Structure And Function Of Sex Hormone Binding Globulin Biology Essay

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Both oestrogens and androgens are carried in the blood by the sex hormone binding globulin (SHBG) plasma glycoprotein, which is secreted by the liver, into the blood stream and it is synthesized by the testis germ cells, it also recognises the specific binding site located on membranes of sex steroid target cells such as the breast or prostate. Because the hormones bind to SHBG with high affinity, its concentration in plasma determines the quantity of bound hormones in contrast to those that are albumin-bound or free (unbound) in the blood (Siiteri et al 1982). SHBG-bound steroids are unable to exit the blood vessels in the target tissues due to their size and only unbound steroid can enter tissues and target cells (Hammond 1997). However, SHBG hormonal activity pathways have been suggested (Rosner 1990). SHBG binds several synthetically produced steroids, including many progestins (which are used in contraceptive treatments and also, as part of hormone replacement therapy). A series of structure and function studies have been carried out involving the analysis and production of recombinant SHBG forms and molecular variants of these (Grishkovskaya et al 2000, 2002) (Avvakumov 2000, 2002). It is also thought that zinc may affect binding to SHBG for oestrogens and androgens.

SHBG Structure

The primary structure of SHBG has previously been determined by protein sequencing (Walsh et al 1986) as seen in Figure 1, and molecular cloning (Hammond et al 1987), SHBG was identified to be made up of two laminin G-like (LG) regions (Joseph et al 1992). It was also established that SHBG did not require glycosylation to form homo-dimers or a functional steroid-binding site (Bocchinfuso 1992) which in turn, led to the determination of a series of SHBG deletion mutants in E. coli. (Hildebrand et al 1995). These studies showed that the binding and dimerisation sites of SHBG lay within the terminal LG region (Hildebrand et al 1995), and provided the required amount proteins for crystallisation of that terminal LG region, with the androgen DHT (Grishkovskaya et al 1999). These crystals were able to show how the ligand is co-ordinated in the binding site and also that each monomer of the SHBG homo-dimer comprised a binding site (these (Grishkovskaya et al 2000). There is a predicted quaternary structure of the homo-dimer (Grishkovskaya et al 2000) Which is analagous with the general shape and dimensions of the SHBG molecule which has been established by chromatography and by the use of electron micrographs (Beck et al 1997).

Figure 1: Linear structure of SHBG protein. Location of glycosylation sites is shown by red lines. (Atlas of Genetics and Cytogenetics in Oncology and Haematology)

Orientation and coordination of ligands

Multiple previous studies have shown both the affinity of SHBG for androgens and oestrogens and the specific nature of the binding (Westphal 1986), as well as some synthetically produced steroids, including drugs (Pugeat et al 1981) . This data allowed for the identification of the functional groups attached to specific carbon atoms in the steroid structure which are required for the high affinity binding exhibited by the SHBG molecule. As androstenedione and oestrone both poorly interact with SHBG, it has been known that a hydroxyl of both androgens and oestradiol plays a crucial role in the determination of high affinity binding and has helped to show that androgens and oestrogens which are found in the binding site as can be seen in Figure 2 (Avvakumov et al 2002). Although it is possible that the steroids may be able to enter the binding site in both directions, crystallograph data has shown the functional groups of the steroid side branches and the hydroxyl group of estradiol hydrogen may bond with Ser42 (Grishkovskaya et al 2002). It should also be noted that experiments on the mutagenesis of the molecule have shown that this is the most important interaction. It is this interaction that is able to contribute to the high affinity of SHBG for those ligands (Grishkovskaya et al 2002).

Figure 2. "(A) Steroid-binding site of SHBG occupied with the androgens DHT, 5α-androstane-3β,17β-diol and 5α-androstane-3β,17α-diol (in different shades of gray), and the synthetic contraceptive levonorgestrel (in black). Important hydrophilic interactions between the steroids and SHBG are highlighted with dash lines. (B) Superposition of the oestrogens estradiol (in black) and 2-methoxyestrastradiol (in light gray) when bound to SHBG. (C) The superposition of the steroids DHT and estradiol reveals that androgens and oestrogens bind to SHBG in opposite direction. Thus, ring A of the C19 steroids and ring D of estradiol reside most deeply within the binding site." (Hammond et al 2003)Image


In tissues that are high in zinc content, It is thought that the availability of the sex hormones to their target cells is affected, for example, in the prostate. Additionally, exogenous zinc also influences the content of oestrogens in the blood circulation. This property has the potential for pharmacological exploiation. {Hammond et al 2003)

Breast and prostate Cancer:

SHBG regulates the proportion of circulating estradiol, which is known to be a key determinate in breast cancer. Previous studies have shown that SHBG levels in post-menopausal women who had developed breast cancer were significantly lower when compared with the controls, while there was no significant difference observed in pre-menopausal women. (Kaaks et al 2005). SHBG is thought to have a direct effect in breast cancer cells by interacting with the cell membranes, initiating the specific intracellular pathway that interacts with the estradiol activated pathway. This has an inhibitory effect on estradiol in breast cancer cell proliferation. It is the Asp327Asn polymorphism of SHBG gene that is thought to be related to breast cancer. It has previously been observed that there is a significant association of the Asp327Asn polymorphism with reduced breast cancer risk (Cui et al. ) and that there was a significantly higher frequency of the polymorphism in post-menopausal patients with ER-positive breast cancer than in ER-negative subjects. It has also been suggested that there is a protective role of this polymorphism as it has been shown that mutated SHBG is more effective at inhibiting estradiol-induced cell proliferation and anti-apoptosis than wild type protein, it is thought that this may be due to D327N SHBG binding to MCF-7 cells to a greater extent than the wild type protein. (Costantino et al 2009)

Patients with prostate cancer showed lower SHBG levels than benign prostate cancer patients and controls. Alternative splicing of SHBG gene is more pronounced in LNCaP and MCF-7 cancer cell lines; It is thought that SHBG may be significant in the prediction of lymph node invasion in prostate cancer patients. The use of pre-operative serum SHBG may help to identify patients that are at risk of lymph node invasion. (Grosman et al 2010)

Type II Diabeties, PCOS and Obesity

Studies have consistently shown that SHBG levels in type II diabetes patients is lower than in non-diabetic individuals, low circulating levels of SHBG are thought to be strongly correlated to the risk of type II diabetes in both, women and men. Carriers of a variant allele of the SNP SHBG polymorphism rs6259 and carriers of a rs6257 variant have been connected with a risk of type II diabetes following their SHBG levels. SHBG concentrations have also found to be inversely associated with insulin resistance, and therefore, with the risk of type II diabetes. (Ding et al 2009) Women with polycystic ovary syndrome (PCOS) present low SHBG levels that are negatively correlated with body mass index and waist to hip ratio, and are, furthermore, associated with insulin resistance. (Xita et al 2003)

Adipose tissue produces the enzymes aromotase and 17ß-hydroxylase dehydrogenase (17ß-HSD). In obese individuals, typically we find an increased aromatase enzyme action, resulting in an increased conversion of testosterone into the oestrone and oestradiol. Obesity also tends to lead to hyperinsulinaemia (insulin resistance) which in turn causes a reduction in the synthesis SHBG molecules. It can be deduced, therefore that obesity may cause an increase in sex hormone levels but this increase does not promote a rise in SHBG as the effect is nullified by high levels of circulating insulin, which in turn cause a decrease in production of SHBG in the liver. It is for this reason that obesity tends to promote certain cancer types such as, breast & endometrial, as there a higher bioavailability of oestrogens unbound by SHBG (free) for the target tissues. (Prep4USMILE 2009)