5 -phosphoadenosine 3 -phosphosulfate PAPS

Kim HJ, Cho JH, Klaassen CD. 1995. Depletion of hepatic 3 -phosphoadenosine 5 -phosphosulfate (PAPS) and sulfate in rats by xenobiotics that are sulfated. J Pharmacol Exp Ther 275 654-658. 

Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The cosubstrate for these reactions is 3 -phosphoadenosine 5 -phosphosulfate (PAPS) (Fig. 4.1). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minoxidil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs lAl to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULTIBI possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULTIEI has substantial activity toward steroid hormones, especially estradiol and dehydroepiandrosterone, and toward the anti-... 

Phosphatidylinositol (Ptdlns) 563, 565, 566s in signalling 563 - 566 Phosphatidylinositol 3-kinase 565 Phosphatidylinositol 4,5-bisphosphate 563 Phosphatidylserine 383s, 564 decarboxylation of 753 Phosphatidylserine decarboxylase 409, 755 3 -Phosphoadenosine 5 -phosphosulfate (PAPS) 659 Phosphoadenylation... 

Among the variety of sulfate esters formed by living cells are the sulfate esters of phenolic and steroid compounds excreted by animals, sulfate polysaccharides, and simple esters, such as choline sulfate. The key intermediate in the formation of all of these compounds lias been shown to be 3 -phosphoadenosine-5/-phosphosulfate (PAPS). This nucleotide also serves as an intermediate in sulfate reduction. 

Formation of 3 -phosphoadenosine-5 -phosphosulfate (PAPS), an active intermediate involved in sulfate reduction. The eight-electron reduction of S042 to HjS is poorly understood except for the initial steps in the activation of sulfate (shown in yellow). Reduction in yeast and plants involves the APS derivative shown. In E. coli a PAPS derivative is used. 

Sulfation is expensive in energy terms for the cell, since two molecules of ATP are necessary for the synthesis of one molecule of 3 -phosphoadenosine 5 -phosphosulfate (PAPS). Both enzymes involved in the synthesis of PAPS, ATP sulfurylase, and APS kinase, reside within a single bifunctional cytosolic protein of approximately 56 kDa, where substrate channeling of APS from ATP sulfurylase to APS kinase occurs. Several group VI anions other than sulfate can also serve as substrates, although the resultant anhydrides are unstable. Because this instability would lead to the overall consumption of ATP, these other anions can exert a toxic effect by depleting the cell of ATP. 

The sulfate molecule used in conjugation reactions is derived from 3-phosphoadenosine-5 -phosphosulfate (PAPS). Efficient synthesis of PAPS requires an adequate amount of inorganic sulfate with L-cysteine, D-cysteine, or L-methionine serving as precursors for the inorganic sulfate. PAPS is likely synthesized in every vertebrate cell, with high concentrations produced in the liver. 

Sulfotransferases (SULTs) are cytosolic phase II detoxification enzymes involved in sulfonation of various xenobiotics and endobiotics. There are also membrane-bound SULTs that are not involved in phase II metabolism but are involved in the sulfonation of proteins and polysaccharides. Substrates of cytosolic SULTs include alcohols (ethanol, 2-butanol, cholesterol, bile acids), phenols (phenol, naphthol, acetaminophen), aromatic amines and hydroxyamines (2-naphthylamine, A-hydroxy 2-naphthylamine). SULTs transfer sulfonate (S03) to a hydroxy or amino group of a substrates from the cofactor 3 -phosphoadenosine-5 -phosphosulfate (PAPS), generating highly water-soluble metabolites for elimination through the kidney and liver. 

Two major pathways are known for the reduction of sulfate. One is the assimilatory pathway, which reduces sulfate to the extent necessary for satisfying the nutritional requirements of the organism. In this pathway, which has been extensively studied in yeast by Robbins and Lip-mann (S68) and Bandurski and his colleagues 369, 370), sulfate is first activated in the presence of ATP by the enzyme ATP-sulfurylase to form adenosine 5 -phosphosulfate (APS). Then in a second reaction, APS is phosphorylated in the 3 position by ATP to form 3 -phosphoadenosine 5 -phosphosulfate (PAPS)... 

Sulfation. Sulfotransferases use 3-phosphoadenosine-5-phosphosulfate (PAPS) as a cosubstrate. It concerns mostly hydroxyl groups. 

With the sulfated polysaccharides, the mechanism of sulfation has aroused much discussion. The chief point at issue is whether sulfation takes place before or after formation of the polysaccharide chain. The biological sulfate carrier, formed enzymatically in chicken embryo cartilage or liver, has been characterized (R4) as 3 -phosphoadenosine-5 -phosphosulfate (PAPS). Following the isolation of chondroitin, it was suggested that this mucopolysaccharide might act as a sulfate acceptor... 

Sulfotransferases transfer sulfo groups to O and N atoms of suitable acceptors (reaction type ID, Table 10-1). Usually, transfer is from the active sulfate," 3 -phosphoadenosine 5 -phosphosulfate (PAPS), 21 whose formation is depicted in Eq. 17-38. Sulfatases catalyze hydrolysis of sulfate esters. The importance of such enzymes is demonstrated by the genetic mucopolysaccharidoses. In four of these disease-specific sulfatases that act on iduronate sulfate, heparan N-sulfate, galactose-6-sulfate, or N-acetylglu-cosamine-4-sulfate are absent. Some of these, such as heparan N-sulfatase deficiency, lead to severe mental retardation, some cause serious skeletal abnormalities, while others are mild in their effects. ... 

Sulfation is another common form of conjugation predominately found with phenolic compounds however, sulfate esters can also be formed with alcohols, aryl-amines, and N-hydroxy compounds. Sulfation involves the transfer of S03 from 3 -phosphoadenosine-5 -phosphosulfate (PAPS) to one of the above-mentioned functional groups by an enzyme-catalyzed reaction involving the cytosolic enzymes (sulfotransferases), as illustrated in Fig. 24 [11]. It is common to find phenolic compounds that are metabolized by both sulfation and glucuronidation, as they are often competing pathways. However, sulfation has a significant limitation... 

Figure 24 Structure of 3 -phosphoadenosine-5 -phosphosulfate (PAPS) and a generalized reaction of sulfation.

Sulfate can be converted to the sulfate donor compound 3 -phosphoadenosine-5 -phosphosulfate (PAPS) in a two-step reaction (Figure 17-17). PAPS participates in the sulfate esterification of alcoholic and phenolic functional groups (e.g., in synthesis of sulfolipids and glycosamino-glycans). 

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