An elusive role for glycosylation in the structure and function of reproductive hormones

Abstract

The crescendo of events leading first to ovulation and subsequently to birth is orchestrated by a broad repertoire of hormones. The major hormones of the ovulatory cycle are representatives of four hormone classes: neurotransmitters, releasing factors, trophic hormones acting on target tissues, and steroid-like molecules released by the target tissues. The punctuate and staccato rhythm of the neurotransmitters and releasing hormones relentlessly drive the swelling and protracted wave of activity by the luteotrophic and steroid hormones. Carbohydrates alone are notably absent as hormones and the predominant role for glycosylation appears to be the conferment of increased solubility to endocrine molecules, either during their manufacture or by modulating circulatory half-life. Rarely considered examples of the importance of glycosylation in reproductive hormones include adenosine, important for spermatozoan activity, and the hormone-binding globulins, which ensure the aqueous transport of hydrophobic steroids. The archetype glycoprotein hormones, especially human chorionic gonadotrophin (HCG), are discussed more extensively, as the structural and functional roles of carbohydrate in these hormones have been studied exhaustively. Conversely, the direct involvement of HCG and the importance of its carbohydrate for autonomous growth, in both placental invasion and tumorigenesis, has received little attention in the literature.

The Superagonistic Activity of Bovine Thyroid-stimulating Hormone (TSH) and the Human TR1401 TSH Analog Is Determined by Specific Amino Acids in the Hinge Region of the Human TSH Receptor

“…So far, we are limited to signaling studies with hTSH. This is due to the known relatively low affinity interaction of hTSH binding to the hTSHR (29), which leads to very low detectable 125 I-hTSH binding (48,49).…”

Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships

“…As shown in Table 3, several rhTSH glycoforms Gonadotropin microheterogeneity has been also extensively studied. Pituitary LH was solved as 24 highly purified isoforms within the pI range of 7.03 to 8.98 that exhibited a wide variability in their respective capacity to stimulate rat testicular steroidogenesis (222). FSH was separated as nine isoforms within pI 4.1-7.1 (232), showing variable receptor binding activity dependent on sialic acid content.…”

“…Deglycosylation of hCG and bovine TSH has long been known to result in increased receptor binding but loss in efficient signal transduction. Many reviews have covered the role of carbohydrate chains in glycoprotein hormone assembly, secretion, and bioactivity, and the reader is invited to refer to them for more detailed information (4,14,146,188,222). It appears that glycosylation can play a role in the life span of the hormone through different glycan structure.…”

Using cell engineering and omic tools for the improvement of cell culture processes

“…The functional biological activity of the glycoprotein is directly affected by glycosylation, including its trafficking and folding within the host cell (Scallon et al 2006;Walsh and Jefferis 2006;Willey 1999). Once secreted, solubility, aggregation, stability and immunogenicity of the protein may be affected by its glycosylation pattern (Kobata 1992;Sinclair and Elliott 2005;Willey 1999;Wyss and Wagner 1996).…”

“…The functional biological activity of the glycoprotein is directly affected by glycosylation, including its trafficking and folding within the host cell (Scallon et al 2006;Walsh and Jefferis 2006;Willey 1999). Once secreted, solubility, aggregation, stability and immunogenicity of the protein may be affected by its glycosylation pattern (Kobata 1992;Sinclair and Elliott 2005;Willey 1999;Wyss and Wagner 1996). N-glycosylation is initiated in the ER, and O-glycosylation can be initiated in either the ER or Golgi apparatus, but due to processing inconstancies glycans can have frequent structural heterogeneities (Patel et al 1992;Seth et al 2006a;Varki 1998).…”