11-Oxygenated androgens in health and disease

Turcu, Adina F.; Rege, Juilee; Auchus, Richard J.; Rainey, William E.

doi:10.1038/s41574-020-0336-x

Cited by 131 publications

(103 citation statements)

References 188 publications

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“…Bacterial metabolism of host and synthetic corticosteroids may have wide ranging effects on the immune system(84-87), the cardiovascular system (20), the structure of the gut microbiome (88,89), and the urogenital tract (41,90). Their importance for human health brings enzymes catalyzing 20-hydroxysteroids significant pharmaceutical value.…”

Section: Discussionmentioning

confidence: 99%

Bacteria on steroids: the enzymatic mechanism of an NADH-dependent dehydrogenase that regulates the conversion of cortisol to androgen in the gut microbiome

Bernardi

Doden

Melo

et al. 2020

Preprint

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The ability to metabolize both endogenous and exogenous compounds to a variety of metabolic products is not exclusive to our human cells. In fact, the bacterial communities that inhabit our digestive system are responsible for a network of steroid transformations that can produce hormones in the gut, which are then absorbed to act in the host. These communities have been shown to impact our health in numerous ways, affecting disease predisposition, pathogenesis, physical fitness, and dietary responsiveness. Steroid biotransformations by gut bacteria are predicted to impact the host endocrine system. A particular set of transformations facilitated by microbial enzymes has been shown to result in the formation of 11-oxy-androgens from hostderived cortisol. Since androgens have been implicated in disease and immune modulations, understanding the structure and catalytic mechanism of enzymes involved in cortisol metabolism is a key step to hasten the development of strategies that reduce the formation of disease-promoting bioactive steroids in certain individuals. Here, we combine experimental and computational techniques to describe DesC, an enzyme capable of creating 20a-dihydrocortisol and siphoning cortisol away from pathways that produce androgens. DesC diverges significantly from previously described bacterial and eukaryotic counterparts, catalyzing an NADH-dependent 20ahydroxysteroid dehydrogenase reaction but presenting little sequence and structure similarity to them. The structural information obtained by X-ray crystallography and hybrid QM/MM simulations, validated through mutagenesis studies, show the reaction occurs through a multi-step proton relay mechanism. Free energy calculations were then used to describe the kinetics of the reaction mechanism. The mechanistic information presented here can be employed in the development of therapeutics to divert microbial pathways away from disease-promoting steroids. AUTHOR INFORMATION Corresponding Author

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Section: Discussionmentioning

confidence: 99%

Bacteria on steroids: the enzymatic mechanism of an NADH-dependent dehydrogenase that regulates the conversion of cortisol to androgen in the gut microbiome

Bernardi

Doden

Melo

et al. 2020

Preprint

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“…The ability of the adrenals to synthesize DHEA varies among species depending on the expression and activity of CYP17A, its interaction with CYB5, and the expression of 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), which competes with CYP17A for substrates (Figure 1). On one end, the zona reticularis of the primate adrenals has the unique enzyme profile that promotes the efficient DHEA production through the 5 pathway, and the low expression of HSB3B2 favors flow of substrates toward DHEA (10,17,(28)(29)(30). On the other end, the CYP17A enzyme in the rodent adrenal lacks the 17,20-lyase activity, thus explaining the low DHEA secretion observed in these species (16,31).…”

Section: Adrenal Dhea/dheas Synthesismentioning

confidence: 99%

“…Age is an important factor affecting DHEA and DHEAS secretion in primates. A pre-pubertal increase in circulating DHEA and DHEAS, defined as adrenarche, is observed in humans and some great apes, but not in Old World monkeys; it was hence suggested that adrenarche has evolved to promote brain development (17,76). In humans, circulating DHEA and DHEAS increase gradually after adrenarche until the mid-twenties and then decline with aging, the adrenals being the main source of these steroids.…”

Section: Factors Affecting Dhea/dheas Concentrations In the Bloodmentioning

confidence: 99%

“…This is a microsomal enzyme which has a dual function: it catalyzes both the 17α-hydroxylation of 4 -and 5 -steroids necessary for glucocorticoid production, and the 17,20-lyase reactions required to produce C19-androgens (i.e., DHEA and androstenedione). The 17,20-lyase activity of CYP17A is enhanced by the allosteric regulator cytochrome b5 (CYB5), thus facilitating the conversion of 17α-hydroxypregnenolone to DHEA (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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Do Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEAS) Play a Role in the Stress Response in Domestic Animals?

et al. 2020

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In animal husbandry, stress is often associated with poor health and welfare. Stress occurs when a physiological control system detects a state of real or presumptive threat to the animal's homeostasis or a failure to control a fitness-critical variable. The definition of stress has mostly relied on glucocorticoids measurement, even though glucocorticoids represent one stress-response system, the hypothalamus-pituitary-adrenocortical axis, which is not precise enough as it is also related to metabolic regulation and activated in non-stressful situations (pleasure, excitement, and arousal). The mammal adrenal can synthesize the androgenic steroid dehydroepiandrosterone (DHEA) and its sulfate metabolite (DHEAS), which have been associated to the stress response in several studies performed mostly in humans and laboratory animals. Although the functions of these steroids are not fully understood, available data suggest their antagonistic effects on glucocorticoids and, in humans, their secretion is affected by stress. This review explores the scientific literature on DHEA and DHEAS release in domestic animals in response to stressors of different nature (inflammatory, physical, or social) and duration, and the extra-adrenal contribution to circulating DHEA. Then, the potential use of DHEA in conjunction with cortisol to improve the definition of the stress phenotype in farmed animals is discussed. Although the focus of this review is on farmed animals, examples from other species are reported when available.

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“…11KT activates the androgen receptor with potency and efficacy similar to T (11)(12)(13) and is the predominant circulating androgen in androgen excess conditions including congenital adrenal hyperplasia, polycystic ovary syndrome and premature adrenarche (12,14,15). 11KT is derived from the abundant adrenal precursor steroid 11βhydroxyandrostenedione (11OHA4) (13,16), which is converted to 11KA4 by peripheral tissue expressing 11β-hydroxysteroid dehydrogenase type 2 (17,18) prior to activation to 11KT by AKR1C3 (10,16).…”

Section: Introductionmentioning

confidence: 99%

Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens

Schiffer

Bossey

Akerman

et al. 2020

Preprint

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ContextAndrogens are important modulators of immune cell function impacting proliferation, differentiation and cytokine production. The local generation of active androgens from circulating androgen precursors is an important mediator of androgen action in peripheral androgen target cells of tissue.ObjectiveTo characterize the activation of classic and 11-oxygenated androgens in human peripheral blood mononuclear cells (PBMCs).MethodsPBMCs and natural killer cells were isolated from healthy male donors and incubated ex vivo with precursors and end products of the classic and 11-oxygenated androgen pathways. Steroid concentrations were quantified by liquid chromatography-tandem mass spectrometry. The expression of genes encoding steroid metabolizing enzymes was assessed by quantitative PCR.ResultsThe enzyme AKR1C3 is the major reductive 17β-hydroxysteroid dehydrogenase in PBMCs and has higher activity for the generation of the active 11-oxygenated androgen 11-ketotestosterone than for the generation of the classic androgen testosterone from their respective precursors. Natural killer cells are the major site of AKR1C3 expression and activity within the PBMC compartment. Steroid 5α-reductase type 1 catalyzes the 5α-reduction of classic but not 11-oxygenated androgens in PBMCs. Lag time prior to the separation of cellular components from whole blood sample increases 11KT serum concentrations in a time-dependent fashion, with significant increases detected from two hours after blood collection.Conclusions11-oxygenated androgens are the preferred substrates for androgen activation by AKR1C3 in PBMCs, primarily conveyed by natural killer cell AKR1C3 activity, yielding 11KT the major active androgen in PBMCs. Androgen metabolism by PBMCs can affect the levels of 11-oxygenated androgens measured in serum samples, if samples are not separated in a timely fashion.

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11-Oxygenated androgens in health and disease

Cited by 131 publications

References 188 publications

Bacteria on steroids: the enzymatic mechanism of an NADH-dependent dehydrogenase that regulates the conversion of cortisol to androgen in the gut microbiome

Bacteria on steroids: the enzymatic mechanism of an NADH-dependent dehydrogenase that regulates the conversion of cortisol to androgen in the gut microbiome

Do Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEAS) Play a Role in the Stress Response in Domestic Animals?

Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens

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