Are Sulfates of the Hydroxyl Amino Acids Threonine and Serine Truly Extremely Rare or Do They Simply Escape Detection?

Sulfonation is important for bioactivity across species—substrates range from small molecules to proteins, in which almost exclusively tyrosine sulfonation (sTyr) has been investigated. Although sulfoalkyl-hydroxyl amino acid residues in peptides and proteins have rarely been found, we will argue that it is highly likely that sSer and sThr are much more abundant than is currently evident. In the context of the recent detection of sThr-containing adipokinetic hormones in insects, the literature was screened to answer questions about the relative stability (lability) of the sulfate moiety at Tyr, Ser and Thr that may explain the historic abundance of sTyr reports; to ascertain if there are special grounds for finding sSer and sThr peptides in insects, and whether specific enzymes (sulfotransferases and sulfatases) involved in the biochemistry of sulfonation are documented in insects. Finally, we assessed detection methods for sThr and sSer-containing peptides to achieve greater accuracy. Our literature screening could not supply a special reason for the preferential formation of sThr/sSer in insects. Although the analysis of sulfonated molecules is challenging because of the lability of the sulfate group, sThr/sSer do not seem to be at a greater disadvantage compared to sTyr; it was even experimentally found that they are more stable than commonly reported. For untargeted studies of sulfoproteomes, special enrichment strategies are still required to identify these sulfonated peptides. Mass spectrometry is very valuable for the detection of the modification, but methods need to be adjusted, because sulfur trioxide is easily lost during measurement.