Steroid metabolism

Steroid metabolism is the complete set of chemical reactions in organisms that produce, modify and consume steroids. These metabolic pathways include:
* steroid synthesis - the manufacture of steroids from more simple precursors
* steroidogenesis - the interconversion of different types of steroids
* steroid degradation.

teroid biosynthesis

Steroid biosynthesis is an anabolic metabolic pathway that produces steroids from simple precursors. This pathway is carried out in different ways in animals than in many other organisms, making the pathway a common target for antibiotics and other anti-infective drugs. In addition, steroid metabolism in humans is the target of cholesterol-lowering drugs such as statins.

It starts in the mevalonate pathway in humans, with Acetyl-CoA as building blocks, which form DMAPP and IPP [cite journal |author=Grochowski L, Xu H, White R |title=Methanocaldococcus jannaschii uses a modified mevalonate pathway for biosynthesis of isopentenyl diphosphate |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16621811 |journal=J Bacteriol |volume=188 |issue=9 |pages=3192–8 |year=2006 |pmid=16621811 |doi=10.1128/JB.188.9.3192-3198.2006] . In following steps, DMAPP and IPP form lanosterol, the first steroid. Further modification belongs to the succeeding steroidogenesis.

Mevalonate pathway

The mevalonate pathway or HMG-CoA reductase pathway starts with and ends with dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP).

Regulation and feedback

Several key enzymes can be activated through DNA transcriptional regulation on activation of SREBP (Sterol Regulatory Element-Binding Protein-1 and -2). This intracellular sensor detects low cholesterol levels and stimulates endogenous production by the HMG-CoA reductase pathway, as well as increasing lipoprotein uptake by up-regulating the LDL receptor. Regulation of this pathway is also achieved by controlling the rate of translation of the mRNA, degradation of reductase and phosphorylation.

Pharmacology

A number of drugs target the "mevalonate pathway":
* Statins (used for elevated cholesterol levels)
* Bisphosphonates (used in treatment of various bone-degenerative diseases)

Plants and bacteria

In plants and bacteria, the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates. [cite journal |author=Lichtenthaler H |title=The 1-Dideoxy-D-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants |journal=Annu Rev Plant Physiol Plant Mol Biol |volume=50 |issue= |pages=47–65 |year=1999 |pmid=15012203 |doi=10.1146/annurev.arplant.50.1.47]

DMAPP to lanosterol

Isopentenyl pyrophosphate and dimethylallyl pyrophosphate donate isoprene units, which are assemblied and modificated to form terpenes and isoprenoidscite journal |author=Kuzuyama T, Seto H |title=Diversity of the biosynthesis of the isoprene units |journal=Nat Prod Rep |volume=20 |issue=2 |pages=171–83 |year=2003 |pmid=12735695 |doi=10.1039/b109860h] , which are a large class of lipids that include the carotenoids, and form the largest class of plant natural products. [cite journal |author=Dubey V, Bhalla R, Luthra R |title=An overview of the non-mevalonate pathway for terpenoid biosynthesis in plants |url=http://www.ias.ac.in/jbiosci/sep2003/637.pdf |journal=J Biosci |volume=28 |issue=5 |pages=637–46 |year=2003 |pmid=14517367 |doi=10.1007/BF02703339]

Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol.cite journal |author=Schroepfer G |title=Sterol biosynthesis |journal=Annu Rev Biochem |volume=50 |issue= |pages=585–621 |year=1981 |pmid=7023367 |doi=10.1146/annurev.bi.50.070181.003101] Lanosterol can then be converted into other steroids such as cholesterol and ergosterol. [cite journal |author=Lees N, Skaggs B, Kirsch D, Bard M |title=Cloning of the late genes in the ergosterol biosynthetic pathway of Saccharomyces cerevisiae—a review |journal=Lipids |volume=30 |issue=3 |pages=221–6 |year=1995 |pmid=7791529 |doi=10.1007/BF02537824]

teroidogenesis

Steroidogenesis is the process wherein desired forms of steroids are generated by transformation of other steroids. The pathways of steroidogenesis can differ from organism to organism, but the pathways of human steroidogenesis are shown in the figure.

Products of steroidogenesis include:
*androgens
**testosterone
*estrogens and progesterone
*corticoids
**cortisol
**aldosterone

Elimination

Steroids are mainly oxidized by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions introduce oxygen into the steroid ring and allows the structure to be broken up by other enzymes, to form bile acids as final products. [cite journal |author=Pikuleva IA |title=Cytochrome P450s and cholesterol homeostasis |journal=Pharmacol. Ther. |volume=112 |issue=3 |pages=761–73 |year=2006 |pmid=16872679 |doi=10.1016/j.pharmthera.2006.05.014] These bile acids can then be eliminated through secretion from the liver in the bile. [cite journal |author=Zollner G, Marschall HU, Wagner M, Trauner M |title=Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations |journal=Mol. Pharm. |volume=3 |issue=3 |pages=231–51 |year=2006 |pmid=16749856 |doi=10.1021/mp060010s] The expression of this oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids.cite journal |author=Kliewer S, Goodwin B, Willson T |title=The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism |journal=Endocr. Rev. |volume=23 |issue=5 |pages=687–702 |year=2002 |pmid=12372848 |doi=10.1210/er.2001-0038]

References

External links

* http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/basics/steroidogenesis.html