However, the enzyme, when it is present like a monomer, can possess a moonlighting function, for example acting like a protease [32]. metabolic pathways and metabolic intermediates that could accumulate upon DLDH inhibition and their related tasks in abrogating oxidative stress in diabetes. We also discussed a couple of DLDH inhibitors that may be tested in animal models of type 2 diabetes. It is our belief that DLDH inhibition could be a novel approach to fighting type 2 diabetes. strong class=”kwd-title” Keywords: diabetes mellitus, dihydrolipoamide dehydrogenase, mitochondria, oxidative stress, reactive oxygen species 1. Intro Adult-onset diabetes mellitus, also known as type 2 diabetes, is caused by insulin resistance followed by -cell dysfunction [1,2,3]. The hallmark of this metabolic disorder is definitely prolonged hyperglycemia in the blood induced by dysregulation of glucose rate of metabolism [4,5,6]. While pathogenesis of type 2 diabetes is definitely multifactorial, oxidative stress has been thought to be the converging event leading to development and progression of type 2 diabetes [7,8,9,10]. As sources of reactive oxygen species-induced oxidative stress are usually endogenous in type 2 diabetes [11,12], controlling diabetic oxidative stress by revitalizing endogenous antioxidation pathways may provide a novel approach to fighting diabetes. 2. Oxidative Stress and Diabetes When blood glucose is constantly high, there can be a variety of pathophysiological effects. These include non-enzymatic modifications of proteins by glucose through a process known as glycation [13,14,15], elevated levels of reactive oxygen varieties (ROS) [15,16] that can cause oxidative damage to proteins, DNA, and lipids [17,18,19,20], and upregulation of metabolic and signaling pathways that can possess detrimental effects on glucose rate of metabolism [21,22,23,24,25]. With respect to elevated ROS production, Cordycepin it has been founded that nearly all the recognized pathways that are upregulated by prolonged hyperglycemia can induce or contribute to redox imbalance and ROS production [12,26]. These include the polyol pathway, the protein kinase C activation pathway, the hexosamine pathway, the advanced glycation end products pathway, and the glyceraldehyde autoxidation pathway [8,10]. In addition, upregulation of the poly adenine diphosphate ADP ribosylation pathway and down rules of the sirtuin 3 pathway have also been implicated in diabetic oxidative stress that accentuates diabetes and its complications [16,27]. Consequently, we believe that activation and encouragement of cellular antioxidation pathways are encouraging strategies for attenuating diabetic oxidative stress and ameliorating diabetes. In this article, we postulate that chronic inhibition Cordycepin of mitochondrial dihydrolipomide dehydrogenase (DLDH) can be explored to manage diabetic oxidative stress in diabetic conditions 3. Mitochondrial Dihydrolipomide Dehydrogenase (DLDH) Mitochondrial dihydrolipomide dehydrogenase Cordycepin (DLDH) is definitely a flavin adenine dinucleotide (FAD)-comprising, nicotinamide adenine dinucleotide (NAD)-dependent disulfide-implicated redox enzyme [28,29,30,31]. DLDH participates in three mitochondrial enzyme complexes, namely pyruvate dehydrogenase complex, -keto glutarate dehydrogenase complex, and branched chain amino acid dehydrogenase complex (Number 1). DLDH is also involved in the glycine cleavage system. In the three dehydrogenase complexes, DLDH catalyzes the same reactions that oxidizes dihydrolipoamide to lipoamide (Number 2) so that the overall enzymatic reactions can continue. Open in a separate window Number 1 Mitochondrial metabolic pathways including dihydrolipomide dehydrogenase (DLDH), which include the pyruvate to acetyl-CoA pathway, the -ketoglutarate to succinyl-CoA pathway, and the branched chain amino acids (leucine, isoleucine, and valine) to acyl-CoA pathway. The glycine cleavage pathway that also entails DLDH is not demonstrated here. DLDH-involved complexes are indicated by dotted reddish arrows within the number. BCAA: branched chain amino acids; NAD+: nicotinamide adenine dinucleotide; NADH: reduced form of NAD+; AAs: amino acids; -KGDC: alpha ketoglutarate dehydrogenase complex; TCA: tricarboxylic acid; BCKA: branched chain keto acid; BCKACD: branched chain alpha keto acid dehydrogenase complex; PDC: pyruvate dehydrogenase complex. Open in a separate window Number 2 The chemical reaction catalyzed by DLDH. Dihydrolipoamide is definitely oxidized to lipoamide at the expense of NAD+. Hence the DLDH-catalyzed reaction generates NADH that feeds into the electron transport chain in the inner mitochondrial membrane. DLDH Cordycepin is definitely a multifunctional protein. In rat, the brain and the testis appear to have the highest DLDH activity while the lung gives the least expensive DLDH activity [31]. When it is present like a homodimer in the above mentioned dehydrogenase complexes, it is a classical redox-dependent enzyme that converts dihydrolipoamide to lipoamide using two cysteine residues at its active IQGAP1 center like a redox relay system (Number 3). However, the enzyme, when it is present like a monomer, can have a moonlighting function, for example acting like a protease [32]. DLDH can either enhance or attenuate production of reactive oxygen species (ROS), depending on experimental or pathophysiological conditions [29,33,34,35,36,37,38]. In particular, DLDH offers two redox-reactive Cordycepin cysteine residues at its active center [39,40].