim Biophys Acta

Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari "A. Moro", via Orabona 4, I-70126 Bari, Italy; Istituto di Biomembrane e Bioenergetica (IBBE), CNR, via Amendola 165/A, I-70126 Bari, Italy. Electronic address:

Published: December 2014

AI Article Synopsis

  • FAD synthase (FADS) is the last enzyme that converts riboflavin into FAD in humans and exists in different isoforms, with Isoform 2 having two specific domains responsible for its catalytic and regulatory functions.
  • Isoform 2 contains ten cysteine residues which may play a critical role in the synthesis of FAD and its delivery to flavoproteins, with specific mutants showing reduced synthesis rates.
  • Research involving mass spectrometry has identified stable and unstable disulfide bonds in FADS, indicating the importance of cysteine residues in its catalytic process and suggesting a redox switch mechanism in its function.

Article Abstract

FAD synthase (FMN:ATP adenylyl transferase, FMNAT or FADS, EC 2.7.7.2) is the last enzyme in the pathway converting riboflavin into FAD. In humans, FADS is localized in different subcellular compartments and exists in different isoforms. Isoform 2 (490-amino acids) is organized in two domains: the 3'-phosphoadenosine-5'-phosphosulfate (PAPS) reductase domain, that is the FAD-forming catalytic domain, and one resembling a molybdopterin-binding (MPTb) domain, with a hypothetical regulatory role. hFADS2 contains ten Cys residues, seven of which located in the PAPS reductase domain, with a possible involvement either in FAD synthesis or in FAD delivery to cognate apo-flavoproteins. A homology model of the PAPS reductase domain of hFADS2 revealed a co-ordinated network among the Cys residues in this domain. In this model, C312 and C303 are very close to the flavin substrate, consistent with a significantly lowered FAD synthesis rate in C303A and C312A mutants. FAD synthesis is also inhibited by thiol-blocking reagents, suggesting the involvement of free cysteines in the hFADS2 catalytic cycle. Mass spectrometry measurements and titration with thiol reagents on wt hFADS2 and on several individual cysteine/alanine mutants allowed us to detect two stably reduced cysteines (C139 and C241, one for each protein domain), two stable disulfide bridges (C399-C402, C303-C312, both in the PAPS domain), and two unstable disulfides (C39-C50; C440-C464). Whereas the C39-C50 unstable disulfide is located in the MPTb domain and appears to have no catalytic relevance, a cysteine-based redox switch may involve formation and breakdown of a disulfide between C440 and C464 in the PAPS domain.

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Source
http://dx.doi.org/10.1016/j.bbapap.2014.08.005DOI Listing

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