# STS

## Overview
The STS gene encodes the enzyme steroid sulfatase, a membrane-bound hydrolase primarily associated with the endoplasmic reticulum. This enzyme plays a pivotal role in steroid metabolism by catalyzing the hydrolysis of sulfate esters from steroid sulfates, thereby converting them into biologically active forms such as estrogens and dehydroepiandrosterone (DHEA) (Hattori2012Interferon; Yen1987Cloning). The steroid sulfatase enzyme is characterized by its unique structural features, including a catalytic site with a conserved cysteine residue modified to formylglycine, which is essential for its activity (Reed2005Steroid). The enzyme's function is crucial in various physiological processes, including skin differentiation, placental estrogen production, and immune responses (Hattori2012Interferon; Suzuki2003Steroid). Mutations or deletions in the STS gene are linked to X-linked ichthyosis and have been associated with cognitive and behavioral conditions such as ADHD and autism spectrum disorders (Afzal2020A; Kent2008Xlinked).

## Structure
The human steroid sulfatase (STS) protein is a membrane-bound enzyme associated with the endoplasmic reticulum. It consists of 583 amino acids and includes a signal peptide of 21-23 residues, with four potential glycosylation sites, two of which are utilized at asparagine residues 47 and 259 (Reed2005Steroid). The protein has a 'mushroom-like' shape, with a crown on the lumen side and a stalk traversing the lipid bilayer, which is characteristic of its highly hydrophobic nature (Reed2005Steroid). 

The STS protein's structure includes a catalytic site with a unique posttranslational modification where a conserved cysteine residue is converted to formylglycine (FGly). This site shares nine identical catalytically important residues with related enzymes, such as arylsulfatase A and B, with the tenth residue being glutamine, differing from asparagine in the other sulfatases (Reed2005Steroid). 

The enzyme's transmembrane domain consists of two antiparallel hydrophobic α-helices that anchor the enzyme to the membrane, contributing to its functional domain on the ER lumen surface (HernandezGuzman2003Structure). The presence of disulfide bonds and glycosylation sites suggests that the catalytic domain is located on the lumen side of the endoplasmic reticulum (Ghosh2007Human).

## Function
The STS gene encodes the enzyme steroid sulfatase, which is crucial in steroid metabolism by hydrolyzing sulfate esters from steroid sulfates. This enzyme is involved in converting sulfated steroid precursors into active forms, such as estrogens and dehydroepiandrosterone (DHEA), which are important for various physiological processes (Hattori2012Interferon; Yen1987Cloning). In healthy human cells, STS is active in tissues like the skin, where it plays a role in skin differentiation and development by regulating local estrogen levels (Hattori2012Interferon). 

The enzyme is also expressed in the placenta, where it contributes to the production of estrogens during pregnancy (Suzuki2003Steroid). STS activity is significant in maintaining cutaneous homeostasis and is involved in inflammatory and immune responses in the skin, as its expression can be induced by interferon gamma (IFNγ) through the PI 3-kinase pathway and NF-κB activation (Hattori2012Interferon). The regulation of STS is essential for hormone economy and is implicated in conditions like psoriasis, where its expression may contribute to inflammation (Hattori2012Interferon).

## Clinical Significance
Mutations or deletions in the STS gene, which encodes the enzyme steroid sulfatase, are primarily associated with X-linked ichthyosis (XLI), a skin disorder characterized by dark brown, polygonal scales and generalized dryness. This condition is caused by a deficiency in the steroid sulfatase enzyme, leading to the accumulation of cholesterol sulfate, which inhibits sterol biosynthesis and contributes to the ichthyosis phenotype (Afzal2020A; Yen1987Cloning).

Beyond dermatological symptoms, STS gene alterations have been linked to various cognitive and behavioral conditions. Individuals with XLI have an increased risk of attention deficit hyperactivity disorder (ADHD), particularly the inattentive subtype, and autism spectrum disorders (Brookes2008Association; Kent2008Xlinked). The STS gene's role in neurosteroid synthesis, such as converting dehydroepiandrosterone sulfate to dehydroepiandrosterone, suggests that its deficiency may impact neurological processes, contributing to these conditions (Afzal2020A).

In some cases, larger deletions involving the STS gene and neighboring genes, such as neuroligin 4 (NLGN4), can result in syndromic conditions that include additional symptoms like short stature, Kallmann syndrome, and neurodevelopmental disorders (Huang2020A; Kent2008Xlinked).

## Interactions
Steroid sulfatase (STS) is involved in several interactions that influence its function and regulation. STS is a membrane-bound enzyme located on the endoplasmic reticulum, and its activity is crucial for the hydrolysis of steroid sulfates, which are precursors to biologically active steroids. The enzyme's catalytic site shares similarities with other sulfatases, such as arylsulfatase A and B, and involves a conserved cysteine residue modified to formylglycine, essential for its catalytic activity (Reed2005Steroid).

STS interacts with inhibitors like EMATE, which mimic the sulfate group of estrone sulfate (E1S). These inhibitors bind to the enzyme's active site, potentially leading to irreversible inactivation through a nucleophilic attack on the sulfamoyl group (Reed2005Steroid). The presence of basic amino acids such as lysine and histidine in the catalytic site facilitates the deprotonation of inhibitors, enhancing their inhibitory action (Reed2005Steroid).

Additionally, STS is involved in the uptake and hydrolysis of steroid sulfates in breast cancer, facilitated by membrane transporter proteins like organic anion transporter polypeptides (OATPs), which help transport E1S into cells for hydrolysis by STS (Reed2005Steroid). These interactions highlight the enzyme's role in steroid metabolism and its potential as a therapeutic target.


## References


[1. (Ghosh2007Human) D. Ghosh. Human sulfatases: a structural perspective to catalysis. Cellular and Molecular Life Sciences, 64(15):2013–2022, June 2007. URL: http://dx.doi.org/10.1007/s00018-007-7175-y, doi:10.1007/s00018-007-7175-y. This article has 105 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-007-7175-y)

[2. (Suzuki2003Steroid) Takashi Suzuki, Yasuhiro Miki, Taisuke Nakata, Yukimasa Shiotsu, Shiro Akinaga, Kengo Inoue, Takanori Ishida, Michio Kimura, Takuya Moriya, and Hironobu Sasano. Steroid sulfatase and estrogen sulfotransferase in normal human tissue and breast carcinoma. The Journal of Steroid Biochemistry and Molecular Biology, 86(3–5):449–454, September 2003. URL: http://dx.doi.org/10.1016/s0960-0760(03)00356-x, doi:10.1016/s0960-0760(03)00356-x. This article has 52 citations.](https://doi.org/10.1016/s0960-0760(03)00356-x)

[3. (Brookes2008Association) K.J. Brookes, Z. Hawi, A. Kirley, E. Barry, M. Gill, and L. Kent. Association of the steroid sulfatase (sts) gene with attention deficit hyperactivity disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B(8):1531–1535, October 2008. URL: http://dx.doi.org/10.1002/ajmg.b.30873, doi:10.1002/ajmg.b.30873. This article has 55 citations.](https://doi.org/10.1002/ajmg.b.30873)

[4. (HernandezGuzman2003Structure) Francisco G. Hernandez-Guzman, Tadayoshi Higashiyama, Walter Pangborn, Yoshio Osawa, and Debashis Ghosh. Structure of human estrone sulfatase suggests functional roles of membrane association. Journal of Biological Chemistry, 278(25):22989–22997, June 2003. URL: http://dx.doi.org/10.1074/jbc.m211497200, doi:10.1074/jbc.m211497200. This article has 145 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m211497200)

5. (Huang2020A) A novel STS mutation and an Xp22.3 microdeletion from one Chinese family with X-linked ichthyosis. This article has 0 citations.

[6. (Yen1987Cloning) Pauline H. Yen, Elizabeth Allen, Birgit Marsh, Thuluvancheri Mohandas, Nancy Wang, R.Thomas Taggart, and Larry J. Shapiro. Cloning and expression of steroid sulfatase cdna and the frequent occurrence of deletions in sts deficiency: implications for x-y interchange. Cell, 49(4):443–454, May 1987. URL: http://dx.doi.org/10.1016/0092-8674(87)90447-8, doi:10.1016/0092-8674(87)90447-8. This article has 195 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/0092-8674(87)90447-8)

[7. (Hattori2012Interferon) Kenji Hattori, Nozomi Yamaguchi, Kazuo Umezawa, and Hiroomi Tamura. Interferon gamma induces steroid sulfatase expression in human keratinocytes. Biological and Pharmaceutical Bulletin, 35(9):1588–1593, 2012. URL: http://dx.doi.org/10.1248/bpb.b12-00028, doi:10.1248/bpb.b12-00028. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.1248/bpb.b12-00028)

[8. (Afzal2020A) Sibtain Afzal, Khushnooda Ramzan, Sajjad Ullah, Salma M. Wakil, Arshad Jamal, Sulman Basit, and Ahmed Bilal Waqar. A novel nonsense mutation in the sts gene in a pakistani family with x-linked recessive ichthyosis: including a very rare case of two homozygous female patients. BMC Medical Genetics, January 2020. URL: http://dx.doi.org/10.1186/s12881-020-0964-y, doi:10.1186/s12881-020-0964-y. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12881-020-0964-y)

[9. (Reed2005Steroid) M. J. Reed, A. Purohit, L. W. L. Woo, S. P. Newman, and B. V. L. Potter. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocrine Reviews, 26(2):171–202, April 2005. URL: http://dx.doi.org/10.1210/er.2004-0003, doi:10.1210/er.2004-0003. This article has 411 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1210/er.2004-0003)

[10. (Kent2008Xlinked) L Kent, J Emerton, V Bhadravathi, E Weisblatt, G Pasco, L R Willatt, R McMahon, and J R W Yates. X-linked ichthyosis (steroid sulfatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits. Journal of Medical Genetics, 45(8):519–524, May 2008. URL: http://dx.doi.org/10.1136/jmg.2008.057729, doi:10.1136/jmg.2008.057729. This article has 124 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1136/jmg.2008.057729)