Regulation of 17,20 Lyase Activity by Cytochrome b5 and by Serine Phosphorylation of P450c17

Pandey, Amit V.; Miller, Walter L.

doi:10.1074/jbc.m414673200

Cited by 148 publications

(104 citation statements)

References 62 publications

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“…It was suggested that variations in fat androstenone levels at puberty might be due to variations in androstenone synthesis, which is probably under genetic control. CYB5 is an important regulator of 17,20-lyase activity of P450C17, the enzyme essential for steroidogenesis (Pandey and Miller, 2005) and particularly for androstenone biosynthesis (Meadus et al, 1993). Genetic polymorphisms in the porcine gene coding for CYB5A result in different phenotypes with respect to the ability to express boar taint due to androstenone (Lin et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Effect of polymorphism in the porcine cytochrome b5 (CYB5A) gene on androstenone and skatole concentrations and sexual development in Swedish pig populations

Zamaratskaia

Lou

Peacock

et al. 2008

Animal

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The present study investigated the presence of a single-nucleotide polymorphism (G . T) at base 28 upstream of ATG in 5 0 untranslated region of cytochrome b5 (CYB5A) gene in Swedish pig populations and evaluated the significance of this polymorphism for androstenone and skatole levels, sexual development and performance parameters in pigs. Frequencies of the T allele were 6.7% for Swedish Yorkshire 3 Landrace crossbred pigs (n 5 245), 6.5% for Swedish Yorkshire (n 5 99) and 12.8% for Landrace breed (n 5 74). No deviations from Hardy-Weinberg equilibrium were observed in the investigated populations. In Swedish Yorkshire 3 Landrace crossbred entire male pigs (n 5 193), plasma samples were analysed for skatole, androstenone, testosterone and oestrone sulphate, and fat samples were analysed for androstenone, skatole and free oestrone. Additionally, testis weight and bulbourethral gland length for crossbred pigs were recorded. Plasma androstenone levels were significantly lower in the G/T genotype at 90 kg live weight compared with the wild G/G genotype at the same live weight (P 5 0.006). In heavier pigs, plasma androstenone levels did not differ between genotypes (P 5 0.382). Fat androstenone levels were not affected by CYB5A genotype (P 5 0.252). Skatole levels in the G/T genotype at 115 kg live weight were lower compared with those in the G/G genotype in plasma (P 5 0.048) and fat (P 5 0.028), although no differences were observed in lighter pigs. Testis weight, bulbourethral gland length, testosterone and oestrone sulphate levels in plasma, and oestrone levels in fat were not affected by genotype. We concluded that the presence of the T allele in the CYB5A gene resulted in lower androstenone levels in plasma, and lower skatole levels in fat and plasma; this reduction, however, was dependent on the live weight of the animals. Reproductive hormones and growth rate did not differ between the pigs of different genotypes, whereas a higher lean meat content was found in the G/T genotype in comparison with the G/G genotype. The practical application of those results in Sweden is doubtful because of lack of the effect on androstenone in fat and the low frequency of the T allele in the studied Swedish pig populations.

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Section: Discussionmentioning

confidence: 99%

Effect of polymorphism in the porcine cytochrome b5 (CYB5A) gene on androstenone and skatole concentrations and sexual development in Swedish pig populations

Zamaratskaia

Lou

Peacock

et al. 2008

Animal

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“…Another study found that male rats fed on a high monounsaturated fatty acid (MUFA) diet for 6 weeks display increased testosterone levels (vs. low MUFA diet), and that free fatty acid with different degree of saturation increased testosterone levels to significantly different extent [86]. In addition, serine phosphorylation of P450c17 have been shown to increase its 17,20-lyase activity [87,88]. Therefore, FFAs may be the serine phosphorylation key factor that induces both an increase in P450c17 activity and a defect in the insulin signalling pathways causing insulin resistance (Fig.…”

Section: Cellular Mechanisms Of Metabolic Insulin Resistance-mostmentioning

confidence: 99%

Insulin and hyperandrogenism in women with polycystic ovary syndrome

Baptiste

Battista

Trottier

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

266

199

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Polycystic ovary syndrome (PCOS) is a very common endocrine disorder characterized by chronic anovulation, clinical and/or biochemical hyperandrogenism, and/or polycystic ovaries. But most experts consider that hyperandrogenism is the main characteristic of PCOS. Several theories propose different mechanisms to explain PCOS manifestations: (1) a primary enzymatic default in the ovarian and/or adrenal steroidogenesis; (2) an impairment in gonadotropin releasing hormone (GnRH) secretion that promotes luteal hormone (LH) secretion; or (3) alterations in insulin actions that lead to insulin resistance with compensatory hyperinsulinemia. However, in the past 20 years there has been growing evidence supporting that defects in insulin actions or in the insulin signalling pathways are central in the pathogenesis of the syndrome. Indeed, most women with PCOS are metabolically insulin resistant, in part due to genetic predisposition and in part secondary to obesity. But some women with typical PCOS do not display insulin resistance, which supports the hypothesis of a genetic predisposition specific to PCOS that would be revealed by the development of insulin resistance and compensatory hyperinsulinemia in most, but not all, women with PCOS. However, these hypotheses are not yet appropriately confirmed, and more research is still needed to unravel the true pathogenesis underlying this syndrome. The present review thus aims at discussing new concepts and findings regarding insulin actions in PCOS women and how it is related to hyperandrogenemia.

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“…In view of the electrostatic association of CYP17 and its redox partners as mentioned previously, it was proposed that the modified negatively charged phosphorylated residues served to enhance electrostatic attraction between the redox partners so as to engage a stronger interaction of CPR with CYP17. Recently, the enhancement of 17,20 lyase by serine phosphorylation and cytochrome b 5 has been shown to occur independently of each other (Pandey & Miller 2005).…”

Section: Additional Factors That Modulate Cyp17 Cleavage Activitymentioning

confidence: 99%

Cytochrome b5 modulation of 17α hydroxylase and 17–20 lyase (CYP17) activities in steroidogenesis

Akhtar¹,

Kelly²,

Kaderbhai³

2005

Journal of Endocrinology

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CYP17 is a steroidogenic enzyme located in the zona fasciculata and zona reticularis of the adrenal cortex and gonad tissues and which has dual functions -hydroxylation and as a lyase. The first activity gives hydroxylation of pregnenolone and progesterone at the C 17 position to generate 17 -hydroxypregnenolone and 17 -hydroxyprogesterone, while the second enzymic activity cleaves the C 17 -C 20 bond of 17 -hydroxypregnenolone and 17 -hydroxyprogesterone to form dehydroepiandrosterone and androstenedione respectively. The modulation of these two activities occurs through cytochrome b 5 . Association of cytochrome b 5 and CYP17 is thought to be based primarily on electrostatic interactions in which the negatively charged residues pair up with positively charged residues on the proximal surface of the CYP17 molecule. Non-specific interactions of the hydrophobic membrane regions of cytochrome b 5 and CYP17 are also thought to play a crucial role in the association of these two haemoproteins. Although cytochrome b 5 is known to stimulate CYP activity by contributing the second electron in the catalytic cycle, in the case of CYP17, the mechanism of cleavage stimulation proceeds via an allosteric mode. It is hypothesised that cytochrome b 5 promotes the cleavage by aligning the iron-oxygen complex attack onto the C 20 rather than the C 17 atom of the steroid substrate molecule. Thus, further understanding of the mechanism of modulation by cytochrome b 5 of the hydroxylase and lyase activities should shed new insights on developing therapeutic targets in CYP17-linked biochemical processes such as adrenarche, polycystic ovary syndrome and prostate cancer.

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Regulation of 17,20 Lyase Activity by Cytochrome b5 and by Serine Phosphorylation of P450c17

Cited by 148 publications

References 62 publications

Effect of polymorphism in the porcine cytochrome b5 (CYB5A) gene on androstenone and skatole concentrations and sexual development in Swedish pig populations

Effect of polymorphism in the porcine cytochrome b5 (CYB5A) gene on androstenone and skatole concentrations and sexual development in Swedish pig populations

Insulin and hyperandrogenism in women with polycystic ovary syndrome

Cytochrome b5 modulation of 17α hydroxylase and 17–20 lyase (CYP17) activities in steroidogenesis

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