Involvement of ST1B Subfamily of Cytosolic Sulfotransferase in Kynurenine Metabolism to Form Natriuretic Xanthurenic Acid Sulfate

Abstract

Natriuretic substances are a group of molecules affecting sodium homeostasis in the body. Recently, two new molecules having natriuresis effects, xanthurenic acid 8-O-␤-D-glucoside and xanthurenic acid 8-O-sulfate (XA sulfate), have been isolated from human urine. In the present study, we have investigated the sulfation of xanthurenic acid (XA) in mouse tissues to assess the contribution of specific sulfotransferases (STs) to the reaction. Cytosols from tissues of both sexes of C57BL/6N mice (liver, stomach, jejunum, colon, and kidney) were capable of forming XA sulfate, with various K m values. Jejunum cytosol showed the lowest K m value, and its V max /K m value was much greater than those of other tissues. The kinetic analyses with recombinant mouse (m) STs (Sult1a1, Sult1b1, Sult1c2, and Sult1d1) showed the lowest K m value for mSult1b1, and the value was comparable with that for jejunum cytosol. The highest expression of mSult1b1 in small intestine was confirmed at the mRNA and protein levels. mSult1b1 is thus suggested as a major enzyme responsible for XA sulfation in jejunum. Similar to mSult1b1, human SULT1B1 and rat Sult1b1 mediated XA sulfation efficiently. Thus, XA is likely to be an endogenous substrate for ST1B members. In contrast to XA, an XA-related compound, kynurenic acid strongly inhibited mSult1b1-mediated sulfations, with IC 50 values at a micromolar range. These results indicate the functional role of ST1B subfamily of ST in XA sulfate formation in the body.

Transport of Xanthurenic Acid by Rat/Human Organic Anion Transporters OAT1 and OAT3

“…28) Sulfation of xanthurenic acid occurred in various tissues including the liver, stomach, jejunum, colon, and kidney, and sulfotransferase SULT1C2 was exhibited to be predominantly expressed in the proximal tubule, where OAT1 and OAT3 work. 29,30) Accordingly, it is intriguing whether the formation of xanthurenic acid sulfate followed by its tubular uptake by OAT1 and OAT3 is responsible for diuresis.…”

Selective Role of Sulfotransferase 2A1 (SULT2A1) in the N-Sulfoconjugation of Quinolone Drugs in Humans

“…35 S]PAPS as a sulfate donor after thin-layer chromatography as described previously (Yoshinari et al, 1998b;Senggunprai et al, 2008) with slight modification. All enzyme assays were conducted under conditions in which the linearity with respect to protein concentration was obtained.…”

“…hSULT1E1 (ST1E4) (Honma et al, 2002) and hSULT2A1 (Honma et al, 2002) were expressed as a histidine-tagged protein, designated His 6 -SULT, and purified from Escherichia coli cytosols with nickel-nitrilotriacetic acid agarose as described previously (Senggunprai et al, 2008). Other SULTs including hSULT1A1 (ST1A3), hSULT1A3 (ST1A5), hSULT1B1 (ST1B2), and hSULT1C2 (ST1C2) were previously expressed and purified (Senggunprai et al, 2008). Protein concentrations of the recombinant enzymes were determined by spectrophotometry and calculated based on their extinction coefficient (Gill and von Hippel, 1989).…”

Inhibitory effects of kynurenic acid, a tryptophan metabolite, and its derivatives on cytosolic sulfotransferases

“…Recently, we have reported the involvement of SULT1B subfamily members in the sulfation of XA (xanthurenic acid) ( Figure 1) to form natriuretic XA sulfate, and that XA is an excellent endogenous substrate for SULT1B members [12]. XA is a product generated in the kynurenine pathway which is the principle route of tryptophan catabolism [13].…”