Disease relevance of Formylglycine

• The iron sulfur protein AtsB is required for posttranslational formation of formylglycine in the Klebsiella sulfatase [1].
• Coexpression of formylglycine-generating enzyme is essential for synthesis and secretion of functional arylsulfatase A in a mouse model of metachromatic leukodystrophy [2].

High impact information on Formylglycine

• Formylglycine (FGly), the key catalytic residue in the active site, is unique to sulfatases [3].
• Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme [3].
• Conversion of cysteine to formylglycine: a protein modification in the endoplasmic reticulum [4].
• Limited proteolytic cleavage at similar sites indicates that both also share a similar three-dimensional structure. pFGE, however, is lacking the formylglycine-generating activity of FGE [5].
• We established an in vitro assay that allowed us to measure formylglycine modification independent of protein translocation [6].

Chemical compound and disease context of Formylglycine

• Arylsulfatase from Klebsiella pneumoniae carries a formylglycine generated from a serine [7].

Biological context of Formylglycine

• Sulfatases contain an active site formylglycine residue that is generated by post-translational modification [8].
• Crystal structures of two lysosomal sulfatases revealed significant similarity to the catalytic site of alkaline phosphatase containing a serine at the position of formylglycine [8].
• Thus, in acting as a geminal diol the formylglycine residue allows for efficient ester hydrolysis in an acidic milieu [8].
• In the present study residues 68-86 flanking formylglycine 69 in arylsulfatase A were subjected to an alanine/glycine scanning mutagenesis [9].
• Hydroxylation of the formylglycine residue by a water molecule forming the activated hydroxylformylglycine (a formylglycine hydrate or a gem-diol) is a necessary step for sulfatase activity of the enzyme [10].

Anatomical context of Formylglycine

• Using in vitro translation in the presence of transport-competent microsomes we found that arylsulfatase B is also modified in a similar way by the formylglycine-generating machinery [11].

Associations of Formylglycine with other chemical compounds

• The formylglycine acts as an aldehyde hydrate with two geminal hydroxyls being involved in catalysis of sulfate ester cleavage [12].
• We postulate that this N-terminal region of FGE mediates the interaction with an ER component to be identified and that this interaction is required for both the generation of FGly residues in nascent sulfatase polypeptides and for retention of FGE in the ER [13].

Gene context of Formylglycine

• In arylsulfatase A and N-acetylgalactosamine 4-sulfatase this formylglycine was found to form the active site together with a divalent cation and a number of polar residues, tightly interconnected by a net of hydrogen bonds [12].
• By contrast, in the arylsulfatase of Klebsiella pneumoniae a formylglycine is found generated by modification of a serine residue [14].
• Formylglycine formation is efficiently inhibited by a synthetic sulfatase peptide representing the sequence directing formylglycine modification [6].
• Residues critical for formylglycine formation and/or catalytic activity of arylsulfatase A [9].

Analytical, diagnostic and therapeutic context of Formylglycine

• Our modeling approach was further complemented experimentally using peptide mapping in tandem with mass spectrometry and site-directed mutagenesis to physically demonstrate the presence of a covalently modified cysteine (formylglycine) within the active site [15].

References