| Tyrosylprotein sulfotransferase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 An image of a single subunit of the catalytic region of TPST-2 from protein structure 3AP1 | |||||||||
| Identifiers | |||||||||
| EC no. | 2.8.2.20 | ||||||||
| CAS no. | 87588-33-8 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
Tyrosylprotein sulfotransferase is an enzyme that catalyzes tyrosine sulfation. [1]
Tyrosylprotein sulfotransferase is the enzyme that catalyzes the sulfation reaction of protein tyrosines, a post-translational modification of proteins. It utilizes 3'-Phosphoadenosine-5'-phosphosulfate (PAPS) as the sulfonate donor and binds proteins with target tyrosine residues to eventually form the tyrosine O-sulfate ester group and the desulfonated 3’-phosphoadenosine-5’-phosphate (PAP). [2] [3] [4]
TPST and tyrosine sulfation is involved in a large number of biological and physiological processes. Tyrosine sulfation has been found to be an important part of the inflammatory process, leukocyte movement and cytosis, viral cell entrance, and other cell-cell and protein-protein interactions. [2] [3] Selection for specific tyrosine residues requires a generally accessible tyrosine residue, and acidic residues within +5 or -5 residues of the target tyrosine. [2] [3] [4] P-selectin glycoprotein ligand-1 (PSGL-1) has been extensively studied as a substrate for TPST and the importance of sulfation in PSGL-1 and its ability to bind its receptor. [5] Another substrate for TPST, CC-chemokine Receptor 5 (CCR5), has generated interest because of its role as the target protein for the viral entrance of HIV into cells. The importance of CCR5's sulfation for HIV invasion has led to research on TPST and CCR5, including a characterization of the pattern of sulfation of CCR5. [6] Beyond these two proteins, other notable protein substrates include Cholecystokinin (CCK), Factor V and Factor VIII, gastrin, the leech enzyme hirudin, fibrinogen, Complement component 4, follicle-stimulating hormone receptor (FSHR), and other chemokine and G-protein coupled receptors. [2] [3] A full, up-to-date list can be found at UniProtKB.
Tyrosylprotein sulfotransferase (TPST) is a type II transmembrane protein. [7] It consists of a short cytosolic region that contains the N-terminus of the protein, a single transmembrane region of about 17 amino acids in length, a small stem region of about 40 amino acids in length, and a larger, catalytic region that is located on the luminal side of the membrane. [2] [4] It is localized to the Golgi apparatus, specifically in the trans-Golgi region, and acts almost exclusively on secretory and plasma membrane proteins. [8] TPST is about 50-54 kD in size, and has two confirmed isoforms in mammals, TPST-1 and TPST-2, that are 370 and 377 residues in length, respectively. [7] [9] Both are quite similar with an approximately 63% amino acid identity, but show slightly different protein substrate specificities. [2] [4]
TPST is a prevalent enzyme, found in many multicellular eukaryotes including mammals, most vertebrates, and a number of invertebrate species as well, including Drosophila melanogaster . [2] [3] [10] Its importance can be further demonstrated by the fact as much as 1% of all secreted and membrane tyrosine residues are found to be sulfated. [6] [11]
Within the last two years, using the crystallized structure of the catalytic region of TPST-2 and different experiments other methods using mass spectrometry methods have come to propose two separate mechanisms.
A two-site ping-pong mechanism for TPST and the tyrosine sulfating has been proposed. PAPS enters one site of TPST and the sulfonate group is transferred to a Histidine residue in the enzyme and PAP is released. Then, the target protein and tyrosine bind TPST and the histidine transfers the sulfonate group to the target tyrosine. [11]
Based on crystal structure of TPST-2 with C4 complement and PAP, an SN2-like in-line displacement mechanism has been proposed. In this mechanism, both PAPS and the target tyrosine bind to the same active site in the enzyme and are orientated in a way such that a glutamic acid residue acts as a catalytic base on the tyrosine hydroxyl group, an arginine residue acts as a catalytic acid, and serine and lysine residues are used to stabilize the SN2-like intermediate. The deprotonated hydroxyl would attack the sulfonate group, then displace the phosphate group and PAP would be released, along with the sulfotyrosine residue. [4]
Human genes that encode protein-tyrosine sulfotransferase enzymes include:
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
In biochemistry, allosteric regulation is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the binding site, and residues that catalyse a reaction of that substrate, the catalytic site. Although the active site occupies only ~10–20% of the volume of an enzyme, it is the most important part as it directly catalyzes the chemical reaction. It usually consists of three to four amino acids, while other amino acids within the protein are required to maintain the tertiary structure of the enzymes.
In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.
Aspartate carbamoyltransferase catalyzes the first step in the pyrimidine biosynthetic pathway.
Tyrosine sulfation is a posttranslational modification where a sulfate group is added to a tyrosine residue of a protein molecule. Secreted proteins and extracellular parts of membrane proteins that pass through the Golgi apparatus may be sulfated. Sulfation was first discovered by Bettelheim in bovine fibrinopeptide B in 1954 and later found to be present in animals and plants but not in prokaryotes or in yeast.
β-Glucuronidases are members of the glycosidase family of enzymes that catalyze breakdown of complex carbohydrates. Human β-glucuronidase is a type of glucuronidase that catalyzes hydrolysis of β-D-glucuronic acid residues from the non-reducing end of mucopolysaccharides such as heparan sulfate. Human β-glucuronidase is located in the lysosome. In the gut, brush border β-glucuronidase converts conjugated bilirubin to the unconjugated form for reabsorption. β-Glucuronidase is also present in breast milk, which contributes to neonatal jaundice. The protein is encoded by the GUSB gene in humans and by the uidA gene in bacteria.
Protein tyrosine phosphatases (EC 3.1.3.48, systematic name protein-tyrosine-phosphate phosphohydrolase) are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins:
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.
Sulfation is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected less directly. Regardless of the mechanism, the installation of a sulfate-like group on a substrate leads to substantial changes.
Chemokine receptors are cytokine receptors found on the surface of certain cells that interact with a type of cytokine called a chemokine. There have been 20 distinct chemokine receptors discovered in humans. Each has a rhodopsin-like 7-transmembrane (7TM) structure and couples to G-protein for signal transduction within a cell, making them members of a large protein family of G protein-coupled receptors. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium (Ca2+) ions (calcium signaling). This causes cell responses, including the onset of a process known as chemotaxis that traffics the cell to a desired location within the organism. Chemokine receptors are divided into different families, CXC chemokine receptors, CC chemokine receptors, CX3C chemokine receptors and XC chemokine receptors that correspond to the 4 distinct subfamilies of chemokines they bind. Four families of chemokine receptors differ in spacing of cysteine residues near N-terminal of the receptor.
The mannose 6-phosphate receptors (MPRs) are transmembrane glycoproteins that target enzymes to lysosomes in vertebrates.
Carboxypeptidase A usually refers to the pancreatic exopeptidase that hydrolyzes peptide bonds of C-terminal residues with aromatic or aliphatic side-chains. Most scientists in the field now refer to this enzyme as CPA1, and to a related pancreatic carboxypeptidase as CPA2.
Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the PTPN1 gene. PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, in particular for treatment of type 2 diabetes. It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well.
The enzyme aminocyclopropane-1-carboxylic acid synthase catalyzes the synthesis of 1-Aminocyclopropane-1-carboxylic acid (ACC), a precursor for ethylene, from S-Adenosyl methionine, an intermediate in the Yang cycle and activated methyl cycle and a useful molecule for methyl transfer:
A non-receptor tyrosine kinase (nRTK) is a cytosolic enzyme that is responsible for catalysing the transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins. Non-receptor tyrosine kinases are a subgroup of protein family tyrosine kinases, enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein (phosphorylation). These enzymes regulate many cellular functions by switching on or switching off other enzymes in a cell.
Carbohydrate sulfotransferases are sulfotransferase enzymes that transfer sulfate to carbohydrate groups in glycoproteins and glycolipids. Carbohydrates are used by cells for a wide range of functions from structural purposes to extracellular communication. Carbohydrates are suitable for such a wide variety of functions due to the diversity in structure generated from monosaccharide composition, glycosidic linkage positions, chain branching, and covalent modification. Possible covalent modifications include acetylation, methylation, phosphorylation, and sulfation. Sulfation, performed by carbohydrate sulfotransferases, generates carbohydrate sulfate esters. These sulfate esters are only located extracellularly, whether through excretion into the extracellular matrix (ECM) or by presentation on the cell surface. As extracellular compounds, sulfated carbohydrates are mediators of intercellular communication, cellular adhesion, and ECM maintenance.
