Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction

Peng J, Alam S, Radhakrishnan K, Mariappan M, Rudolph MG, May C, Dierks T, von Figura K, Schmidt B (2015)
FEBS Journal 282(17): 3262-3274.

Journal Article | Published | English

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Abstract
C alpha-formylglycine (FGly) is the catalytic residue of sulfatases in eukaryotes. It is generated by a unique post-translational modification catalysed by the FGly-generating enzyme (FGE) in the endoplasmic reticulum. FGE oxidizes a cysteine residue within the conserved CxPxR sequence motif of nascent sulfatase polypeptides to FGly. Here we show that this oxidation is strictly dependent on molecular oxygen (O-2) and consumes 1 mol O-2 per mol FGly formed. For maximal activity FGE requires an O-2 concentration of 9% (105 mu M). Sustained FGE activity further requires the presence of a thiol-based reductant such as DTT. FGly is also formed in the absence of DTT, but its formation ceases rapidly. Thus inactivated FGE accumulates in which the cysteine pair Cys336/Cys341 in the catalytic site is oxidized to form disulfide bridges between either Cys336 and Cys341 or Cys341 and the CxPxR cysteine of the sulfatase. These results strongly suggest that the Cys336/Cys341 pair is directly involved in the O-2-dependent conversion of the CxPxR cysteine to FGly. The available data characterize eukaryotic FGE as a monooxygenase, in which Cys336/Cys341 disulfide bridge formation donates the electrons required to reduce one oxygen atom of O-2 to water while the other oxygen atom oxidizes the CxPxR cysteine to FGly. Regeneration of a reduced Cys336/Cys341 pair is accomplished in vivo by a yet unknown reductant of the endoplasmic reticulum or in vitro by DTT. Remarkably, this monooxygenase reaction utilizes O-2 without involvement of any activating cofactor.
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Peng J, Alam S, Radhakrishnan K, et al. Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction. FEBS Journal. 2015;282(17):3262-3274.
Peng, J., Alam, S., Radhakrishnan, K., Mariappan, M., Rudolph, M. G., May, C., Dierks, T., et al. (2015). Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction. FEBS Journal, 282(17), 3262-3274.
Peng, J., Alam, S., Radhakrishnan, K., Mariappan, M., Rudolph, M. G., May, C., Dierks, T., von Figura, K., and Schmidt, B. (2015). Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction. FEBS Journal 282, 3262-3274.
Peng, J., et al., 2015. Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction. FEBS Journal, 282(17), p 3262-3274.
J. Peng, et al., “Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction”, FEBS Journal, vol. 282, 2015, pp. 3262-3274.
Peng, J., Alam, S., Radhakrishnan, K., Mariappan, M., Rudolph, M.G., May, C., Dierks, T., von Figura, K., Schmidt, B.: Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction. FEBS Journal. 282, 3262-3274 (2015).
Peng, Jianhe, Alam, Sarfaraz, Radhakrishnan, Karthikeyan, Mariappan, Malaiyalam, Rudolph, Markus Georg, May, Caroline, Dierks, Thomas, von Figura, Kurt, and Schmidt, Bernhard. “Eukaryotic formylglycine-generating enzyme catalyses a monooxygenase type of reaction”. FEBS Journal 282.17 (2015): 3262-3274.
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