NMNAT Expression and its Relation to NAD Metabolism

Abstract

Nicotinamide mononucleotide adenylyltransferease (NMNAT), a rate-limiting enzyme present in all organisms, reversibly catalyzes the important step in the biosynthesis of NAD from ATP and NMN. NAD and NADP are used reversibly in anabolic and catabolic reactions. NAD is necessary for cell survival in oxidative stress and DNA damage. Based on their localization, three different NMNAT's have been recognized, NMNAT-1 (homohexamer) in the nucleus (chromosome 1 p32-35), NMNAT-2 (homodimer) in the cytoplasm (chromosome 1q25) and NMNAT-3 (homotetramer) in the mitochondria. NMNAT also catalyzes the metabolic conversion of potent antitumor prodrugs like tiazofurin and benzamide riboside to their active forms which are analogs of NAD. NAD synthase-NMNAT acts as a chaperone to protect against neurodegeneration, injury-induced axonal degeneration and also correlates with DNA synthesis during cell cycle. Since its activity is rather low in tumor cells it can be exploited as a source for therapeutic targeting. Steps involved in NAD synthesis are being utilized as targets for chemoprevention, radiosensitization and therapy of wide range of diseases, such as cancer, multiple sclerosis, neurodegeneration and Huntington's disease.

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

“…Nicotinamide mononucleotide adenylyltransferease ( NMNAT1 ), upstream of WCadjBMI variant rs17396340, is responsible for the synthesis of NAD from ATP and NMN45. NAD is necessary for cellular repair following oxidative stress.…”

Construction of a metabolomics profile of arsenic trioxide effect in gastric carcinoma cell line SGC7901

“…At 6 h, there was a significant accumulation of nicotinamide riboside and nicotinamide mononucleotide (NMN) in the ATOtreated group, suggesting the inhibition of NMN adenylytransferase (NMNAT). NMNAT is a rate-limiting enzyme that catalyzes the biosynthesis of NAD from adenosine triphosphate and NMN, and is essential for cell survival under conditions of oxidative stress and DNA damage [33]. These results suggest that NAD + biosynthesis inhibitor and ATO may have a synergistic effect.…”

Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin

“…In regards to the nervous system, cell injury related to toxin exposure (Wang et al , 2012b; Xie et al , 2012), cerebral ischemia (Chong et al , 2010a; Du et al , 2012; Li et al , 2006b; Simao et al , 2011), inflammation (Kato et al , 2011; Kigerl et al , 2012; L'Episcopo et al , 2012; Shang et al , 2009b, 2010), and Aβ exposure (Chong et al , 2005c; Lee et al , 2012; Liu et al , 2010b; Shang et al , 2012; Zeng et al , 2011) can be the result of oxidant stress. Oxidative stress in conjunction with mitochondrial dysfunction (Chong et al , 2004b; Escobar et al , 2012; Ghosh et al , 2011; Jayaram et al , 2011; Kang et al , 2003b; Maiese and Chong, 2004) can lead to neurovascular diabetic complications (Jiang et al , 2011; Maiese et al , 2008g, 2011a; Yang et al , 2011; Zengi et al , 2011), cognitive disorders (Chong et al , 2005b; Leuner et al , 2007; Maiese et al , 2009d; Zhang et al , 2011), Alzheimer's disease (AD) (Bajda et al , 2011; Maiese et al , 2009a; Srivastava and Haigis, 2011), Parkinson's disease (PD) (Asaithambi et al , 2011; Chong et al , 2005d; Khan et al , 2010; Park et al , 2011), and epilepsy (Lehtinen et al , 2009; Maiese et al , 2009c; Sales Santos et al , 2009). …”

“…Once generated, ROS alter mitochondrial function, DNA integrity, and the misfolding of proteins leading to cellular injury and the progression of aging mechanisms (Jayaram et al , 2011; Maiese et al , 2010; Yang et al , 2011). Detrimental effects of ROS are usually prevented by endogenous antioxidant systems that include superoxide dismutase, glutathione peroxidase, catalase, and vitamins that include C, D, E, and K (Chong et al , 2005e; Goffus et al , 2010; Herbas et al , 2011; Kuypers and Hoane, 2010; Lappas and Permezel, 2011; Maiese and Chong, 2003; Maiese et al , 2009b; Suzen et al , 2012; Vonder Haar et al , 2011; Wang et al , 2012b; Yuan et al , 2012).…”