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Sulphation in health and disease

Sulphur is an essential component of all living cells and fundamental for a healthy human physiology. Dissecting the biochemical pathway of its addition to biomolecules was the subject of an EU-funded study.
Sulphation in health and disease
The incorporation of sulphur in biological macromolecules such as steroid hormones occurs through a pathway that comprises the enzymatic activation, transfer and removal of a sulphate moiety. Sulphate activation is catalysed by two PAPS synthases, PAPSS1 and PAPSS2 and genetic defects in the PAPSS2 gene have been implicated in bone and cartilage malformation as well as androgen metabolism.

The scope of the EU-funded SUPA-HD (Sulfation pathways in health and disease: SUPA-HD) project was to illuminate this genotype-phenotype relation and characterise novel interaction partners for human PAPS synthases. Researchers characterised novel PAPSS2 mutations of two boys with delayed growth and bone malformation. They detected residual enzymatic activity for the novel missense mutation G270D, but no activity for the novel frameshift mutation W462Cfs*3.

Various techniques such as fluorescence microscopy, proteasome inhibitors and protein unfolding were used to characterise the impact of additional point mutations on PAPSS2 stability. Scientists classified mutants based on their impact on stability, which aligned with phenotypic appearance.

With respect to PAPSS2 interacting partners, pull-down studies identified over 400 putative candidates including proteasomal subunits and ubiquitin ligases. These results indicated that PAPSS2 is subject to proteasomal turnover although the biological significance of this finding warrants further investigation. Furthermore, a direct association of PAPSS2 with the cytoplasmic sulfotransferase SULT2A1 was unveiled alongside bioinformatics information on the macromolecular docking and molecular dynamics of this interaction.

Collectively, the results and developed technologies of the SUPA-HD study shed light into sulphation processes in mammalian cells. Given its implication in steroid metabolism, the outcome of the study will help understand the biochemical nature of many pathological conditions.

Related information


Sulphation, steroid hormones, PAPS synthase, mutation, SULT2A1
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