Inhibition of AMP deaminase as therapeutic target in cardiovascular pathology

Abstract

AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. This reaction helps to maintain healthy cellular energetics by removing excess AMP that accumulates in energy depleted cells. Furthermore, AMPD permits the synthesis of guanine nucleotides from the larger adenylate pool. This enzyme competes with cytosolic 5'-nucleotidases (c5NT) for AMP. Adenosine, a product of c5NT is a vasodilator, antagonizes inotropic effects of catecholamines and exerts anti-platelet, anti-inflammatory and immunosuppressive activities. The ratio of AMPD/c5NT defines the amount of adenosine produced in adenine nucleotide catabolic pathway. Inhibition of AMPD could alter this ratio resulting in increased adenosine production. Besides the potential effect on adenosine production, elevation of AMP due to inhibition of AMPD could also lead to activation of AMP regulated protein kinase (AMPK) with myriad of downstream events including enhanced energetic metabolism, mitochondrial biogenesis and cytoprotection. While the benefits of these processes are well appreciated in cells such as skeletal or cardiac myocytes its role in protection of endothelium could be even more important. Therapeutic use of AMPD inhibition has been limited due to difficulties with obtaining compounds with adequate characteristics. However, endothelium seems to be the easiest target as effective inhibition of AMPD could be achieved at much lower concentration than in the other types of cells. New generation of AMPD inhibitors has recently been established and its testing in context of endothelial and organ protection could provide important basic knowledge and potential therapeutic tools.

Molecular implications of adenosine in obesity

“…The nucleoside adenosine is an endogenous purine formed by and adenine and Dribose bound by a β-N9-glycosidic bond that is produced by the degradation of ATP, ADP and AMP. Produced in almost all mammalian cells, the extracellular adenosine concentration is highly regulated, and depend of ATP, ADP and AMP levels, CD73 and adenosine deaminase (ADA) enzymatic activity and the nucleoside uptake transport capacity of the cell (Fernandez et al, 2013;Zabielska et al, 2015). The broad actions of adenosine are largely due to the existence of multiple receptors.…”

Up-regulated Ectonucleotidases in Fas-Associated Death Domain Protein– and Receptor-Interacting Protein Kinase 1–Deficient Jurkat Leukemia Cells Counteract Extracellular ATP/AMP Accumulation via Pannexin-1 Channels during Chemotherapeutic Drug-Induced Apoptosis

“…7A and Table 1). AMP deaminase, which has been described in extracellular neuromuscular synaptic junctions (Magalhães-Cardoso et al, 2003), catalyzes conversion of AMP to IMP, is distinct from adenosine deaminase, and can be inhibited by pentostatin/deoxycoformycin (Matsumoto et al, 1979;Fishbein et al, 1981;Zabielska et al, 2015). TNAP acts as a potent ecto-AMPase in some tissues and can be inhibited by levamisole or tetramisole (Picher et al, 2003;Millán, 2006).…”

MicroRNA‑217 is involved in the progression of atherosclerosis through regulating inflammatory responses by targeting sirtuin 1

“…AMPK activation mediates vascular inflammation and leukocyte adhesiveness (45). Therefore, AMPK may have potential roles in cardiovascular disease through its anti-inflammatory effect (46). To explore the molecular mechanism of the effect of miR-217 inhibitor on ox-LDL treated THP-1 macrophages, the SIRT1/AMPK-α/nF-κB pathway was analyzed in the present study.…”