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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The polyol pathway enzyme aldose reductase (for an overview on docking studies with aldose reductase inhibitors see Zeyad et al., 2016) is implicated in diabetic complications. In the case of hyperglycemia glucose becomes reduced by aldose reductase at the expense of NADPH to sorbitol that subsequently is converted to fructose in presence of NAD+. The resulting shortage of NADPH and NAD+ leads among others to diminished glutathione levels associated with enhanced occurrence of oxidative stress and inflammatory processes, e.g., in eyes (retinopathy), heart (cardiovascular disease), kidney (nephropathy), and nerves and feet (neuropathy). The tripeptide glutathione (cysteine, glutamic acid, and glycine) is present in most mammalian tissue and acts as an antioxidant, a free radical scavenger and a detoxifying agent. The relation between cancer as well as other chronic diseases and oxidative stress relies on the fact that oxidative stress activates transcription factors (NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, Nrf2, MAFK, etc.) leading to the expression of several hundred genes encoding growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules (Reuter et al., 2010; Sosa et al., 2013; Okita et al., 2017).
Marine Algae in Diabetes and Its Complications
Published in Se-Kwon Kim, Marine Biochemistry, 2023
The polyol pathway of glucose metabolism plays a crucial function in the development of neuropathy (Gabbay, 1973). It is an alternative route of glucose metabolism in which the enzyme aldose reductase catalyzes the reduction of glucose to sorbitol, then to fructose by sorbitol dehydrogenase. Aldose reductase (AR) requires NADPH as a co-factor, and sorbitol dehydrogenase (SDH) needs NAD+. During hyperglycemia, sorbitol accumulates in AR-containing tissues, as it is impermeable to the cell membranes and cannot diffuse out and, hence, creates hyperosmotic stress on the cell, thereby inducing neuropathic pain (Niimi et al., 2021; Kinoshita and Nishimura, 1988). Treatment with inhibitors of aldose reductase has been shown to prevent various complications, including nephropathy, neuropathy, and cataractin animal models (Oates and Mylari, 1999). It is reported that the AR inhibitor epalrestat prevents high glucose–induced smooth muscle cell proliferation and hypertrophy (Yasunari et al., 1995), thereby preventing their dysfunction and remodeling (Tawata et al., 1992). Accumulation of intracellular sorbitol and fructose due to polyol activation leads to diminution of other organic electrolytes like taurine and myo-inositol that regulate cellular osmolality (Stevens et al., 1993). Lessening of myo-inositol in the peripheral nerves gets in the way of phosphoinositide production, leading to inadequate diacylglycerol to sustain the content of protein kinase C (PKC) essential for Na+/K+-ATPase activation (Zhu and Eichberg, 1990; Greene et al., 1987). Amendments in PKC activation also interfere with an important myelin protein’s (PO) phosphorylation of peripheral nerves and play an important pathogenetic role in primary segmental demyelination (Row-Rendleman and Eichberg, 1994). Enhanced activity of vascular PKC-β is thought to play a noteworthy role in microvascular complications.
Bio-medical potential of chalcone derivatives and their metal complexes as antidiabetic agents: a review
Published in Journal of Coordination Chemistry, 2021
Hyperglycaemic conditions in bloodstreams are an important aspect of diabetes mellitus and certain secondary complications related to heart, nerves, retina and kidney that come along as a domino effect [56, 57]. These complications occur because of the accretion of ROS viz. reactive oxygen species inside the cells of tissues of diabetes mellitus. Glucose in bloodstreams undergoes its major metabolic fate that is glycolysis, glycogen synthesis and fatty acid synthesis. In hyperglycemia conditions, insulin dependent adipose tissues are stimulated by insulin to consume glucose. But, when adipose tissues become resistant to insulin or in the case of limited insulin secretion, micro vascular tissues of retina, kidney, liver, red blood cells, neurons, and peripheral nerves play a part to normalize the glucose concentration in bloodstreams since they are independent of insulin stimulus. Since their glucose transporters do not need insulin to be present over the membrane, they get more and more glucose into the cells. So, they follow a polyol pathway as an alternative way for glucose fluidity, which is believed to be increased by 33% of total consumption of glucose by tissues in their studies of Flemingia species extracts [58, 59]. In the polyol pathway, aldose reductase is the first key enzyme which transforms glucose into sorbitol by metabolizing aldehydes and carbonyls into alcohols using NADPH [60]. The mechanism of the polyol pathway is shown in Scheme 2.