Steroidogenic enzymes: Structure, function, and role in regulation of steroid hormone biosynthesis

Hanukoglu, Israel

doi:10.1016/0960-0760(92)90307-5

Cited by 480 publications

(308 citation statements)

References 277 publications

(380 reference statements)

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“…Since AR is a membrane-associated protein (18,19), it is tempting to speculate that these sulfate positions mark interaction sites of AR with phospholipids in the membrane. This hypothesis is supported by the observed arrangement of hydrophobic (e.g.…”

Section: Resultsmentioning

confidence: 99%

Adrenodoxin Reductase-Adrenodoxin Complex Structure Suggests Electron Transfer Path in Steroid Biosynthesis

Müller¹,

Лапко²,

Bourenkov³

et al. 2001

Journal of Biological Chemistry

158

122

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The steroid hydroxylating system of adrenal cortex mitochondria consists of the membrane-attached NADPH-dependent adrenodoxin reductase (AR), the soluble one-electron transport protein adrenodoxin (Adx), and a membrane-integrated cytochrome P450 of the CYP11 family. In the 2.3-Å resolution crystal structure of the Adx⅐AR complex, 580 In mitochondria of the adrenal cortex, the cytochrome P450 enzymes of the CYP11 family catalyze the side chain cleavage of cholesterol to form pregnenolone (P450scc, 1 CYP11A1) and are involved in the formation of cortisol (P45011␤, CYP11B1) and aldosterone (P450aldo, CYP11B2) (1). The enzymatic activity of the cytochrome P450-dependent steroid hydroxylases is based on their ability to activate molecular oxygen by reductive splitting of dioxygen. This multistep reaction requires the transfer of electrons from the flavoprotein adrenodoxin reductase (AR) via adrenodoxin (Adx) to the terminal cytochromes P450 as electron acceptors in dependence on the specific hydroxylation substrate (1-3). Several models for electron transfer have been discussed, including a shuttle model in which Adx forms consecutive 1:1 complexes (4) with AR and cytochrome P450scc and models requiring the formation of an organized 1:1:1 ternary complex (5) or a 1:2:1 quaternary complex (6) between AR, Adx, and cytochrome P450scc. Common to these models is a complex between AR and Adx during the first steps of electron transfer from the reductase to the cytochrome P450.Recently, the crystal structures of two forms of bovine adrenodoxin (7, 8) and of adrenodoxin reductase (9) were determined. These structures revealed the general topology of the two proteins and the molecular environments of the [2Fe-2S] cluster of Adx and the FAD moiety of AR. Here, we report the 2.3-Å resolution crystal structure of a cross-linked 1:1 complex of full-length Adx and AR. This structure shows the geometry of an electron transfer complex of soluble, freely dissociable proteins from a higher eukaryote for the first time, highlights structural adaptations that accompany the binding of AR to Adx, and permits us to predict electron transport paths in their complex. EXPERIMENTAL PROCEDURESSample Preparation-Recombinant bovine Adx and AR were purified and crystallized as described (10). The synthesized Adx differs from the wild-type protein by the exchange of Ser 1 for glycine and is composed of 128 amino acids, including the N-and C-terminal residues missing in the truncated adrenodoxin, Adx-(4 -108), studied earlier (7). Crosslinking of AR to Adx has also been described (11,12). The native complex is formed at low ionic strength between the two proteins, and the cross-linking was carried out with the water-soluble coupling reagent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC, purchased from Sigma). The mixture of Adx (1.2 mol) and AR (300 nmol) was dialyzed for 18 -20 h against 20 mM potassium phosphate, pH 7.2, followed by addition of an equal volume of fresh 8 mM EDC solution in distilled water and incubation at 4°C in the dark wi...

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Section: Resultsmentioning

confidence: 99%

Adrenodoxin Reductase-Adrenodoxin Complex Structure Suggests Electron Transfer Path in Steroid Biosynthesis

Müller¹,

Лапко²,

Bourenkov³

et al. 2001

Journal of Biological Chemistry

158

122

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“…The stimulation of steroidogenic cells by trophic hormones affects both their morphology and function [1][2][3][4]. Many of these effects depend on changes in the expression of specific genes that encode structural and regulatory proteins and enzymes.…”

Section: Introduction Materials and Methodsmentioning

confidence: 99%

“…Many of these effects depend on changes in the expression of specific genes that encode structural and regulatory proteins and enzymes. ACTH and other trophic hormones have been shown to enhance the expression of protooncogenes within <60 min and of steroidogenic enzymes within hours [4][5][6]. The present study was initiated to examine the scope of ACTH effects on the expression of other genes in adrenocortical cells.…”

Section: Introduction Materials and Methodsmentioning

confidence: 99%

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Cloning of ACTH-regulated genes in the adrenal cortex

Raikhinstein

Hanukoglu

1994

The Journal of Steroid Biochemistry and Molecular Biology

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To search for genes that are induced by ACTH in adrenocortical cells, we screened adrenal cortex cDNA libraries by a differential hybridization method using cDNA probes representing mRNAs from cells with or without ACTH stimulation. Forty clones were identified as ACTH induced (yielding a frequency of about 1/2500 plaques screened), and two clones as ACTH repressed. The cDNAs isolated and sequenced include nuclear genes for microsomal steroidogenic enzymes and novel proteins of yet unidentified functions, and mitochondrial genes encoding subunits of oxidative phosphorylation enzymes. Northern blot analysis of RNA from cells stimulated with ACTH confirmed the induction of these genes by ACTH, yet revealed important differences in the relative responses of the respective mRNAs. The time courses showed the major increase in the initial 6 h; and a decline after 24-36h. The enhancement of the levels of the mRNAs could be ascribed to transcriptional activation. Since the mitochondrial genome is transcribed as a single polycistronic unit, to account for the > 20-fold differences in the levels of the mitochondrial mRNAs it is necessary to invoke differential stabilities of these mRNAs. The synchronous increase in the expression of both the steroidogenic enzymes and the mitochondrial oxidative phosphorylation system subunits, provides evidence for coregulation of steroidogenic and energy producing capacities of adrenal cells to meet the metabolic needs of steroid hormone production. Suppression of fl-actin gene expression may be related to changes in actin polymerization during ACTH-dependent cytoskeletal reorganization. Steroid Biochem.

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“…It is structural component of plasma membrane [1] and in the insulating layer of myelin wound around neurons, precursor of the synthesis of steroid hormone and vitamin D [2]. Cholesterol is synthesizes from small molecules by enzyme HMG-CoA reductase [3].…”

Section: Introductionmentioning

confidence: 99%

Awareness and trends of Blood Cholesterol and Susceptibility to Develop Heart disease

OS¹,

Sonali²

2015

Adv Genet Eng

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Objectives: Cholesterol is the essential steroids for life which created and used by our bodies to keep us healthy. Approximately 75% blood cholesterol produced from liver and ~25% produced from the food we eat. Hypercholesterolemia is a condition of abnormal cholesterol levels. Abnormal cholesterol levels are strongly associated with coronary heart disease. Therefore, we aimed to evaluate the awareness and frequency of trends of blood cholesterol levels (total cholesterol, LDL, HDL, triglycerides) and its associated complications.Methods: This is a cross-sectional pilot study. The total no. of participant consisted of 200. We enrolled 100 unrelated healthy individuals by door to door visit to check awareness status of blood cholesterol and 100 referral individuals of lab undergone for lipid profile were enrolled in this study. Blood cholesterol awareness was calculated using Microsoft excel version 7.0. Frequency of LDL, HDL and triglycerides were calculated using chi square by SPSS version 15.0 version. Results:Frequency of awareness of blood cholesterol was found to be 29% among all survey participants while as frequency of awareness of blood cholesterol were found to be 54% and 4% among educated and non-educated participants. Frequency of Desirable Cholesterol Level was found to be higher (81.0%) as compared to Borderline High (19.0%) in between lab survey participants. Frequency of Above Optimal Low density lipoprotein (LDL) level was found to be higher (64.0%) as compared to above borderline high (27.0%) and high (9.0%) among lab survey participant. Frequency of Optimal High density lipoprotein (HDL) Level was found to be to be higher (94.0%) as compare to borderline low (5.0%) and high 1.0%) among lab survey participant. Frequency of Optimal Serum Triglyceride Level was found to be higher (53.0%) in optimal as compare to borderline high (33.0%) and High (4.0%) among lab survey participant. Conclusion:The survey data of dore to dore visit strongly suggest the lack of awareness of blood cholesterol level and its associated complications among educated and non-educated people. Individuals with borderline high Serum triglyceride level may have the risk for heart disease and they may require for therapeutic intervention in Indian setting.

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Steroidogenic enzymes: Structure, function, and role in regulation of steroid hormone biosynthesis

Cited by 480 publications

References 277 publications

Adrenodoxin Reductase-Adrenodoxin Complex Structure Suggests Electron Transfer Path in Steroid Biosynthesis

Adrenodoxin Reductase-Adrenodoxin Complex Structure Suggests Electron Transfer Path in Steroid Biosynthesis

Cloning of ACTH-regulated genes in the adrenal cortex

Awareness and trends of Blood Cholesterol and Susceptibility to Develop Heart disease

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