PAPSS2 is a bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two reactions to generate 3'-Phosphoadenosine-5'-phosphosulfate, a critical intermediate in the sulfate activation pathway. PAPS is the sulfate donor co-substrate for all sulfotransferase enzymes and is required to catalyze the sulfate conjugation of many endogenous and exogenous compounds. Mutations in PAPSS2 lead to an autosomal recessive form of spondyloepimetaphyseal dysplasia in humans, whereas mutant mice lacking PAPSS2 activity demonstrate defective postnatal skeletal development leading to premature joint degeneration and brachymorphism. In conjunction with SULT1E1, PAPSS2 and its paralogue PAPSS1 are responsible for sulfation and subsequent inactivation of estrogen in target tissues. Expression levels of PAPSS2 were found to be significantly higher in tumorous breast and endometrial tissues than in adjacent normal tissues, suggesting that targeting PAPSS2 could be an important approach for estrogen-dependent cancers. Additionally, PAPSS2 provides the universal sulfate donor PAPS to SULT2A1, which is responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone. TGF-β signaling has been shown to regulate the expression of PAPSS2 via stabilization of SOX9 protein in mouse articular cartilage and bovine chondrocytes.
[1] Venkatachalam, K.V. (2003) IUBMB Life 55, 1-11.
[2] Xu, Z.H. et al. (2000) Biochem Biophys Res Commun 268, 437-44.
[3] Faiyaz ul Haque, M. et al. (1998) Nat Genet 20, 157-62.
[4] Ford-Hutchinson, A.F. et al. (2005) Osteoarthritis Cartilage 13, 418-25.
[5] Xu, Y. et al. (2012) Cancer Sci 103, 1000-9.
[6] Oostdijk, W. et al. (2015) J Clin Endocrinol Metab 100, E672-80.
[7] Ramaswamy, G. et al. (2012) Arthritis Res Ther 14, R49.
[8] Chavez, R.D. et al. (2017) Osteoarthritis Cartilage 25, 332-40.
