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Frontiers in Endocrinology 2021Cytochrome P450s (CYPs) are an essential family of enzymes in the human body. They play a crucial role in metabolism, especially in human steroid biosynthesis. Reactions...
Cytochrome P450s (CYPs) are an essential family of enzymes in the human body. They play a crucial role in metabolism, especially in human steroid biosynthesis. Reactions catalyzed by these enzymes are highly stereo- and regio-specific. Lack or severe malfunctions of CYPs can cause severe diseases and even shorten life. Hence, investigations on metabolic reactions and structural requirements of substrates are crucial to gain further knowledge on the relevance of different enzymes in the human body functions and the origin of diseases. One key enzyme in the biosynthesis of gluco- and mineralocorticoids is CYP21A2, also known as steroid 21-hydroxylase. To investigate the steric and regional requirements of substrates for this enzyme, we performed whole-cell biotransformation assays using a strain of fission yeast recombinantly expressing CYP21A2. The progestogens progesterone, pregnenolone, and their 17α-hydroxy-derivatives were used as substrates. After incubation, samples were analyzed using gas chromatography coupled to mass spectrometry. For progesterone and 17α-hydroxyprogesterone, their corresponding 21-hydroxylated metabolites 11-deoxycorticosterone and 11-deoxycortisol were detected, while after incubation of pregnenolone and 17α-hydroxypregnenolone, no hydroxylated product was observed. Findings were confirmed with authentic reference material. Molecular docking experiments agree with these results and suggest that interaction between the 3-oxo group and arginine-234 of the enzyme is a strict requirement. The presented results demonstrate once more that the presence of an oxo-group in position 3 of the steroid is indispensable, while a 3-hydroxy group prevents hydroxylation in position C-21 by CYP21A2. This knowledge may be transferred to other CYP21A2 substrates and hence help to gain essential insights into steroid metabolism.
Topics: 17-alpha-Hydroxypregnenolone; Adrenal Cortex Hormones; Catalytic Domain; Cytochrome P-450 Enzyme System; Gas Chromatography-Mass Spectrometry; Humans; Hydroxylation; Models, Molecular; Molecular Docking Simulation; Pregnenolone; Progesterone; Schizosaccharomyces; Steroid 17-alpha-Hydroxylase; Steroid 21-Hydroxylase; Steroids; Substrate Specificity
PubMed: 34149610
DOI: 10.3389/fendo.2021.633785 -
Molecules (Basel, Switzerland) Jul 2019As a result of the findings of scientists working on the biosynthesis and metabolism of steroids in the plant and animal kingdoms over the past five decades, it has... (Review)
Review
As a result of the findings of scientists working on the biosynthesis and metabolism of steroids in the plant and animal kingdoms over the past five decades, it has become apparent that those compounds that naturally occur in animals can also be found as natural constituents of plants and vice versa, i.e., they have essentially the same fate in the majority of living organisms. This review summarizes the current state of knowledge on the occurrence of animal steroid hormones in the plant kingdom, particularly focusing on progesterone, testosterone, androstadienedione (boldione), androstenedione, and estrogens.
Topics: Androstadienes; Androstenedione; Animals; Biosynthetic Pathways; Estrogens; Phytosterols; Plants; Progesterone; Steroids; Testosterone
PubMed: 31315257
DOI: 10.3390/molecules24142585 -
Endocrine Jan 2016Steroid hormones are an important class of regulatory molecules that are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta, brain, and skin, and... (Review)
Review
Steroid hormones are an important class of regulatory molecules that are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta, brain, and skin, and influence a spectrum of developmental and physiological processes. The steroidogenic acute regulatory protein (STAR) predominantly mediates the rate-limiting step in steroid biosynthesis, i.e., the transport of the substrate of all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane. At the inner membrane, cytochrome P450 cholesterol side chain cleavage enzyme cleaves the cholesterol side chain to form the first steroid, pregnenolone, which is converted by a series of enzymes to various steroid hormones in specific tissues. Both basic and clinical evidence have demonstrated the crucial involvement of the STAR protein in the regulation of steroid biosynthesis. Multiple levels of regulation impinge on STAR action. Recent findings demonstrate that hormone-sensitive lipase, through its action on the hydrolysis of cholesteryl esters, plays an important role in regulating STAR expression and steroidogenesis which involve the liver X receptor pathway. Activation of the latter influences macrophage cholesterol efflux that is a key process in the prevention of atherosclerotic cardiovascular disease. Appropriate regulation of steroid hormones is vital for proper functioning of many important biological activities, which are also paramount for geriatric populations to live longer and healthier. This review summarizes the current level of understanding on tissue-specific and hormone-induced regulation of STAR expression and steroidogenesis, and provides insights into a number of cholesterol and/or steroid coupled physiological and pathophysiological consequences.
Topics: Disease; Female; Gonadal Steroid Hormones; Health; Hormones; Humans; Liver X Receptors; Male; Metabolic Networks and Pathways; Orphan Nuclear Receptors; Phosphoproteins; Steroids; Sterol Esterase
PubMed: 26271515
DOI: 10.1007/s12020-015-0715-6 -
Frontiers in Endocrinology 2022Although the role of steroid hormones in lipid levels has been partly discussed in the context of separate sexes, the causal relationship between steroid hormones and...
BACKGROUND
Although the role of steroid hormones in lipid levels has been partly discussed in the context of separate sexes, the causal relationship between steroid hormones and lipid metabolism according to sex has not been elucidated because of the limitations of observational studies. We assessed the relationship between steroid hormones and lipid metabolism in separate sexes using a two-sample Mendelian randomization (MR) study.
METHODS
Instrumental variables for dehydroepiandrosterone sulfate (DHEAS), progesterone, estradiol, and androstenedione were selected. MR analysis was performed using inverse-variance weighted, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier tests. Cochran's Q test, the MR-Egger intercept test, and leave-one-out analysis were used for sensitivity analyses.
RESULTS
The results showed that the three steroid hormones affected lipid metabolism and exhibited sex differences. In males, DHEAS was negatively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B ( = 0.007; = 0.006; = 0.041, respectively), and progesterone was negatively correlated with TC and LDL-C ( = 0.019; = 0.038, respectively). In females, DHEAS was negatively correlated with TC ( = 0.026) and androstenedione was negatively correlated with triglycerides and apolipoprotein A ( = 0.022; = 0.009, respectively). No statistically significant association was observed between the estradiol levels and lipid metabolism in male or female participants.
CONCLUSIONS
Our findings identified sex-specific causal networks between steroid hormones and lipid metabolism. Steroid hormones, including DHEAS, progesterone, and androstenedione, exhibited beneficial effects on lipid metabolism in both sexes; however, the specific lipid profiles affected by steroid hormones differed between the sexes.
Topics: Humans; Male; Female; Lipid Metabolism; Sex Characteristics; Cholesterol, LDL; Progesterone; Mendelian Randomization Analysis; Androstenedione; Cholesterol, HDL; Steroids; Estradiol; Apolipoproteins
PubMed: 36726474
DOI: 10.3389/fendo.2022.1119154 -
Journal of Molecular Endocrinology Feb 2018Corticosteroid-binding globulin (CBG) is a plasma carrier of glucocorticoids. Human and rat CBGs have six -glycosylation sites. Glycosylation of human CBG influences its...
Corticosteroid-binding globulin (CBG) is a plasma carrier of glucocorticoids. Human and rat CBGs have six -glycosylation sites. Glycosylation of human CBG influences its steroid-binding activity, and there are -glycosylation sites in the reactive center loops (RCLs) of human and rat CBGs. Proteolysis of the RCL of human CBG causes a structural change that disrupts steroid binding. We now show that mutations of conserved -glycosylation sites at N238 in human CBG and N230 in rat CBG disrupt steroid binding. Inhibiting glycosylation by tunicamycin also markedly reduced human and rat CBG steroid-binding activities. Deglycosylation of fully glycosylated human CBG or human CBG with only one -glycan at N238 with Endo H-reduced steroid-binding affinity, while PNGase F-mediated deglycosylation does not, indicating that steroid binding is preserved by deamidation of N238 when its -glycan is removed. When expressed in -acetylglucosaminyltransferase-I-deficient Lec1 cells, human and rat CBGs, and a human CBG mutant with only one glycosylation site at N238, have higher (2-4 fold) steroid-binding affinities than when produced by sialylation-deficient Lec2 cells or glycosylation-competent CHO-S cells. Thus, the presence and composition of an -glycan in this conserved position both appear to influence the steroid binding of CBG. We also demonstrate that neutrophil elastase cleaves the RCL of human CBG and reduces its steroid-binding capacity more efficiently than does chymotrypsin or the protease LasB. Moreover, while glycosylation of N347 in the RCL limits these activities, -glycans at other sites also appear to protect CBG from neutrophil elastase or chymotrypsin.
Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Glycosylation; Humans; Polysaccharides; Proteolysis; Rats; Steroids; Transcortin
PubMed: 29273683
DOI: 10.1530/JME-17-0234 -
Steroids Jul 2010Steroid hormones participate in organ development, reproduction, body homeostasis, and stress responses. The steroid machinery is expressed in a development- and... (Review)
Review
Steroid hormones participate in organ development, reproduction, body homeostasis, and stress responses. The steroid machinery is expressed in a development- and tissue-specific manner, with the expression of these factors being tightly regulated by an array of transcription factors (TFs). Epigenetics provides an additional layer of gene regulation through DNA methylation and histone tail modifications. Evidence of epigenetic regulation of key steroidogenic enzymes is increasing, though this does not seem to be a predominant regulatory pathway. Steroid hormones exert their action in target tissues through steroid nuclear receptors belonging to the NR3A and NR3C families. Nuclear receptor expression levels and post-translational modifications regulate their function and dictate their sensitivity to steroid ligands. Nuclear receptors and TFs are more likely to be epigenetically regulated than proteins involved in steroidogenesis and have secondary impact on the expression of these steroidogenic enzymes. Here we review evidence for epigenetic regulation of enzymes, transcription factors, and nuclear receptors related to steroid biogenesis and action.
Topics: Animals; Biosynthetic Pathways; Epigenesis, Genetic; Gene Expression Regulation; Humans; Phosphoproteins; Steroid 17-alpha-Hydroxylase; Steroidogenic Factor 1; Steroids
PubMed: 20156469
DOI: 10.1016/j.steroids.2010.02.004 -
Clinical Cancer Research : An Official... Jul 2013A significant proportion of castration-resistant prostate cancers (CRPC) remains driven by ligand activation of the androgen receptor. Although the testes are the... (Review)
Review
A significant proportion of castration-resistant prostate cancers (CRPC) remains driven by ligand activation of the androgen receptor. Although the testes are the primary source of testosterone, testosterone can also be produced from peripheral conversion of adrenal sex hormone precursors DHEA and androstenedione in the prostate and other tissues. CYP17A1 catalyzes two essential reactions in the production of DHEA and androstenedione: the hydroxylation (hydroxylase activity) and the subsequent cleavage of the C17-20 side chain (lyase activity). Potent and selective inhibition of CYP17A1 by abiraterone depletes residual nongonadal androgens and is an effective treatment for CRPC. Elucidation of the mechanisms that underlie resistance to abiraterone will inform the development of novel therapeutic strategies post-abiraterone. Preclinical evidence that androgen biosynthesis in prostate cancer cells does not necessarily follow a single dominant pathway, and residual androgens or alternative ligands (including administered glucocorticoids) can reactivate androgen receptor signaling, supports cotargeting of more than one enzyme involved in steroidogenesis and combining a CYP17A1 inhibitor with an antiandrogen. Furthermore, given the drawbacks of 17α-hydroxylase inhibition, there is considerable interest in developing new CYP17A1 inhibitors that more specifically inhibit lyase activity and are therefore less likely to require glucocorticoid coadministration.
Topics: Antineoplastic Agents; Biosynthetic Pathways; Humans; Male; Prostatic Neoplasms; Signal Transduction; Steroids; Translational Research, Biomedical
PubMed: 23470964
DOI: 10.1158/1078-0432.CCR-12-0931 -
FASEB Journal : Official Publication of... Jan 2019Cholesterol is an important component of plasma membranes (PMs) and the precursor of all steroid hormones. In steroidogenic tissues, upon hormone stimulation, there is a...
Cholesterol is an important component of plasma membranes (PMs) and the precursor of all steroid hormones. In steroidogenic tissues, upon hormone stimulation, there is a rapid transfer of cholesterol to the mitochondria, which is the site of the initial step in steroidogenesis. In the current study, we examined PM cholesterol trafficking for steroidogenesis. In a mitochondrial reconstitution assay, adrenal PMs supported steroidogenesis in the absence of additional transport proteins. Depletion of cholesterol in PMs by 50% eliminated the membranes' ability to support steroidogenesis in vitro and reduced steroid production in intact Y1 adrenocortical cells. Syntaxin (STX)-5 and α-soluble N-ethylmaleimide-sensitive factor attachment protein (α-SNAP) are enriched in adrenal PMs, and adrenocorticotropic hormone treatment of rats recruited STX5 and α-SNAP to adrenal PMs and mitochondria. Immunodepletion of STX5 and α-SNAP from PMs decreased steroidogenesis supported by PMs in vitro. Protease digestion of PMs decreased, whereas recombinant STX5 or α-SNAP restored, the PMs' ability to support steroidogenesis. Knockdown of either STX5 or α-SNAP in Y1 cells decreased stimulated steroidogenesis. These results indicate that STX5 and α-SNAP facilitate cholesterol trafficking from PMs to mitochondria for adrenal steroid synthesis and underscore the importance of vesicular trafficking of PM cholesterol for steroidogenesis.-Deng, B., Shen, W.-J., Dong, D., Azhar, S., Kraemer, F. B. Plasma membrane cholesterol trafficking in steroidogenesis.
Topics: Animals; Biological Transport; Cells, Cultured; Lipid Droplets; Male; Membrane Lipids; Mice; Rats; Rats, Sprague-Dawley; SNARE Proteins; Steroids
PubMed: 30133326
DOI: 10.1096/fj.201800697RRR -
Marine Drugs Nov 2021This review focuses on a rare group of steroids and triterpenoids that share common properties as regulators of lipid metabolism. This group of compounds is divided by... (Review)
Review
This review focuses on a rare group of steroids and triterpenoids that share common properties as regulators of lipid metabolism. This group of compounds is divided by the type of chemical structure, and they represent: aromatic steroids, steroid phosphate esters, highly oxygenated steroids such as steroid endoperoxides and hydroperoxides, α,β-epoxy steroids, and secosteroids. In addition, subgroups of carbon-bridged steroids, neo steroids, miscellaneous steroids, as well as synthetic steroids containing heteroatoms S (), Se (), Te (), and At () were presented. Natural steroids and triterpenoids have been found and identified from various sources such as marine sponges, soft corals, starfish, and other marine invertebrates. In addition, this group of rare lipids is found in fungi, fungal endophytes, and plants. The pharmacological profile of the presented steroids and triterpenoids was determined using the well-known computer program PASS, which is currently available online for all interested scientists and pharmacologists and is currently used by research teams from more than 130 countries of the world. Our attention has been focused on the biological activities of steroids and triterpenoids associated with the regulation of cholesterol metabolism and related processes such as anti-hyperlipoproteinemic activity, as well as the treatment of atherosclerosis, lipoprotein disorders, or inhibitors of cholesterol synthesis. In addition, individual steroids and triterpenoids were identified that demonstrated rare or unique biological activities such as treating neurodegenerative diseases, Alzheimer's, and Parkinson's diseases with a high degree of certainty over 95 percent. For individual steroids or triterpenoids or a group of compounds, 3D drawings of their predicted biological activities are presented.
Topics: Animals; Anthozoa; Aquatic Organisms; Lipid Metabolism; Porifera; Starfish; Steroids; Triterpenes
PubMed: 34822521
DOI: 10.3390/md19110650 -
Molecular and Cellular Endocrinology Jun 2015Steroidogenesis begins with cholesterol transfer into mitochondria through the transduceosome, a complex composed of cytosolic proteins that include steroidogenesis... (Review)
Review
Steroidogenesis begins with cholesterol transfer into mitochondria through the transduceosome, a complex composed of cytosolic proteins that include steroidogenesis acute regulatory protein (STAR), 14-3-3 adaptor proteins, and the outer mitochondrial membrane proteins Translocator Protein (TSPO) and Voltage-Dependent Anion Channel (VDAC). TSPO is a drug- and cholesterol-binding protein found at particularly high levels in steroid synthesizing cells. Its aberrant expression has been linked to cancer, neurodegeneration, neuropsychiatric disorders and primary hypogonadism. Brain steroids serve as local regulators of neural development and excitability. Reduced levels of these steroids have been linked to depression, anxiety and neurodegeneration. Reduced serum testosterone is common among subfertile young men and aging men, and is associated with depression, metabolic syndrome and reduced sexual function. Although testosterone-replacement therapy is available, there are undesired side-effects. TSPO drug ligands have been proposed as therapeutic agents to regulate steroid levels in the brain and testis.
Topics: Animals; Biological Transport; Cholesterol; Humans; Models, Biological; Molecular Targeted Therapy; Receptors, GABA; Steroids
PubMed: 25818881
DOI: 10.1016/j.mce.2015.03.014