Alternative pathways in human corticosteroid biosynthesis

Kaufmann, St.; Sinterhauf, K.; Lommer, D.

doi:10.1016/0022-4731(80)90025-4

Cited by 4 publications

(4 citation statements)

References 24 publications

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“…However, in 1980 Kaufmann et al hypothesized that alternative pathways of corticosteroid biosynthesis exist. As postulated, T, and R are most likely generated via 21-hydroxy- or 17,21-dihydroxydesmosterol involving adrenocorticotropin (ACTH) rather than direct hydroxylation of PRE or 17PRE ( 31 ). According to our results we consider it likely that also the 21-hydroxylation of desmosterol is not catalyzed by steroid 21-hydroxylase in humans ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 98%

“… Hypothesized corticosteroid biosynthesis, adapted from Kaufmann et al. ( 31 ) steroid precursor desmosterol (DES) is converted via different pathways to corticosterone (B) and cortisol (M) involving 21-hydroxydesmosterol (21DES), 17,21-dihydroxydesmosterol (17,21DES), pregnenolone (PRE), 17-hydroxypregnenolone (17PRE), progesterone (PRO), 17-hydroxyprogesterone (17PRO), 11-deoxycorticosterone (DOC), 21-hydroxypregnenolone (T), 11-deoxycortisol (RSS) and 17,21-dihydroxypregnenolone (R). …”

Section: Discussionmentioning

confidence: 99%

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Corticosteroid Biosynthesis Revisited: No Direct Hydroxylation of Pregnenolone by Steroid 21-Hydroxylase

et al. 2021

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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 Schizosaccharomyces pombe 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.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Corticosteroid Biosynthesis Revisited: No Direct Hydroxylation of Pregnenolone by Steroid 21-Hydroxylase

et al. 2021

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“…In our study, abnormalities of the corticosteroid‐related pathway were detected in ONFH samples compared with control groups, with compounds such as pregnenolone, 21‐hydroxypregnenolone disulfate, DHEA‐S, epiandrosterone sulfate, and androsterone sulfate affected, most of which were down‐regulated in ONFH samples. These are all essential intermediates for corticosteroid synthesis . Serum DHEA‐S is regarded as a classic marker of the individual hormonal milieu .…”

Section: Discussionmentioning

confidence: 99%

“…These are all essential intermediates for corticosteroid synthesis. [33][34][35] Serum DHEA-S is regarded as a classic marker of the individual hormonal milieu. 36 Abnormal expression of DHEA-S has been detected in several pathological conditions, including decreased bone density, increased cardiovascular disease, and elevated fat-to-muscle ratio.…”

Section: Abnormal Lipid-associated Pathways and Inflammationmentioning

confidence: 99%

Unique plasma metabolomic signature of osteonecrosis of the femoral head

Liu

Sheng

et al. 2015

Journal Orthopaedic Research

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Metabolomic analysis was performed to determine the metabolomic signature of osteonecrosis of the femoral head (ONFH), and to investigate the underlying relationship between the metabolomic signature and the pathogenesis of ONFH. Plasma samples were collected from 30 ONFH patients and 30 normal subjects. The global metabolomic profile was obtained through a combination of high-throughput liquid-and gas-chromatography-based mass spectrometry analyses. All statistical analyses were conducted using the R software. The results showed clear differences in the metabolomic signature between the plasma of ONFH patients compared with normal subjects. Among the 354 identified metabolites, the expression of 123 metabolites were significantly changed in ONFH patients compared with normal subjects (p < 0.05, q < 0.10). Bioinformatics analysis revealed that these abnormal metabolites were mainly involved in lipid-, glutathione-, nucleotide-, and energy-associated pathways, which might be related to enhanced inflammation, oxidative stress, and energy deficiency due to ONFH. This study provides the first metabolomic analysis of ONFH, and identifies a previously unrecognized metabolic signature in ONFH plasma. The results offer new insights into the pathological mechanisms of ONFH through its influence on metabolic pathways, providing the requisite framework for identifying biomarkers or novel targets for therapeutic intervention. ß

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