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• W2129136359 abstract "Sulfatases form a widespread family of extremely efficient enzymes that generally catalyze the hydrolytic release of sulfate from a variety of alkanesulfate esters (Fig. 1). Impairments in their functions potentially lead to several devastating genetic diseases. For instance, certain lysosomal storage disorders are caused by mutations in lysosomal sulfatases, whereas mutations of the Golgi-localized enzyme cause a defined type of chondrodysplasia punctata [1]. Among these genetic pathologies, patients with a lysosomal storage disorder, known as multiple sulfatase deficiency, were found to possess wild-type (i.e. non-mutated) sulfatase enzymes that nevertheless lack enzymatic activity. It was found that the disease is due to mutations in the so-called formylglycine-generating enzyme (FGE) [2, 3], an observation that heralded a fascinating chapter of human biochemistry and enzymology. FGE catalyzes conversion of a Cys side chain into the essential formylglycine of the sulfatase active site. This process may be thought of as enzymatic synthesis of a post-translationally modified side-chain derivative that functions as essential cofactor for sulfatase catalysis [4]. In this issue of FEBS Journal, Peng et al. [5] report interesting experimental data that provide insight into the unusual and intriguing FGE-catalyzed reaction. Their starting point is that FGE enzymatic activity is known to depend on molecular oxygen as a co-substrate as well as on two essential catalytic residues, Cys336 and Cys341 (with reference to the human FGE sequence). Peng et al. [5] demonstrated that the reaction also requires an electron donor as additional substrate. Moreover, they confirmed that no additional cofactors (such as metals) are indispensable for the reaction, i.e. FGE is a cofactor-less enzyme that is nonetheless able to perform an oxygen-dependent reaction. This finding distinguishes FGE from other oxygen-reacting thiol enzymes such as the dioxygenases that convert Cys and other thiols to sulfinic acids [Cys-S(O)-OH] using iron as an essential prosthetic group [6]. Peng et al. [5] highlight several features of the FGE reaction. How may these data be rationalized within the framework of a chemically reasonable reaction mechanism? A first possibility is that the Cys thiol of the sulfatase substrate is oxidized by FGE to a thiolaldehyde, which is then hydrolyzed to an aldehyde. Such reactivity is well known, as recently exemplified by flavoenzyme oxidases [7]. This catalytic scheme requires a redox group (cofactor) and oxygen to function as an electron acceptor. However, no hydrogen peroxide is produced as expected for a true oxidase. Conversely, as the authors point out, the experimental data may be interpreted in the context of a monooxygenase-type reaction. This mechanism implies that molecular oxygen is used to oxygenate Cys thiols of both the sulfatase substrate and FGE active site (Fig. 1). In the case of the substrate, the resulting highly reactive sulfenic group (Cys-S-OH) may spontaneously dehydrate, generating a thioaldehyde whose hydrolysis gives rise to the aldehyde product. On the other hand, the FGE Cys-S-OH may react with an adjacent Cys to produce a disulfide bridge, which requires an electron donor (e.g. DTT) to be reduced and become available for another catalytic cycle. Previous structural data are fully consistent with this mechanistic proposal [8, 9]. Indeed, the catalytic Cys336 and Cys441 are suitably located to form a disulfide bridge, and a Cl− ion (often thought to be an oxygen mimic) has been found in direct contact with these two catalytically essential residues. Finally, the sulfatase peptide substrate binds in a cleft with its reacting Cys residue in direct contact with the Cys336/Cys441 pair. The mechanistic conundrum concerns the actual step in which molecular oxygen promotes oxidation of both catalytic and substrate Cys residues to their corresponding sulfenic derivatives. Peng et al. [5] correctly point out that their data leave this problem open for further investigation. X-ray crystallographic studies on human FGE have shown that, upon aging, the crystalline enzyme oxidizes so that the peroxysulfenic form of the catalytic Cys336 (Cys-S-O-O−) accumulates. Thus, it may be speculated that sulfatase binding to FGE may promote the reaction with O2 and formation of the peroxysulfenic Cys336. This intermediate may then function as an oxygen atom donor for the sulfatase Cys substrate, leading to Cys-S-OH formation and eventually to the final aldehyde product (Fig. 1). Essentially, this represents a case of a thiol-activated oxygen intermediate that enables a monooxygenase-type reaction in which the oxygen atom acceptor is another thiol. Obviously, other mechanisms may underlie this critical step of the FGE reaction, which may add an interesting twist to our current knowledge on oxygen enzymology. Another intriguing observation concerns the molecular evolution of FGE. A recent article by Goncharenko et al. [10] describes the crystal structure of a bacterial sulfoxide synthase involved in ergothioneine biosynthesis. This enzyme uses oxygen and a non-heme iron to form a covalent C–S bond linking γ-glutamyl cysteine and N-α-trimethyl histidine in the ergothioneine scaffold. The three-dimensional structure of the protein features two domains: an iron-binding four-helix bundle and a lectin-type domain that is similar to the structure of the single domain of FGE. Indeed, the sulfoxide synthase of ergothioneine biosynthesis is the only protein present so far in the Protein Data Bank whose topology is clearly related to that of FGE (as indicated by a Dali search [11]). Moreover, the active sites occupy the same region of the lectin-type domain, the difference being that, in the sulfoxide synthase, the catalytic center is integrated by an iron-binding domain that is not present in FGE. Thus, it appears that the ‘FGE domain’ topology may be characteristic of enzymes that act on thiol-containing (peptide/amino acid) substrates using oxygen as a co-substrate. The outstanding property of FGE is that it is self-sufficient in that it does not need an auxiliary cofactor, and is a reaction that may well lead to more surprising observations." @default.
• W2129136359 created "2016-06-24" @default.
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• W2129136359 date "2015-08-04" @default.
• W2129136359 modified "2023-09-27" @default.
• W2129136359 title "Dealing with oxygen using bare hands" @default.
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• W2129136359 doi "https://doi.org/10.1111/febs.13374" @default.
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