bims-supasi 2023-07-09 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2023–07–09
nine papers selected by
Jonathan Wolf Mueller, University of Birmingham

Spatiotemporal Localisation of Heparan Sulphate Proteoglycans throughout Mouse Lens Morphogenesis.
Human Cytochrome P450 3A7 Binding Four Copies of Its Native Substrate Dehydroepiandrosterone 3-Sulfate.
Fibrolamellar Carcinomas-Growth arrested by paracrine signals complexed with synthesized 3-O sulfated heparan sulfate oligosaccharides.
Sulfate-reducing bacteria loaded in hydrogel as a long-lasting H2S factory for tumor therapy.
Indoxyl sulfate in atherosclerosis.
Epitope prediction and designing of receptor inhibitor of Dengue Envelope Protein: An in silico approach.
The Immunosuppressive Potential of Cholesterol Sulfate Through T Cell Microvilli Disruption.
A tale of two switches: Redox regulation of adenosine-5'-phosphosulfate kinase in humans and plants.
Detection, production, modification, and application of arylsulfatases.

Cells. 2023 May 11. pii: 1364. [Epub ahead of print]12(10):

Spatiotemporal Localisation of Heparan Sulphate Proteoglycans throughout Mouse Lens Morphogenesis.

Tayler F L Wishart, Frank J Lovicu.

  Heparan sulphate proteoglycans (HSPGs) consist of a core protein decorated with sulphated HS-glycosaminoglycan (GAG) chains. These negatively charged HS-GAG chains rely on the activity of PAPSS synthesising enzymes for their sulfation, which allows them to bind to and regulate the activity of many positively charged HS-binding proteins. HSPGs are found on the surfaces of cells and in the pericellular matrix, where they interact with various components of the cell microenvironment, including growth factors. By binding to and regulating ocular morphogens and growth factors, HSPGs are positioned to orchestrate growth factor-mediated signalling events that are essential for lens epithelial cell proliferation, migration, and lens fibre differentiation. Previous studies have shown that HS sulfation is essential for lens development. Moreover, each of the full-time HSPGs, differentiated by thirteen different core proteins, are differentially localised in a cell-type specific manner with regional differences in the postnatal rat lens. Here, the same thirteen HSPG-associated GAGs and core proteins as well as PAPSS2, are shown to be differentially regulated throughout murine lens development in a spatiotemporal manner. These findings suggest that HS-GAG sulfation is essential for growth factor-induced cellular processes during embryogenesis, and the unique and divergent localisation of different lens HSPG core proteins indicates that different HSPGs likely play specialized roles during lens induction and morphogenesis.

Keywords:  PAPSS; glypican; heparan sulphate proteoglycan (HSPG); lens development; syndecan

DOI:  https://doi.org/10.3390/cells12101364
J Biol Chem. 2023 Jun 29. pii: S0021-9258(23)02021-5. [Epub ahead of print] 104993

Human Cytochrome P450 3A7 Binding Four Copies of Its Native Substrate Dehydroepiandrosterone 3-Sulfate.

Jinghan Liu, Sylvie E Kandel, Jed N Lampe, Emily E Scott.

  Human fetal cytochrome P450 3A7 (CYP3A7) is involved in both xenobiotic metabolism and the estriol biosynthetic pathway. Although much is understood about cytochrome P450 3A4 (CYP3A4) and its role in adult drug metabolism, CYP3A7 is poorly characterized in terms of its interactions with both categories of substrates. Herein, a crystallizable mutated form of CYP3A7 was saturated with its primary endogenous substrate dehydroepiandrosterone 3-sulfate (DHEA-S) to yield a 2.6 Å X-ray structure revealing the unexpected capacity to simultaneously bind four copies of DHEA-S. Two DHEA-S molecules are located in the active site proper, one in a ligand access channel, and one on the hydrophobic F'-G' surface normally embedded in the membrane. While neither DHEA-S binding or metabolism exhibit cooperative kinetics, the current structure is consistent with cooperativity common to CYP3A enzymes. Overall, this information suggests that mechanism(s) of CYP3A7 interactions with steroidal substrates are complex.

Keywords:  CYP3A7; DHEA-S; X-ray crystallography; cytochrome P450; dehydroepiandrosterone sulfate; enzyme kinetics; steroid

DOI:  https://doi.org/10.1016/j.jbc.2023.104993
Matrix Biol. 2023 Jul 02. pii: S0945-053X(23)00078-1. [Epub ahead of print]

Fibrolamellar Carcinomas-Growth arrested by paracrine signals complexed with synthesized 3-O sulfated heparan sulfate oligosaccharides.

Wencheng Zhang, Yongmei Xu, Xicheng Wang, Tsunekazu Oikawa, Guowei Su, Eliane Wauthier, Guoxiu Wu, Praveen Sethupathy, Zhiying He, Jian Liu, Lola M Reid.

  Fibrolamellar carcinomas (FLCs), lethal tumors occurring in children to young adults, have genetic signatures implicating derivation from biliary tree stem cell (BTSC) subpopulations, co-hepato/pancreatic stem cells, involved in hepatic and pancreatic regeneration. FLCs and BTSCs express pluripotency genes, endodermal transcription factors, and stem cell surface, cytoplasmic and proliferation biomarkers. The FLC-PDX model, FLC-TD-2010, is driven ex vivo to express pancreatic acinar traits, hypothesized responsible for this model's propensity for enzymatic degradation of cultures. A stable ex vivo model of FLC-TD-2010 was achieved using organoids in serum-free Kubota's Medium (KM) supplemented with 0.1% hyaluronans (KM/HA). Heparins (10 ng/ml) caused slow expansion of organoids with doubling times of ∼7-9 days. Spheroids, organoids depleted of mesenchymal cells, survived indefinitely in KM/HA in a state of growth arrest for more than 2 months. Expansion was restored with FLCs co-cultured with mesenchymal cell precursors in a ratio of 3:7, implicating paracrine signaling. Signals identified included FGFs, VEGFs, EGFs, Wnts, and others, produced by associated stellate and endothelial cell precursors. Fifty-three, unique heparan sulfate (HS) oligosaccharides were synthesized, assessed for formation of high affinity complexes with paracrine signals, and each complex screened for biological activity(ies) on organoids. Ten distinct HS-oligosaccharides, all 10-12 mers or larger, and in specific paracrine signal complexes elicited particular biological responses. Of note, complexes of paracrine signals and 3-O sulfated HS-oligosaccharides elicited slowed growth, and with Wnt3a, elicited growth arrest of organoids for months. If future efforts are used to prepare HS-oligosaccharides resistant to breakdown in vivo, then [paracrine signal-HS-oligosaccharide] complexes are potential therapeutic agents for clinical treatments of FLCs, an exciting prospect for a deadly disease.

Keywords:  fibrolamellar carcinomas, biliary tree stem cells (hepato/pancreatic stem cells); organoids; paracrine signals; synthetic heparan sulfate oligosaccharides

DOI:  https://doi.org/10.1016/j.matbio.2023.06.008
J Control Release. 2023 Jul 03. pii: S0168-3659(23)00420-0. [Epub ahead of print]

Sulfate-reducing bacteria loaded in hydrogel as a long-lasting H2S factory for tumor therapy.

Yuzhi Qiu, Man Fan, Yiqian Wang, Xiuwen Hu, Jiawen Chen, Samir Kamel, Yajiang Yang, Xiangliang Yang, Hongfang Liu, Yanhong Zhu, Qin Wang.

  The continuous supply of hydrogen sulfide (H2S) gas at high concentrations to tumors is considered a promising and safe strategy for tumor therapy. However, the absence of a durable and cost-effective H2S-producing donor hampers its extensive application. Sulfate-reducing bacteria (SRB) can serve as an excellent H2S factory due to their ability to metabolize sulfate into H2S. Herein, a novel injectable chondroitin sulfate (ChS) hydrogel loaded with SRB (SRB@ChS Gel) is proposed to sustainably produce H2S in tumor tissues to overcome the limitations of current H2S gas therapy. In vitro, the ChS Gel not only supports the growth of encapsulated SRB, but also supplies a sulfate source to the SRB to produce high concentrations of H2S for at least 7 days, resulting in mitochondrial damage and immunogenic cell death. Once injected into tumor tissue, the SRB@ChS Gel can constantly produce H2S for >5 days, significantly inhibiting tumor growth. Furthermore, such treatment activates systemic anti-tumor immune responses, suppresses the growth of distant and recurrent tumors, as well as lung metastases, meanwhile with negligible side effects. Therefore, the injectable SRB@ChS Gel, as a safe and long-term, self-sustained H2S-generating factory, provides a promising strategy for anti-tumor therapy.

Keywords:  Gas therapy; Injectable chondroitin sulfate hydrogel; Self-driven H(2)S-generating factory; Sulfate-reducing bacteria; Tumor therapy

DOI:  https://doi.org/10.1016/j.jconrel.2023.06.037
Toxicol Lett. 2023 Jul 05. pii: S0378-4274(23)00215-1. [Epub ahead of print]

Indoxyl sulfate in atherosclerosis.

Cong Lu, Li Wu, Mu-Yao Tang, Yi-Fan Liu, Lei Liu, Xi-Ya Liu, Chun Zhang, Liang Huang.

  Atherosclerosis (AS), a chronic vascular inflammatory disease, has become a main focus of attention worldwide for its chronic progressing disease course and serious complications in the later period. Nevertheless, explanations for the exact molecular mechanisms of AS initiation and development remain to be an unsolved problem. The classic pathogenesis theories, such as lipid percolation and deposition, endothelium injury, inflammation and immune damage, provide the foundation for discovering the new key molecules or signaling mechanisms. Recently, indoxyl sulfate (IS), one of non-free uremia toxins, has been noticeable for its multiple atherogenic effects. IS exists at high concentration in plasma for its great albumin binding rate. Patients with uremia have markedly elevated serum levels of IS due both to the deterioration of renal function and to the high binding affinity of IS to albumin. Nowadays, elevated incidence of circulatory disease among patients with renal dysfunction indicates correlation of uremic toxins with cardiovascular damage. In this review, the atherogenic effects of IS and the underlying mechanisms are summarized with emphasis on several key pathological events associated with AS developments, such as vascular endothelium dysfunction, arterial medial lesions, vascular oxidative stress, excessive inflammatory responses, calcification, thrombosis and foam cell formation. Although recent studies have proved the great correlation between IS and AS, deciphering cellular and pathophysiological signaling by confirming key factors involved in IS-mediated atherosclerosis development may enable identification of novel therapeutic targets.

Keywords:  Atherosclerosis; Calcification; Indoxyl sulfate; Inflammation; Thrombosis

DOI:  https://doi.org/10.1016/j.toxlet.2023.07.001
J Vector Borne Dis. 2023 Apr-Jun;60(2):60(2): 161-171

Epitope prediction and designing of receptor inhibitor of Dengue Envelope Protein: An in silico approach.

Gunjan Uttam, Ankita Kumari, Karuna Singh.

   BACKGROUND & OBJECTIVES: Dengue virus (DENV) is the causative agent of dengue fever (DF) and dengue hemorrhagic fever (DHF). It has four distinct serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) based on their antigenic properties. Mostly, the immunogenic epitopes are present in the envelope (E) protein of the virus. Heparan sulfate (HS) acts as a receptor and interacts with the E protein of the virus thus facilitating the entry of dengue virus into human cells. This study focuses on epitope prediction on the E protein of the DENV serotype. The non-competitive inhibitors of HS were designed using bioinformatics.
METHODS: In the present study, epitope prediction of the E protein of DENV serotypes was performed using the ABCpred server and IEDB analysis resource. The interactions of HS and viral E proteins (PDB ID: 3WE1 and PDB ID:1TG8) were evaluated through AutoDock. Subsequently, non-competitive inhibitors were designed to bind the E protein of DENV better than HS. All the docking results were validated by re-docking the ligand-receptor complexes and superimposing them onto their co-crystallized complexes using AutoDock and visualizing them in Discovery Studio.
RESULTS: The result predicted B-cell and T-cell epitopes on the E protein of DENV serotypes. The designed HS ligand 1 (non-competitive inhibitor) demonstrated potential binding with the DENV E protein, thereby inhibiting HS-E protein binding. The re-docked complexes were superimposed entirely onto the native co-crystallized complexes (low root mean square deviation values), which validates the docking protocols.
INTERPRETATION & CONCLUSION: The identified B-cell and T-cell epitopes of the E protein and non-competitive inhibitors of HS (ligand 1) could be used in the designing of potential drug candidates against the dengue virus.

Keywords:  Dengue virus; Envelope protein; Epitope prediction; Heparan sulfate; Non-competitive inhibitors; in silico

DOI:  https://doi.org/10.4103/0972-9062.361168
Immune Netw. 2023 Jun;23(3): e29

The Immunosuppressive Potential of Cholesterol Sulfate Through T Cell Microvilli Disruption.

Jeong-Su Park, Ik-Joo Chung, Hye-Ran Kim, Chang-Duk Jun.

  Cholesterol (CL) is required for various biomolecular production processes, including those of cell membrane components. Therefore, to meet these needs, CL is converted into various derivatives. Among these derivatives is cholesterol sulfate (CS), a naturally produced CL derivative by the sulfotransferase family 2B1 (SULT2B1), which is widely present in human plasma. CS is involved in cell membrane stabilization, blood clotting, keratinocyte differentiation, and TCR nanocluster deformation. This study shows that treatment of T cells with CS resulted in the decreased surface expression of some surface T-cell proteins and reduced IL-2 release. Furthermore, T cells treated with CS significantly reduced lipid raft contents and membrane CLs. Surprisingly, using the electron microscope, we also observed that CS led to the disruption of T-cell microvilli, releasing small microvilli particles containing TCRs and other microvillar proteins. However, in vivo, T cells with CS showed aberrant migration to high endothelial venules and limited infiltrating splenic T-cell zones compared with the untreated T cells. Additionally, we observed significant alleviation of atopic dermatitis in mice injected with CS in the animal model. Based on these results, we conclude that CS is an immunosuppressive natural lipid that impairs TCR signaling by disrupting microvillar function in T cells, suggesting its usefulness as a therapeutic agent for alleviating T-cell-mediated hypersensitivity and a potential target for treating autoimmune diseases.

Keywords:  Autoimmune disease; Cell microvilli disruption; Cholesterol; Cholesterol sulfate; T cells

DOI:  https://doi.org/10.4110/in.2023.23.e29
Structure. 2023 Jul 06. pii: S0969-2126(23)00202-2. [Epub ahead of print]31(7): 757-759

A tale of two switches: Redox regulation of adenosine-5'-phosphosulfate kinase in humans and plants.

Jeremy S Morris, Joseph M Jez.

The sulfate donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) is a near-universal component of sulfur metabolism. In a report by Zhang et al. in this issue of Structure, X-ray crystal structures of the APS kinase domains from human PAPS synthase reveal dynamic substrate recognition and a regulatory "redox switch" analogous to that previously described only in plant APS kinases.

DOI: https://doi.org/10.1016/j.str.2023.06.006
Biotechnol Adv. 2023 Jul 03. pii: S0734-9750(23)00114-3. [Epub ahead of print] 108207

Detection, production, modification, and application of arylsulfatases.

Mengjiao Yu, Meixian Wu, Francesco Secundo, Zhen Liu.

  Arylsulfatase is a subset of sulfatase which catalyze the hydrolysis of aryl sulfate ester. Arylsulfatase is widely distributed among microorganisms, mammals and green algae, but the arylsulfatase-encoding gene has not yet been found in the genomes of higher plants so far. Arylsulfatase plays an important role in the sulfur flows between nature and organisms. In this review, we present the maturation and catalytic mechanism of arylsulfatase, and the recent literature on the expression and production of arylsulfatase in wild-type and engineered microorganisms, as well as the modification of arylsulfatase by genetic engineering are summarized. We focus on arylsulfatases from microbial origin and give an overview of different assays and substrates used to determine the arylsulfatase activity. Furthermore, the researches about the progress of arylsulfatase application on the field of agar desulfation, soil sulfur cycle and soil evaluation are also discussed. Finally, the perspectives concerning the future research on arylsulfatase are prospected.

Keywords:  Agar; Arylsulfatase; Enzymes; Production; Soil; Sulfur cycle

DOI:  https://doi.org/10.1016/j.biotechadv.2023.108207