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Results: 5

1.
Fig. 2.

Fig. 2. From: Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates.

(A) Linear correlation between log(Vmax/Km) and Hammett σp (r = 0.964) for 2-arylsubstituted-6-hydroxybenzothiazole derivatives. Compounds 2g (4 = NHCOCH3) and 2k (SO2-CH3) are apparent outliers due to possible steric hindrance of the large 4-substituents affecting binding with SULT1E1. (B) Linear correlation between δC2 and the log(Vmax/Km) (r = 0.987). Compounds 2g and 2k are apparent outliers due to steric hindrance. (C) 6-Hydroxy proton chemical shifts (δOH) and the log(Vmax/Km) (r = 0.963). Compounds 2g and 2k are outliers due to steric hindrance. All numbers represent the average of triplicate values.

Graham B. Cole, et al. Proc Natl Acad Sci U S A. 2010 April 6;107(14):6222-6227.
2.
Fig. 1.

Fig. 1. From: Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates.

(A) Interplay of estrogen sulfation and estrogen receptor (ER). Tissue levels of E2 are regulated by SULT1E1 and STS, thus, modulating E2 interaction with the estrogen receptor (ER). (B): Active site of human SULT1E1 with E2 (Green) bound in the active site. Amino acid residues that form the binding pocket are show in Beige (oxygen, Red; nitrogen, Blue; sulfur, Red; and free water molecures, Cyan) [Modified with permission from (25).© National Institute of Environmental Health Sciences, 2003].

Graham B. Cole, et al. Proc Natl Acad Sci U S A. 2010 April 6;107(14):6222-6227.
3.
Fig. 3.

Fig. 3. From: Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates.

(Top) Representative microPET scans in rat brain (Top, Left) and whole-body mice (Top, Right) with 11C-(2b) co-registered with microCT images. The animals were scanned in a dynamic mode for 25 min. (Bottom): Western blot data obtained from the same tissues. Lane 1: 80 μg frontal cortical area (Cortex 1); Lane 2: 80 μg superior cortical areas (Cortex 2); Lane 3: 80 μg subcortical areas; Lane 4: 80 μg cerebellum; Lane 5: 80 μg brain stem; Lane 6: 50 μg testis; Lane 7 100 μg testis; and Lane 8: 150 μg testis

Graham B. Cole, et al. Proc Natl Acad Sci U S A. 2010 April 6;107(14):6222-6227.
4.
Scheme 2.

Scheme 2. From: Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates.

Therapeutic agents such as raloxifene and 4-hydroxytamoxifen (Scheme 2) (19), as well as naturally occurring dietary flavonoids, are substrates or inhibitors of sulfotransferases (SULT1A1 and SULT1E1) to varying degrees (16, 20). Until now, no family of structurally related compounds has been reported to provide substrate preference for SULT1E1 as is seen with estrogens. 2-Aryl-6-hydroxybenzothiazoles 2b-2f, 2j-2k, several of which have been recently reported in connection with amyloid Aβ aggregate detection in the brain of Alzheimer’s disease patients (21, 22) or as possessing breast cancer cell cytotoxicity (23), are shown here to be highly specific substrates for SULT1E1. These compounds have afforded a unique opportunity to examine the effect of changing substituent electronic properties on the specificity of SULT1E1. This was previously examined with SULT1A1 (18) but has remained elusive for SULT1E1.

Graham B. Cole, et al. Proc Natl Acad Sci U S A. 2010 April 6;107(14):6222-6227.
5.
Scheme 1.

Scheme 1. From: Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates.

The effect of 4′-substitution was examined in enzyme assays with 2-phenyl-6-(and 5-)hydroxybenzothiazoles (Scheme 1, Table 1) against SULT1E1, SULT1A1*1, SULT1A1*2, SULT1A3, and SULT2A1 enzymes. With the 6-hydroxybenzothiazole derivatives (2a–2d, 2f–2l), there was a correlation between the polarity of the 4′-substitution on the 2-phenyl ring (Hammett σp) and SULT1E1 substrate sensitivity (Vmax/Km) (Fig. 2A) (17). This is due to the electron-donating or withdrawing effects of the 4′-substituents on the acidity of the 6-arylhydroxyl moiety. To corroborate this interpretation, the 1H NMR chemical shift of the hydroxyl group (δOH) is also tightly correlated with the log(Vmax/Km) kinetic parameter (Fig. 2C). Furthermore, there is an analogous correlation of the 13C NMR chemical shift of C-2 (δC2) in these benzothiazoles with the log(Vmax/Km) (Fig 2B). Exceptions to these correlations included compounds with large 4′-substituents, such as sulfone (2k) or acetamide (2g), which have lower Vmax/Km values (Table 1) than expected from their electronic character.Table 1.Michaelis–Menten kinetic parameters for 2-aryl substituted hydroxybenzothiazolesSULT1E1SULT1A1*1KmVmaxVmax/KmKmVmaxVmax/Km2a0.99 ± 0.033.18 ± 0.873.22 ± 0.90.018 ± 0.0064.97 ± 0.57275 ± 972b1.42 ± 0.121.99 ± 0.071.40 ± 0.13***2c1.42 ± 0.322.18 ± 0.081.54 ± 0.35***2d2.11 ± 0.202.88 ± 0.141.36 ± 0.15***2e1.00 ± 0.061.98 ± 0.051.97 ± 0.08***2f0.90 ± 0.111.97 ± 0.082.19 ± 0.26***2g2.36 ± 0.142.04 ± 0.040.87 ± 0.050.025 ± 0.0050.88 ± 0.0536 ± 72h0.56 ± 0.094.08 ± 0.257.29 ± 1.250.029 ± 0.0080.91 ± 0.0931 ± 92i0.52 ± 0.052.95 ± 0.085.64 ± 0.560.01 ± 0.0030.67 ± 0.0567 ± 212j0.25 ± 0.024.33 ± 0.1217.1 ± 1.4***2k1.32 ± 0.083.57 ± 0.062.69 ± 0.16***2l0.12 ± 0.023.33 ± 0.1927.75 ± 4.890.058 ± 0.0191.24 ± 0.0921 ± 72m0.77 ± 0.081.74 ± 0.052.26 ± 0.242n0.43 ± 0.101.05 ± 0.082.44 ± 0.60SULT1A1*2 assay with compound 2a yielded Km = 0.045 ± 0.01 and Vmax = 5.25 ± 0.55 (Vmax/Km 117 ± 23); sulfate formation was seen for compounds 2m and 2n, however, kinetic parameters could not be reliably measured. All 2-aryl substituted hydroxybenzothiazoles were assayed against SULT1A3 and SULT2A1 with no detectable activity. Compound 2b was additionally assayed against the SULT1B1 enzyme from 20 nM to 3 μM with no detectable activity. All experiments were performed in triplicate and all values are expressed as mean ± s.d. Units: Km as μM, Vmax as nmol/ min /mg, andVmax/Km as (nmol/ min /mg)/μM.
*No detectable activity.Activity was seen, however kinetic parameters could not be reliably measured.

Graham B. Cole, et al. Proc Natl Acad Sci U S A. 2010 April 6;107(14):6222-6227.

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