Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Pérez-Jiménez, Mercedes M.; Moreno, José Manuel Monje; Brokate-Llanos, Ana María; Venegas-Calerón, Mónica; Sánchez‐García, Alicia; Sansigre, Paula; Valladares, Amador; Esteban-García, Sara; Suárez-Pereira, Irene; Vitórica, Javier; Ríos, José Julián; Artal‐Sanz, Marta; Carrión, Ángel Manuel; Muñoz, Manuel J.

doi:10.1038/s41467-020-20269-y

Cited by 31 publications

(30 citation statements)

References 61 publications

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“…Loss of function of the C. elegans sul-2 gene (steroid sulfatase, STS) increased the concentration of sulfated steroid hormones, as well as longevity, and improved the phenotype in several C. elegans models of protein aggregation diseases. The same effects were obtained in C. elegans models using STX64, a specific STS inhibitor that also ameliorated the phenotype in a mammalian model of AD [ 157 ].…”

Section: Use Of C Elegans Models Of Alzheimer’s Di...mentioning

confidence: 53%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.

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Section: Use Of C Elegans Models Of Alzheimer’s Di...mentioning

confidence: 53%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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“…Results indicated that STS inhibition may be neuroprotective against neurotoxic amyloid β accumulations in the brain and that this is possibly due to increased DHEA-S availability. Recently, these findings have been supported by a study using Caenorhabditis elegans who have had their STS activity (sul-2) deleted [144]. Loss of steroid sulfation led to a rise in sulphated steroids, increased life span, and inhibited protein aggregation diseases.…”

Section: Future Outlook For Sts Inhibitorsmentioning

confidence: 88%

Steroid Sulphatase and Its Inhibitors: Past, Present, and Future

Foster

2021

Molecules

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Steroid sulphatase (STS), involved in the hydrolysis of steroid sulphates, plays an important role in the formation of both active oestrogens and androgens. Since these steroids significantly impact the proliferation of both oestrogen- and androgen-dependent cancers, many research groups over the past 30 years have designed and developed STS inhibitors. One of the main contributors to this field has been Prof. Barry Potter, previously at the University of Bath and now at the University of Oxford. Upon Prof. Potter’s imminent retirement, this review takes a look back at the work on STS inhibitors and their contribution to our understanding of sulphate biology and as potential therapeutic agents in hormone-dependent disease. A number of potent STS inhibitors have now been developed, one of which, Irosustat (STX64, 667Coumate, BN83495), remains the only one to have completed phase I/II clinical trials against numerous indications (breast, prostate, endometrial). These studies have provided new insights into the origins of androgens and oestrogens in women and men. In addition to the therapeutic role of STS inhibition in breast and prostate cancer, there is now good evidence to suggest they may also provide benefits in patients with colorectal and ovarian cancer, and in treating endometriosis. To explore the potential of STS inhibitors further, a number of second- and third-generation inhibitors have been developed, together with single molecules that possess aromatase–STS inhibitory properties. The further development of potent STS inhibitors will allow their potential therapeutic value to be explored in a variety of hormone-dependent cancers and possibly other non-oncological conditions.

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“…The protein was mixed with 1.0 µL of crystallization solution in the wells. Protein was also incubated on ice for 30 min with sulfatase irreversible inhibitor STX64 (Axon Medchem, Reston, VA, USA) [ 43 , 44 ] with a final inhibitor concentration of 1.0 mM before setting drops. However, the inhibitor did not solubilize well in the protein mixture and precipitated out of solution in the crystallization drops.…”

Section: Methodsmentioning

confidence: 99%

Purification, Characterization, and Structural Studies of a Sulfatase from Pedobacter yulinensis

Schlachter¹,

O’Malley

Grimes³

et al. 2021

Molecules

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Sulfatases are ubiquitous enzymes that hydrolyze sulfate from sulfated organic substrates such as carbohydrates, steroids, and flavones. These enzymes can be exploited in the field of biotechnology to analyze sulfated metabolites in humans, such as steroids and drugs of abuse. Because genomic data far outstrip biochemical characterization, the analysis of sulfatases from published sequences can lead to the discovery of new and unique activities advantageous for biotechnological applications. We expressed and characterized a putative sulfatase (PyuS) from the bacterium Pedobacter yulinensis. PyuS contains the (C/S)XPXR sulfatase motif, where the Cys or Ser is post-translationally converted into a formylglycine residue (FGly). His-tagged PyuS was co-expressed in Escherichia coli with a formylglycine-generating enzyme (FGE) from Mycobacterium tuberculosis and purified. We obtained several crystal structures of PyuS, and the FGly modification was detected at the active site. The enzyme has sulfatase activity on aromatic sulfated substrates as well as phosphatase activity on some aromatic phosphates; however, PyuS did not have detectable activity on 17α-estradiol sulfate, cortisol 21-sulfate, or boldenone sulfate.

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Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Cited by 31 publications

References 61 publications

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Steroid Sulphatase and Its Inhibitors: Past, Present, and Future

Purification, Characterization, and Structural Studies of a Sulfatase from Pedobacter yulinensis

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