desogestrel australia br Introduction Glucokinase GCK hexoki

Introduction Glucokinase (GCK, hexokinase IV) is a monomeric enzyme that catalyzes the ATP-dependent conversion of glucose to glucose 6-phosphate, the first and rate-limiting step of glycolysis in the liver and pancreas [1,2]. GCK was first discovered in the early 1960's, and shortly thereafter it became the subject of intense study due to its unique sigmoidal kinetic response to glucose and its essential role in glucose metabolism [[3], [4], [5]]. Although it shares extensive sequence identity with the three other human hexokinase isozymes, GCK is considered the body's primary glucose sensor because small fluctuations in its activity alter the threshold for glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells [[6], [7], [8]]. GCK's midpoint of glucose responsiveness (K0.5) is ∼30-fold lower than that of homologous isozymes (7 mM for GCK vs. ∼0.2 mM for hexokinases I-III) and this value closely matches physiological, circulatory glucose concentrations [9]. Unlike the other hexokinases, GCK is not susceptible to feedback inhibition by physiological concentrations of its product glucose 6-phosphate [5,9,10]. In humans, GCK is primarily produced in pancreatic β-cells and liver hepatoparenchymal cells. Within pancreatic β-cells, GCK acts to maintain glucose homeostasis by governing the rate of insulin secretion, while in the liver GCK participates in glycogen synthesis [2,11]. The importance of precise control over GCK activity in both tissues is emphasized by several disease phenotypes that result from mutations in the human gck locus (Fig. 1). Maturity onset diabetes of the young type 2 (MODY2) and the more serious permanent neonatal desogestrel australia (PNDM) are caused by heterozygous inactivating gck mutations [[12], [13], [14]]. By contrast, gain-of-function, activating gck mutations produce persistent hyperinsulinemic hypoglycemia of infancy (PHHI), the severity of which directly correlates with the level of enzyme activation [12]. The importance of GCK in glucose metabolism and disease has stimulated much interest from the pharmaceutical industry to develop activators of the enzyme [[15], [16], [17], [18]]. A variety of lead molecules that stimulate GCK in vivo, either directly or indirectly, have been identified. To date, however, a viable therapeutic agent has yet to emerge from these efforts. Given the significance of GCK to glucose homeostatic maintenance, it is not surprising that considerable efforts have been made to characterize the full suite of biochemical processes that regulate its activity. GCK regulation is complex and a number of unique regulatory strategies have been discovered. Alternative and tissue-specific promoters drive GCK transcription and gene expression to varying degrees [3,[19], [20], [21], [22]]. In addition, several hormones and metabolites, including insulin and glucose, regulate GCK expression at the transcriptional level [5,[23], [24], [25], [26]]. The hormonal, metabolic and transcriptional basis of GCK regulation has been recently reviewed elsewhere, so these topics will not be discussed here [27]. Instead, the focus of this review is to discuss our current understanding of GCK regulation, with a special emphasis on bridging the gap between regulation of GCK at the molecular and the cellular levels Table 1. We begin with a brief update of our current knowledge regarding the mechanistic origin of GCK's unique kinetic cooperativity, which has advanced significantly in recent years as a result of many diverse biochemical and biophysical studies of the isolated enzyme. We then turn our attention to the regulation of GCK within the cellular context, which appears to be dominated by interactions with a number of established and putative binding partners. Finally, we conclude with a look to the future, emphasizing the need for continued studies aimed at providing a comprehensive understanding of how GCK's dynamic conformational landscape is linked to regulation within the cell.