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Reproductive Biology and Endocrinology... Apr 2003The ability of the testis to convert irreversibly androgens into estrogens is related to the presence of a microsomal enzymatic complex named aromatase, which is... (Review)
Review
The ability of the testis to convert irreversibly androgens into estrogens is related to the presence of a microsomal enzymatic complex named aromatase, which is composed of a specific glycoprotein, the cytochrome P450 aromatase (P450arom) and an ubiquitous reductase. The aromatase gene is unique in humans and contained 18 exons, 9 of them being translated. In the rat testis we have immunolocalized the P450arom not only in Leydig cells but also in germ cells and especially in elongated spermatids. Related to the stage of germ cell maturation, we have shown that the level of P450arom mRNA transcripts decreases, it is much more abundant in pachytene spermatocytes and round spermatids than in mature germ cells whereas the aromatase activity is 2-4 fold greater in spermatozoa when compared to the younger germ cells. Using a highly specific quantitative competitive RT-PCR method we have evidenced that several factors direct the expression of the aromatase gene in Leydig cells, Sertoli cells, pachytene spermatocytes and round spermatids, and it is obvious that promoter PII is the main one but other promoters could be concerned. In the bank-vole testis we have observed a positive correlation between a fully developed spermatogenesis and a strong immunoreactivity for both P450arom and estrogen receptor beta not only in Sertoli cells but also in pachytene spermatocytes and round spermatids. Our recent data obtained from ejaculated human spermatozoa demonstrate the presence of aromatase both in terms of mRNA and protein, and in addition, we suggest that aromatase could be involved in the acquisition of sperm motility. Indeed in men the congenital aromatase deficiency is associated with severe bone maturation problems and sterility. Together with the widespread distribution of estrogen receptors in testicular cells these data clearly show that estrogens play a physiological role in the regulation of spermatogenesis in mammals.
Topics: Animals; Aromatase; Arvicolinae; Estrogens; Fertility; Humans; Leydig Cells; Male; Mice; Mice, Knockout; Rats; Receptors, Estrogen; Seminiferous Tubules; Sertoli Cells; Species Specificity; Sperm Motility; Spermatogenesis; Spermatozoa; Testis
PubMed: 12747806
DOI: 10.1186/1477-7827-1-35 -
Biology Direct Apr 2021Human aromatase is a member of the cytochrome P450 superfamily, involved in steroid hormones biosynthesis. In particular, it converts androgen into estrogens being...
Human aromatase is a member of the cytochrome P450 superfamily, involved in steroid hormones biosynthesis. In particular, it converts androgen into estrogens being therefore responsible for the correct sex steroids balance. Due to its capacity in producing estrogens it has also been considered as a promising target for breast cancer therapy. Two single-nucleotide polymorphisms (R264C and R264H) have been shown to alter aromatase activity and they have been associated to an increased or decreased risk for estrogen-dependent pathologies. Here, the effect of these mutations on the protein dynamics is investigated by UV/FTIR and time resolved fluorescence spectroscopy. H/D exchange rates were measured by FTIR for the three proteins in the ligand-free, substrate- and inhibitor-bound forms and the data indicate that the wild-type enzyme undergoes a conformational change leading to a more compact tertiary structure upon substrate or inhibitor binding. Indeed, the H/D exchange rates are decreased when a ligand is present. In the variants, the exchange rates in the ligand-free and -bound forms are similar, indicating that a structural change is lacking, despite the single amino acid substitution is located in the peripheral shell of the protein molecule. Moreover, the fluorescence lifetimes data show that the quenching effect on tryptophan-224 observed upon ligand binding in the wild-type, is absent in both variants. Since this residue is located in the catalytic pocket, these findings suggest that substrate entrance and/or retention in the active site is partially compromised in both mutants. A contact network analysis demonstrates that the protein structure is organized in two main clusters, whose connectivity is altered by ligand binding, especially in correspondence of helix-G, where the amino acid substitutions occur. Our findings demonstrate that SNPs resulting in mutations on aromatase surface modify the protein flexibility that is required for substrate binding and catalysis. The cluster analysis provides a rationale for such effect, suggesting helix G as a possible target for aromatase inhibition.
Topics: Aromatase; Catalysis; Catalytic Domain; Humans; Polymorphism, Genetic; Protein Binding; Spectrometry, Fluorescence
PubMed: 33902660
DOI: 10.1186/s13062-021-00292-9 -
Journal of Neuroendocrinology Apr 2022We previously reported that aromatase protein levels do not parallel aromatase enzyme activity. This suggests that oestrogenic signalling may be modulated via...
We previously reported that aromatase protein levels do not parallel aromatase enzyme activity. This suggests that oestrogenic signalling may be modulated via post-translational modification of aromatase protein. The tyrosine and serine phosphorylation state of aromatase are known to influence its activity. To investigate the possible relevance of aromatase phosphorylation to the incongruity observed between aromatase protein and its activity, we explored interactions between aromatase and the tyrosine kinase c-Src and the serine protein phosphatases 2A and 5 (PP2A and PP5), as well as the relationship between levels of tyrosine-phosphorylated aromatase and the extrapolated aromatase activity. We found that (a) hypothalamic aromatase was significantly more heavily tyrosine-phosphorylated than spinal aromatase; (b) aromatase was oligomerized with c-Src and PP2A/PP5, potentially activating aromatase via tyrosine-phosphorylation and serine-dephosphorylation; (c) the associations of c-Src and PP2A/PP5 with hypothalamic aromatase were substantially greater than with spinal aromatase; and (d) aromatase, oestrogen receptor α, PP2A, and c-Src were present in a common membrane oligomer. The existence of c-Src and PP2A in an oligomer that also contains aromatase and membrane oestrogen receptor α (and presumably other signalling molecules) indicates the presence in the CNS of a potentially self-regulating oestrogenic signalling unit. The degree to which such a complex operates autonomously and the regulatory factors thereof are likely to have substantial physiological implications and clinical relevance.
Topics: Animals; Aromatase; Central Nervous System; Estrogen Receptor alpha; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein-Tyrosine Kinases; Rats; Serine; Tyrosine
PubMed: 35043508
DOI: 10.1111/jne.13089 -
Steroids May 2008Estrogens are synthesized by the aromatase enzyme encoded by the Cyp19a1 gene, which contains an unusually large regulatory region. In most mammals, aromatase expression... (Review)
Review
Estrogens are synthesized by the aromatase enzyme encoded by the Cyp19a1 gene, which contains an unusually large regulatory region. In most mammals, aromatase expression is under the control of two distinct promoters a gonad- and a brain-specific promoter. In humans, this gene contains 10 tissue-specific promoters that are alternatively used in various cell types and tumors. Each promoter is regulated by a distinct set of regulatory sequences and transcription factors that bind to these specific sequences. The cAMP/PKA/CREB pathway is considered to be the primary signaling cascade through which the gonad Cyp19 promoter is regulated. Very interestingly, in rat luteal cells, the proximal promoter is not controlled in a cAMP dependent manner. Strikingly, these cells express aromatase at high levels similar to those found in preovulatory follicles, suggesting that alternative and powerful mechanisms control aromatase expression in luteal cells and that the rat corpus luteum represents an important paradigm for understanding alternative controls of the aromatase gene. Here, the molecular and cellular mechanisms controlling the expression of the aromatase gene in granulosa and luteal cells are discussed.
Topics: Animals; Aromatase; Female; Gene Expression Regulation; Humans; Models, Biological; Ovary; Pregnancy; Promoter Regions, Genetic; Rats; Signal Transduction
PubMed: 18321551
DOI: 10.1016/j.steroids.2008.01.017 -
International Journal of Molecular... Dec 2021In addition to being a steroid hormone, 17β-estradiol (E) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans.... (Review)
Review
In addition to being a steroid hormone, 17β-estradiol (E) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans. Neuron-derived E (NDE) is synthesized from androgen precursors via the action of the biosynthetic enzyme aromatase, which is located at synapses and in presynaptic terminals in neurons in both the male and female brain. In this review, we discuss evidence supporting a key role for NDE as a neuromodulator that regulates synaptic plasticity and memory. Evidence supporting an important neuromodulatory role of NDE in the brain has come from studies using aromatase inhibitors, aromatase overexpression in neurons, global aromatase knockout mice, and the recent development of conditional forebrain neuron-specific knockout mice. Collectively, these studies demonstrate a key role of NDE in the regulation of synapse and spine density, efficacy of excitatory synaptic transmission and long-term potentiation, and regulation of hippocampal-dependent recognition memory, spatial reference memory, and contextual fear memory. NDE is suggested to achieve these effects through estrogen receptor-mediated regulation of rapid kinase signaling and CREB-BDNF signaling pathways, which regulate actin remodeling, as well as transcription, translation, and transport of synaptic proteins critical for synaptic plasticity and function.
Topics: Animals; Aromatase; Estradiol; Female; Humans; Male; Neuronal Plasticity; Neurons; Signal Transduction; Spatial Memory; Synapses
PubMed: 34948039
DOI: 10.3390/ijms222413242 -
International Journal of Molecular... Jan 2021Aromatase is the cytochrome P450 enzyme converting androgens into estrogen in the last phase of steroidogenesis. As estrogens are crucial in reproductive biology,...
Aromatase is the cytochrome P450 enzyme converting androgens into estrogen in the last phase of steroidogenesis. As estrogens are crucial in reproductive biology, aromatase is found in vertebrates and the invertebrates of the genus , where it carries out the aromatization reaction of the A-ring of androgens that produces estrogens. Here, we investigate the molecular evolution of this unique and highly substrate-selective enzyme by means of structural, sequence alignment, and homology modeling, shedding light on its key role in species conservation. The alignments led to the identification of a core structure that, together with key and unique amino acids located in the active site and the substrate recognition sites, has been well conserved during evolution. Structural analysis shows what their roles are and the reason why they have been preserved. Moreover, the residues involved in the interaction with the redox partner and some phosphorylation sites appeared late during evolution. These data reveal how highly substrate-selective cytochrome P450 has evolved, indicating that the driving forces for evolution have been the optimization of the interaction with the redox partner and the introduction of phosphorylation sites that give the possibility of modulating its activity in a rapid way.
Topics: Amino Acid Sequence; Animals; Aromatase; Catalytic Domain; Estrogens; Evolution, Molecular; Humans; Models, Molecular; Sequence Alignment; Structure-Activity Relationship; Vertebrates
PubMed: 33435208
DOI: 10.3390/ijms22020631 -
Brazilian Journal of Medical and... Sep 2011Organotin compounds are typical environmental contaminants and suspected endocrine-disrupting substances, which cause irreversible sexual abnormality in female mollusks,... (Review)
Review
Organotin compounds are typical environmental contaminants and suspected endocrine-disrupting substances, which cause irreversible sexual abnormality in female mollusks, called "imposex". However, little is known about the capability of triorganotin compounds, such as tributyltin and triphenyltin, to cause disorders in the sexual development and reproductive functions of mammals, including humans and rodents. Moreover, these compounds can act as potential competitive inhibitors of aromatase enzyme and other steroidogenic enzymes, affecting the reproductive capacity of male and female mammals. In this review, we discuss the cellular, biochemical, and molecular mechanisms by which triorganotin compounds induce adverse effects in the mammalian reproductive function.
Topics: Animals; Aromatase; Endocrine System; Female; Genitalia; Humans; Male; Mammals; Organotin Compounds; Reproduction; Trialkyltin Compounds
PubMed: 21876874
DOI: 10.1590/s0100-879x2011007500110 -
Biology of Sex Differences Sep 2023Aromatase catalyzes the synthesis of estrogens from androgens. Knowledge on its regional expression in the brain is of relevance to the behavioral implications of these...
BACKGROUND
Aromatase catalyzes the synthesis of estrogens from androgens. Knowledge on its regional expression in the brain is of relevance to the behavioral implications of these hormones that might be linked to sex differences in mental health. The present study investigated the distribution of cells expressing the aromatase coding gene (Cyp19a1) in limbic regions of young adult rats of both sexes, and characterized the cell types expressing this gene.
METHODS
Cyp19a1 mRNA was mapped using fluorescent in situ hybridization (FISH). Co-expression with specific cell markers was assessed with double FISH; glutamatergic, gamma-aminobutyric acid (GABA)-ergic, glial, monoaminergic, as well as interneuron markers were tested. Automated quantification of the cells expressing the different genes was performed using CellProfiler. Sex differences in the number of cells expressing Cyp19a1 was tested non-parametrically, with the effect size indicated by the rank-biserial correlation. FDR correction for multiple testing was applied.
RESULTS
In the male brain, the highest percentage of Cyp19a1 cells was found in the medial amygdaloid nucleus and the bed nucleus of stria terminalis, followed by the medial preoptic area, the CA2/3 fields of the hippocampus, the cortical amygdaloid nucleus and the amygdalo-hippocampal area. A lower percentage was detected in the caudate putamen, the nucleus accumbens, and the ventromedial hypothalamus. In females, the distribution of Cyp19a1 cells was similar but at a lower percentage. In most regions, the majority of Cyp19a1 cells were GABAergic, except for in the cortical-like regions of the amygdala where most were glutamatergic. A smaller fraction of cells co-expressed Slc1a3, suggesting expression of Cyp19a1 in astrocytes; monoaminergic markers were not co-expressed. Moreover, sex differences were detected regarding the identity of Cyp19a1 cells.
CONCLUSIONS
Females show overall a lower number of cells expressing Cyp19a1 in the limbic brain. In both sexes, aromatase is expressed in a region-specific manner in GABAergic and glutamatergic neurons. These findings call for investigations of the relevance of sex-specific and region-dependent expression of Cyp19a1 in the limbic brain to sex differences in behavior and mental health.
Topics: Female; Male; Animals; Rats; Sex Characteristics; Aromatase; In Situ Hybridization, Fluorescence; Neuroglia; Brain
PubMed: 37658400
DOI: 10.1186/s13293-023-00541-8 -
Molecular and Cellular Endocrinology Jul 2011Aromatase, estrone sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 are involved in the key steps of 17β-estradiol biosynthesis. Structure-function studies of... (Review)
Review
Aromatase, estrone sulfatase, and 17β-hydroxysteroid dehydrogenase type 1 are involved in the key steps of 17β-estradiol biosynthesis. Structure-function studies of aromatase, estrone sulfatase and 17β-hydroxysteroid dehydrogenase type 1 are important to evaluate the molecular basis of the interaction between these enzymes and their inhibitors. Selective and potent inhibitors of the three enzymes have been developed as antiproliferative agents in hormone-dependent breast carcinoma. New treatment strategies for hormone-dependent breast cancer are discussed.
Topics: 17-Hydroxysteroid Dehydrogenases; Animals; Aromatase; Drug Design; Enzyme Inhibitors; Humans; Structure-Activity Relationship; Sulfatases
PubMed: 20888390
DOI: 10.1016/j.mce.2010.09.012 -
Brazilian Journal of Medical and... Jun 2007The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the... (Review)
Review
The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the irreversible transformation of androgens by a microsomal enzymatic complex named aromatase. The aromatase is encoded by a single gene (cyp19) in humans which contains 18 exons, 9 of them being translated. In rats, the aromatase activity is mainly located in Sertoli cells of immature rats and then in Leydig cells of adult rats. We have demonstrated that germ cells represent an important source of estrogens: the amount of P450arom transcript is 3-fold higher in pachytene spermatocytes compared to gonocytes or round spermatids; conversely, aromatase activity is more intense in haploid cells. Male germ cells of mice, bank voles, bears, and monkeys express aromatase. In humans, we have shown the presence of a biologically active aromatase and of estrogen receptors (alpha and ss) in ejaculated spermatozoa and in immature germ cells in addition to Leydig cells. Moreover, we have demonstrated that the amount of P450arom transcripts is 30% lower in immotile than in motile spermatozoa. Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations, together with our data showing a significant decrease of aromatase in immotile spermatozoa, suggest that aromatase could be involved in the acquisition of sperm motility. Thus, taking into account the widespread localization of aromatase and estrogen receptors in testicular cells, it is obvious that, besides gonadotrophins and androgens, estrogens produced locally should be considered to be physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.
Topics: Animals; Aromatase; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Gene Expression Regulation; Humans; Male; Reproduction; Spermatogenesis; Spermatozoa; Testis
PubMed: 17581673
DOI: 10.1590/s0100-879x2007000600003