Mammalian Sulfatases: Biochemistry, Disease Manifestation, and Therapy

Abstract

Sulfatases are enzymes that catalyze the removal of sulfate from biological substances, an essential process for the homeostasis of the body. They are commonly activated by the unusual amino acid formylglycine, which is formed from cysteine at the catalytic center, mediated by a formylglycine-generating enzyme as a post-translational modification. Sulfatases are expressed in various cellular compartments such as the lysosome, the endoplasmic reticulum, and the Golgi apparatus. The substrates of mammalian sulfatases are sulfolipids, glycosaminoglycans, and steroid hormones. These enzymes maintain neuronal function in both the central and the peripheral nervous system, chondrogenesis and cartilage in the connective tissue, detoxification from xenobiotics and pharmacological compounds in the liver, steroid hormone inactivation in the placenta, and the proper regulation of skin humidification. Human sulfatases comprise 17 genes, 10 of which are involved in congenital disorders, including lysosomal storage disorders, while the function of the remaining seven is still unclear. As for the genes responsible for pathogenesis, therapeutic strategies have been developed. Enzyme replacement therapy with recombinant enzyme agents and gene therapy with therapeutic transgenes delivered by viral vectors are administered to patients. In this review, the biochemical substrates, disease manifestation, and therapy for sulfatases are summarized.

New Insights into the Plutella xylostella Detoxifying Enzymes: Sequence Evolution, Structural Similarity, Functional Diversity, and Application Prospects of Glucosinolate Sulfatases

“…The latest study used eukaryotic expressing proteins generated in the Sf9 insect cell line and reported that P. xylostella contains three functional PxGSSs (PxGSS1–3) . On the contrary, for the 17 Sulf genes in humans, no function related to GLs hydrolysis and its corresponding genes have been identified yet . In summary, the findings from these studies strongly indicate that strategic targeting of PxGSSs represents a promising and reliable strategy for managing P. xylostella populations.…”

Promiscuous Enzymes for Residue‐Specific Peptide and Protein Late‐Stage Functionalization

“…[74][75][76] Their native function is to activate type-I sulfatases via oxidation and subsequent hydrolysis and their deficiency is associated with several diseases. [77,78] Different bacterial FGEs were found to be promiscuous in recognizing their Cys-containing peptide sequence and modified protein with the tag Cxxxx. [79] FGEs' ability to install a bioorthogonal aldehyde functional group have allowed them to mediate ligation reactions [80] including trapped-Knoevenagel ligation [81] using a thiopyrazolone-maytansine and aminooxymaytansine compounds or undergo a hydazino-iso-Pictet-Spengler [82] or reaction with hydrazide-or aminooxy-functionalized reagents.…”

“…Aerobic FGEs catalyze the conversion of the thiol side chain of cysteine to an electrophilic aldehyde‐bearing group via copper and oxygen‐dependent catalysis (Figure 3B). [74–76] Their native function is to activate type‐I sulfatases via oxidation and subsequent hydrolysis and their deficiency is associated with several diseases [77,78] . Different bacterial FGEs were found to be promiscuous in recognizing their Cys‐containing peptide sequence and modified protein with the tag Cxxxx [79] .…”

Lipid Nanoparticles: A Novel Gene Delivery Technique for Clinical Application

“…Lysosomal storage disorders (LSDs) are characterized by an accumulation of unprocessed biochemicals in the lysosome involving 50–60 enzymes [ 57 , 58 , 59 ]. These disorders present CNS, skeletal, and visceral disorders such as hepatomegaly and splenomegaly.…”