Adrenocortical pregnenolone binding activity resides with estrogen sulfotransferase

Lee, Y. C.

doi:10.1210/en.136.1.361

Cited by 6 publications

(2 citation statements)

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“…Progress in the P2 receptor field has been slowed by the lack of availability of receptor subtype-selective antagonists. Thus, the observation by Boyer et al that adenosine 3‘-phosphate 5‘-phosphosulfate ( 2 , A3P5PS or PAPS, Figure ), a cofactor for sulfotransferase enzymes, and adenosine 3‘,5‘-bisphosphate ( 1 , A3P5P or PAP, Figure ), a metabolite of PAPS, were both partial agonists at the P2Y 1 receptor in turkey erythrocyte membranes was of considerable interest. Moreover, A3P5PS and A3P5P were shown to be competitive P2Y 1 receptor antagonists at both turkey and human P2Y 1 receptors with p K B values in the micromolar range .…”

Section: Introductionmentioning

confidence: 99%

Deoxyadenosine Bisphosphate Derivatives as Potent Antagonists at P2Y₁ Receptors

et al. 1998

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Adenosine 3',5'- and 2',5'-bisphosphates previously were demonstrated to act as competitive antagonists at the P2Y1 receptor (Boyer et al. Mol. Pharmacol. 1996, 50, 1323-1329). 2'- and 3'-Deoxyadenosine bisphosphate analogues containing various structural modifications at the 2- and 6-positions of the adenine ring, on the ribose moiety, and on the phosphate groups have been synthesized with the goal of developing more potent and selective P2Y1 antagonists. Single-step phosphorylation reactions of adenosine nucleoside precursors were carried out. The activity of each analogue at P2Y1 receptors was determined by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit phospholipase C stimulation elicited by 10 nM 2-MeSATP (antagonist effect). Both 2'- and 3'-deoxy modifications were well tolerated. The N6-methyl modification both enhanced antagonistic potency (IC50 330 nM) of 2'-deoxyadenosine 3',5'-bisphosphate by 17-fold and eliminated residual agonist properties observed with the lead compounds. The N6-ethyl modification provided intermediate potency as an antagonist, while the N6-propyl group completely abolished both agonist and antagonist properties. 2-Methylthio and 2-chloro analogues were partial agonists of intermediate potency. A 2'-methoxy group provided intermediate potency as an antagonist while enhancing agonist activity. An N1-methyl analogue was a weak antagonist with no agonist activity. An 8-bromo substitution and replacement of the N6-amino group with methylthio, chloro, or hydroxy groups greatly reduced the ability to interact with P2Y1 receptors. Benzoylation or dimethylation of the N6-amino group also abolished or greatly diminished the antagonist activity. In summary, our results further define the structure-activity of adenosine bisphosphates as P2Y1 receptor antagonists and have led to the identification of the most potent antagonist reported to date for this receptor.

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Section: Introductionmentioning

confidence: 99%

Deoxyadenosine Bisphosphate Derivatives as Potent Antagonists at P2Y₁ Receptors

et al. 1998

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“…Since the mechanisms of cytochrome P450 and steroid‐dehydrogenase mediated steroid biosynthesis were first described, and the importance of the transfer of steroid intermediates from mitochondrial to microsomal sites of enzyme activity (and back again) were first noted, little attention has been directed to addressing how this might be achieved. Although the question has certainly been asked whether binding proteins have a role [31–34], in some cases it seems clearer [31] than in others [35]. It is also possible that a carrier protein could be involved with intercellular steroid transport.…”

Section: Discussionmentioning

confidence: 99%

Identification of the rat adrenal zona fasciculata/reticularis specific protein, inner zone antigen (IZAg), as the putative membrane progesterone receptor

Raza

Takemori

Tojo

et al. 2001

European Journal of Biochemistry

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Using immunological methods, a protein specific to the inner zones of the rat adrenal cortex, and called inner zone antigen (IZAg), was previously shown to have two interrelated forms of 26 kDa (IZAg1) and 55±60 kDa (IZAg2), and to have an action on steroid hydroxylation. After twodimensional gel electrophoresis, and immunoaffinity column purification, N-terminal amino-acid analysis showed that the first 12 amino acids were identical to those of a recently described putative membrane located progesterone receptor (PPMR). RT-PCR was then used to generate the cDNA of this protein, using RNA extracted from rat adrenals. A glutathione S-transferase (GST)-fusion construct was expressed in Escherichia coli, and shown to generate an immunoreactive product of molecular mass consistent with its identification as IZAg1. More detailed examination of the distribution of this protein, not only in the zona fasciculata/reticularis of the adrenal cortex, but also in the Leydig cell, kidney and liver, suggest it may have a role in steroid hormone synthesis and/or metabolism.

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