The Biochemistry of the 17-Hydroxysteroid Dehydrogenases
Ronald Hobkirk in Steroid Biochemistry, 1979
Studies in our laboratory indicate that, in the rabbit liver, there may be a special relationship between oxidoreduction at C-17 of the estrogen molecule and conjugation with glucuronic acid at C-3. In rabbit liver cytosol, 17-hydroxysteroid dehydrogenase activity favors interconversion of estrone and 17β-estradiol rather than formation of 17α-estradiol. However, with the glucuronide derivatives of the steroids, formation of the 17α-epimer predominates (Table 4). Rabbit liver cytosol contains a 17α-hydroxysteroid dehydrogenase that, with estrogen substrates, is specific for the 3-glucuronide derivative.17,87 These findings may have significance with respect to the control of estrogen metabolism in the rabbit. This metabolic pathway involves formation of 17αestradiol and conjugation first with glucuronic acid at C-3 and then with N-acetylglucosamine at C-17.11,139,140 The transfer of N-acetylglucosamine to the steroid molecule is very specific and requires prior formation of the 17α-epimer and prior conjugation at C-3 with glucuronic acid. The double conjugate formed is subsequently excreted in the urine. Therefore, in rabbit liver, conjugation of the estrogen molecule at C-3 with glucuronic acid directs metabolism towards elimination of this steroid owing to the presence of a 17α-hydroxysteroid dehydrogenase specific to the steroid glucuronide derivative.
Phosphonic Acids And Phosphonates As Antimetabolites
Richard L. Hilderbrand in The Role of Phosphonates in Living Systems, 2018
The analogues (75) and (76) are particularly interesting as they bear, on the carbon replacing the normal esteratic oxygen, a function capable of binding; that is, it has an unshared electron pair. Work with these materials illustrates a significant point of stereochemistry. Only one epimer of (75) serves as a substrate with pig muscle AMP kinase230 and with muscle pyruvate kinase only one epimer of (76) could serve as a substrate.229 Interestingly, both epimers of (76) could be phosphorylated by muscle adenylate kinase.229 Again, with the species (Structure 84) related to ATP, only one epimer could serve as phosphoryl donor in the AMP kinase reaction; moreover, that epimer of (84) is opposite in configuration to that of (76) which is noted above as operating with muscle pyruvate kinase.229Further structural analysis and coorelation of data will prove of value in better understanding of this enzyme process.
Total Synthesis of Some Important Natural Products from Brazilian Flora
Luzia Valentina Modolo, Mary Ann Foglio in Brazilian Medicinal Plants, 2019
In 2002, Brown et al. described an approach to access three heteroyohimbine alkaloids from secologanin, a natural biogenetic source of indole alkaloids (Contin et al., 1998). There are many pharmacological properties reported for heteroyohimbine alkaloids, a group repeatedly found in the Rubiaceae family, mainly in the Uncaria genus. In South America, Uncaria tomentosa (Rubiaceae; unha-de-gato) and Uncaria guianensis (Rubiaceae; unha-de-gato), known as cat's claw, are commonly used in local popular medicine (Sandoval et al., 2002). Working with the extracts of powdered leaves of U. guianensis (Rubiaceae), collected from the Viro forest reserve in Pará state, Brazil, Bolzani and coworkers (2004) isolated some oxindole alkaloids, including the less common 3-iso-ajmalicine 21. The synthesis of this alkaloid was reported by Brown et al. in 2002 in four steps and a 38% overall yield (Figure 12.7). The key step of this proposal was the final step, where the two central rings were constructed, and the five-ring system was all connected. This process was accomplished by employing a Pictet-Spengler condensation, which occurs when compound 22 is treated in acidic media to afford the desired alkaloid 21. This reaction sequence can be inverted, with the Pictet-Spengler step being performed in the initial steps, as previously reported by Brown and Leonard (1979); however, the route described herein allowed better control over the C-3 stereochemistry, although a minor amount (∼10%) of the C-3 epimer was observed on some occasions.
Clot activators and anticoagulant additives for blood collection. A critical review on behalf of COLABIOCLI WG-PRE-LATAM
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
G. Lima-Oliveira, L. M. Brennan-Bourdon, B. Varela, M. E. Arredondo, E. Aranda, S. Flores, P. Ochoa
The additives, sodium fluoride and iodoacetate, are used to improve the accuracy of glucose determination by reducing glycolysis in vitro [147] (Figure 9). However, these additives should be used in combination with an anticoagulant additive – EDTA, oxalate, or heparin – with or without mannose. It should be noted that at least 3 h are required to stabilize the glucose in blood samples [148,149]. Mannose is a C-2 epimer of glucose and a sugar monomer of the aldohexose series of carbohydrates, differing structurally from glucose in the configuration around just one carbon atom [150]. Thus, in vitro mannose is a competitive inhibitor of hexokinase with a short half-life (4 h) [151]. While fluoride is able to move rapidly across the erythrocyte membrane [152], the additives, fluoride and oxalate, do not completely prevent the in vitro decrease of glucose [153,154]. Sodium fluoride inhibits enolase [155,156] in the presence of inorganic phosphate; the fluorophosphate ion is the inhibitory species, which, when bound to magnesium, forms a complex with enolase and inactivates the enzyme [157]. It is noteworthy that samples collected with fluoride and oxalate show hemolysis [158], making the samples unsuitable for other assays.
Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Maša Sinreih, Rebeka Jójárt, Zoltán Kele, Tomaž Büdefeld, Gábor Paragi, Erzsébet Mernyák, Tea Lanišnik Rižner
Electrophilic substitutions with N-halosuccinimides were carried out in our recent studies, starting from the 13β-methyl-oestrone (1), its 13α-methyl epimer (2) and the 17-deoxy-13α-methyl-oestrone (3; Figure 2)26,27. Halogenations occurred at the ortho positions relative to the phenolic OH group. Mono-substituted and bis-substituted derivatives were formed. Starting from the 3-methyl ethers (1Me, 2Me, 3Me), mono-halogenated derivatives were obtained exclusively. Some of these halogenated oestrone derivatives showed potent inhibition of aromatase, oestrone sulphatase, and 17β-hydroxysteroid dehydrogenase, and/or OATP2B1 actions26,27. Important structure–activity relationships were identified. These studies indicated that the 13α-methyl epimer of the natural oestrone might be superior to its 13β-methyl counterpart, as it is readily available and hormonally inactive and has other promising biological properties. The group of 2,4-bis halogenated compounds provided the most promising inhibitors from the biological point of view.
Intra-site differential inhibition of multi-specific enzymes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mario Cappiello, Francesco Balestri, Roberta Moschini, Umberto Mura, Antonella Del-Corso
Although a “complete” intra-site differential inhibitor as defined above has not as yet been envisaged for AKR1B1, molecules able to differentially inhibit aldoses reduction and/or GSHNE reduction versus HNE reduction have been proposed. The typical basic conditions to illustrate in vitro the differential inhibition of AKR1B1 mimic those occurring in a hyperglycaemic status, with the aldose substrates kept at the mM level, and the toxic aldehydes (i.e., HNE) or their glutathionyl-derivatives (i.e., GSHNE) kept at the µM level. D,L-glyceraldehyde, the most common substrate used in AKR1B1 inhibition studies, was also utilised as a substrate in differential inhibition studies. However, the evidence of incomplete inhibitory action exerted on the enzyme activity by aldose hemiacetals51,52, which cannot take place with a triose, suggested the use of an aldohexose as the substrate. Thus, L-idose, an epimer of D-glucose at C5, with a free aldehyde form approximately 80 times higher than what was observed for glucose, was chosen as elective substrate for inhibition studies53. Finally, the problem of poor solubility of molecules often encountered in inhibition studies of AKR1B1 was overcome by using a proper aqueous cocktail of either methanol or dimethyl sulfoxide, after evaluating the limits of their suitability for the enzyme assay20. In these conditions, supported by kinetic analysis of the inhibitory action towards the different substrates, a number of molecules, coming both from organic synthesis and from natural sources, were identified as having differential inhibitory abilities.
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