Homeostasis of Dopamine
Nira Ben-Jonathan in Dopamine, 2020
The sulfation reaction is catalyzed by members of the sulfotransferase (SULT) superfamily (Table 1.2). Sulfation is involved in the conjugation of numerous endogenous and xenobiotic chemicals, thus exerting considerable influence over their biological activity [29]. The sulfation reaction entails the enzymatic transfer of a sulfonate group (SO3−1) from a universal donor, 3′-phosphoadenosine, 5′-phosphosulfate, to recipient molecules. Sulfation is a major contributor to the homeostasis and regulation of catecholamines, steroids, and iodothyronines, as well as the detoxication of xenobiotics. SULT enzymes are widely expressed in a variety of human tissues, including liver, intestine, and brain. They are classified on the basis of their substrate specificity and amino acid sequence into two subfamilies: SULT1 (phenol sulfotransferases or PST) and SULT2 (steroid sulfotransferases).
Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Sheryl S. Smith in Neurosteroid Effects in the Central Nervous System, 2003
Sulfation of free 3β -hydroxysteroids is a major enzymatic reaction of metabolism, excretion, and homeostasis of steroids and bile acids (reviewed in Hobkirk108). Sulfation and sulfohydrolation activities have been reported in lung, kidney, adrenal, and testis, and have been described as crucial during development. 16-Hydroxy DHEA sulfate (DHEAS) originating from the liver, DHEAS originating from the adrenal, and DHEA originating from the placenta serve as precursors for the production of estrone, estradiol, and estriol in the developing human placenta109-111 (Figure 1.1). Sulfotransferases are a family of cytosolic enzymes that conjugate steroid and phenolic substrates with inorganic sulfate derived from an active donor, PAPS.112,113 The hydroxysteroid sulfotransferase specifically uses Δ 5 steroid substrates that are hydroxylated at C3, 5, 17, or 21.113 The resulting steroid sulfate esters are hydrophilic. However, sulfation has a role greater than facilitating secretion, since it can also change the pharmacological activity of steroids, such as changing the way in which pregnenolone binds to the GABAA receptor (reviewed in Majewska114,115). HST is mainly found in adrenal in humans and in liver in other mammals.1161.2.4.6 Sulfatase (STS)
Renal Drug-Metabolizing Enzymes in Experimental Animals and Humans
Robin S. Goldstein in Mechanisms of Injury in Renal Disease and Toxicity, 2020
Usually the biological activity of a substance is reduced by sulfation. However, this is not always the case. Certain sulfate conjugates of morphine, e.g., morphine 6-sulfate, are considerably more active as an analgesic than the parent compound when injected intraventricularly (Brown et al., 1985). There is also increasing evidence that sulfation may enhance the toxicity of certain chemicals for instance, N-hydroxy-2-acetylaminofluorene (see reviews by Miller et al. [1985] and Mulder et al. [1988]). Sulfation of the carcinogen 5-hydroxymethyl-chrysene (5-HCR) to the active metabolite 5-HCR sulfate occurs in renal cytosol from rats, mice, guinea pigs, and hamsters, although the activity is highest in females of the latter two species (Okuda et al., 1989).
In silico prediction of post-translational modifications in therapeutic antibodies
Published in mAbs, 2022
Shabdita Vatsa
Tyrosine sulfation is an enzymatic modification that is catalyzed by tyrosylprotein sulfotransferases (TPSTs). During sulfation, a sulfate group is attached to the hydroxyl group of tyrosine residues.111 Tyrosine sulfation has been reported for a few monoclonal and bispecific antibodies.111–114 Sulfation of mAbs can occur in Chinese hamster ovary (CHO) cells during the cell culture. The degree of tyrosine sulfation in CHO cells varies due to differential expression of phosphoadenosine-5ʹ-phosphosulfate (PAPS) synthetase and TPST. PAPS synthetase converts ATP to PAPS; TPST transfers the sulfo group from PAPs to tyrosine residues.115 Sulfation in mAbs generates acidic variants,111 but the impact of tyrosine sulfation on the safety and efficacy of therapeutic antibodies has not yet been established.5
Platelet activation by charged ligands and nanoparticles: platelet glycoprotein receptors as pattern recognition receptors
Published in Platelets, 2021
Samantha J. Montague, Pushpa Patel, Eleyna M. Martin, Alexandre Slater, Lourdes Garcia Quintanilla, Gina Perrella, Caroline Kardeby, Magdolna Nagy, Diego Mezzano, Paula M. Mendes, Steve P. Watson
Human PEAR1 is a novel platelet and endothelial receptor that mediates powerful activation of platelet by sulfated polysaccharides, including fucoidans and dextran-sulfate.59 Sulfation is critical for activation. The site of interaction has been mapped to the thirteenth EGF-like repeat in PEAR1 which contains a cluster of positively charged amino acids in a conserved heparin binding-like consensus sequence. The co-crystallization of PEAR1 with its ligands will map the critical amino acids and potentially provide information on the endogenous ligand. Interestingly, we have shown that in mouse platelets, sulfated glycopolymers mediate activation through CLEC-2 with only a partial role for PEAR159 and speculate that this may be due to the much higher expression of CLEC-2 in mouse platelets compared to humans.88 If this is the case, this illustrates the promiscuity of charged ligands consistent with the charge playing a dominant role in mediating activation.
Recent developments in predicting CYP-independent metabolism
Published in Drug Metabolism Reviews, 2021
Nikhilesh V. Dhuria, Bianka Haro, Amit Kapadia, Khadjia A. Lobo, Bernice Matusow, Mary A. Schleiff, Christina Tantoy, Jasleen K. Sodhi
In general, the sulfation reaction is a detoxification process in which the substrate is metabolized to a more polar water-soluble moiety that can more easily be excreted in the urine, however, SULTs are also involved in the bioactivation of certain compounds that contain allylic alcohols, benzyl alcohols, aromatic hydroxylamines, amino azo dyes, terpenes, and other compounds (Banoglu 2000; Glatt 2000; Gamage et al. 2006; Diao et al. 2014). More recently, pirifenidone has been shown to be bioactivated by CYP enzymes and SULTs resulting in covalent binding to proteins (Zhou et al. 2020). It has been well documented that pirifenidone, a drug that is used to treat idiopathic lung fibrosis, is also associated with idiosyncratic hepatic injury often leading to acute liver failure (Verma et al. 2018), thus these findings provide valuable information for medicinal chemists and drug metabolism scientists toward the future design of safer therapeutics.
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