Steroid synthesis pathway

As indicated in the Figure above showing the pathway of cholesterol biosynthesis a molecule of geranylpyrophosphate (GPP) and a molecule of isopentenylpyrophosphate (IPP) are condensed into farnesylpyrophosphate (FPP) through the action of the farnesyl diphosphate synthase enzyme which is encoded by the FDPS gene. Through the action of the ER-localized enzyme, dehydrodolichyl diphosphate synthase (encoded by the DHDDS gene), farnesylpyrophosphate is elongated via the sequential head-to-tail addition of multiple isopentenylpyrophosphate groups in a reaction referred to as cis -prenylation. The number of IPP substrates added ultimately determines the overall number of isoprene units in dolichol which in humans ranges from 17 to 21. The DHDDS gene is located on chromosome and is composed of 10 exons that generate five alternatively spliced mRNAs each of which encode a distince protein isoform. The product(s) of the DHDDS reaction is referred to as a polyprenolpyrophosphate. The pyrophosphate is removed by an as yet uncharacterized enzyme activity that may be either a polyprenol pyrophosphate phosphatase or a polyprenol phosphatase resulting in the formation of a polyprenol.

Cells of the zona fasciculata and zona reticularis lack aldosterone synthase (CYP11B2) that converts corticosterone to aldosterone, and thus these tissues produce only the weak mineralocorticoid corticosterone. However, both these zones do contain the CYP17A1 missing in zona glomerulosa and thus produce the major glucocorticoid, cortisol. Zona fasciculata and zona reticularis cells also contain CYP17A1, whose 17,20-lyase activity is responsible for producing the androgens, dehydroepiandosterone (DHEA) and androstenedione. Thus, fasciculata and reticularis cells can make corticosteroids and the adrenal androgens, but not aldosterone.

Steroid and thyroid hormones are classes of endocrine signalers that are major regulators of development, reproduction, stress, and growth.  Steroids begin with a cholesterol backbone and are transformed into different steroids with different capabilities through a series of enzymes.  Similarly, thyroid hormones have similar backbones but differ on the number and placement of iodine molecules.  Although they are similar in structure and therefore difficult to distinguish, hormones work in concert to produce a myriad of physiological responses.  Hormone measurement methods are moving towards pathway analyses to better describe and monitor endocrine changes.  NIST scientists have developed mass spectrometry methods for the measurement of steroid hormone pathways which better describe physiological changes than one hormone at a time analyses, and are applying them to human and wildlife matrices to better understand endocrine changes including medical diagnostics and environmental health.

ONC1-0013B inhibits AR activity in vitro. A. ONC1-0013B structure. B. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 1 day. PSA expression plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). Ki values: ± (ONC1-13B), ± (MDV3100), (ARN-509). Mean±SEM from 5 replicate experiments (except ARN-509). C. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 5 days. Viable cells plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). IC50 values: 30nM (ONC1-13B), 148nM (MDV3100), 240nM (ARN-509). D. Competitive-binding assay vs AR ligand Fluormone™ (PolarScreen™ Androgen Receptor Competitor Assay). IC50 values: 19nM (DHT), (ONC1-13B), (MDV3100).

Steroid synthesis pathway

steroid synthesis pathway

ONC1-0013B inhibits AR activity in vitro. A. ONC1-0013B structure. B. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 1 day. PSA expression plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). Ki values: ± (ONC1-13B), ± (MDV3100), (ARN-509). Mean±SEM from 5 replicate experiments (except ARN-509). C. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 5 days. Viable cells plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). IC50 values: 30nM (ONC1-13B), 148nM (MDV3100), 240nM (ARN-509). D. Competitive-binding assay vs AR ligand Fluormone™ (PolarScreen™ Androgen Receptor Competitor Assay). IC50 values: 19nM (DHT), (ONC1-13B), (MDV3100).

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