Conformational changes induced in lens α- and γ-crystallins by modification with glucose 6-phosphate. Implications for cataract

Abstract

There is good evidence that the non-enzymic chemical modification of proteins plays a role in the aetiology of cataract and diabetic sequelae. This paper presents new evidence that glycosylation of two major lens structural crystallins, alpha- and gamma-crystallins, by glucose 6-phosphate (G6P) induces conformational changes in the proteins. In addition the surface charge on the molecules is altered. These changes would affect protein-protein and protein-water interactions within the lens and could lead to disruption of the short-range order of the lens proteins which is essential for lens transparency. Conformational changes to lens proteins are known to occur in human cataractous lenses but their cause in vivo is not established. Cumulative chemical modification of proteins, over a period of decades, is a strong candidate as a causal agent.

Serum Paraoxonase Activity and Genotype Distribution in Japanese Patients with Diabetes Mellitus.

“…However, the absence of a correlation between paraoxonase activity and HDLcholesterol suggests that the lower paraoxonase activity in diabetes is caused by factors other than the lower HDLcholesterol level. Furthermore, the glycation, or nonenzymatic glycosylation, of several structural and functional proteins has been described previously (15,16). Glycation often leads to alterations in the conformation and/or function ofproteins ( 17, 1 8).…”

Alpha‐crystallin acting as a molecular chaperone protects catalase against steroid‐induced inactivation

“…With in vitro non-enzymic glycosylation of lens proteins and in human diabetic cataracts, lens proteins become modified, unfold and aggregate [31,32]. Enzyme activities are reduced [2,3].…”

“…The fact that these changes occur with age and not immediately suggests that a molecule with properties exhibited in vitro by a-crystallin must exist. Beswick and Harding [31] have postulated that unfolding of lens proteins by sugars could lead to structures that resemble the molten globule state. Such a scheme could present many substrates for the chaperone properties of a-crystallin.…”

Adherence to diabetic eye examination guidelines in Australia: the National Eye Health Survey

“…Increased retinal blood flow is thus initiated by high blood glucose levels and exacerbated by high blood pressure (BP) 228 and impaired autoregulation. High glucose levels have a direct damaging effect on both pericytes and endothelial cells, with further vessel wall damage, occlusion of vessels and ischaemia, resulting in PDR 227 .…”