Is there any physiological role for gonadotrophin oligosaccharide heterogeneity in humans? II. A biochemical point of view

Heterogeneity of gonadotrophin oligosaccharides caused either by pharmacolo gical intervention or which occurs naturally during normal physiological ch anges is well documented, Recent advances in structure determination of oli gosaccharides has to some extent led to a better appreciation of how oligos accharide heterogeneity may affect protein folding, stability, measurement and modulation of receptor binding. Here it is discussed how carbohydrate s tructure can impact upon gonadotrophin structure and function, It is well d ocumented that oligosaccharides can serve as a cognate site for protein bin ding. One functional aspect of gonadotrophin glycosylation heterogeneity is the modulation of receptor binding affinity, yielding partially agonistic glycoforms, Carbohydrate heterogeneity is problematic for a clinical chemis t if immunochemical assays are sensitive to heterogeneity. However, even me asurements made without such interference may not accurately reflect the bi ological activity that is a collective result of all isoforms in the circul ation, and perhaps of the genotype of each individual. Moreover, oligosacch aride heterogeneity may affect heterodimer stability, therefore, biological activity and immunochemical activity, not to mention clearance. It seems r easonable to conclude that from a biochemical point of view oligosaccharide heterogeneity is of considerable importance. However, accurate measurement of isoforms in blood, and appropriate in-vitro bioassays that are insensit ive to matrix effects are needed to define the physiological significance o f each glycoform, and thereby better define target therapeutics and interpr et diagnostic results.