Recent advances with alkaline phosphatase isoenzymes and their inhibitors

Abstract

Alkaline phosphatases are found in different living species and play crucial roles in various significant functions, such as hydrolyzing a variable spectrum of phosphatecontaining physiological compounds, contributing to DNA synthesis, bone calcification, and attenuation of inflammation. They are homodimeric enzymes; each subunit contains one magnesium ion and two zinc ions crucial for the catalytic activity of the enzyme. Alkaline phosphatases exist in four distinct isoenzymes (placental, intestinal, germ cell, and tissue nonspecific alkaline phosphatases), which are expressed by four different genes; each one of them has distinguished functions. Any disturbance in the gene expression of alkaline phosphatase eventually induces serious disease conditions. Thus, the need to explore new lead inhibitors has increased recently. In this literature review, we aim to investigate the role of alkaline phosphatase in different diseases and physiological conditions and to study the structure-activity relationships of recently reported inhibitors. We focused on the lead compounds reported in the last 5 years (between 2015 and 2019). K E Y W O R D S alkaline phosphatase, inhibitors, isoenzymes, structure-activity relationship

2-Benzylidenebenzofuran-3(2H)-ones as a new class of alkaline phosphatase inhibitors: synthesis, SAR analysis, enzyme inhibitory kinetics and computational studies

“…General procedures for the synthesis of chalcones (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) and aurones (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) In step 1, a mixture of substituted 2 0 -hydroxyacetophenone (1.0 mmol) and aqueous sodium hydroxide solution (30%, 5.0 mL) was dissolved in distilled methanol (20.0 mL) and stirred for 30 min at room temperature followed by the dropwise addition of substituted aryl aldehyde (1.0 mmol). Subsequently, the reaction mixture was stirred at the same temperature for 3-4 h. The progress of the formation of 2 0 -hydroxychalcone was examined by TLC using cyclohexane : ethyl acetate (3 : 1) as the mobile phase.…”

“…3.1.3.1) are membrane-bound ectonucleotidases/hydrolase enzymes, which are ubiquitous in nature from bacteria to mammals, with the ability to perform signicant physiological functions that accelerate the hydrolysis of esters containing phosphate groups. [1][2][3][4][5][6][7][8][9] They are responsible for the effective removal of phosphate groups from alkaloids, nucleotides and proteins in alkaline medium. 10 APs are dimeric non-specic enzymes with regard to the substrate, and thus hydrolyze various substrates.…”

Targeting the Intestinal Barrier to Prevent Gut-Derived Inflammation and Disease: A Role for Intestinal Alkaline Phosphatase

“…Previous studies have demonstrated that a high levels of adenosine triphosphate (ATP) lead to a disturbance of intestinal microbial homeostasis. Thus, the influence of IAP on regulation of the number and diversity of commensal bacteria in the intestine may be achieved by dephosphorylation of ATP [12].…”

“…Here, IAP forms a regulatory loop together with extracellular detrimental ATP, and G-protein coupled purinergic receptor P2Y1 (located on the brush border membrane of duodenal villi), to control intestinal surface pH [13]; ATP stimulates P2Y receptors to secrete bicarbonate ions. Bicarbonate neutralizes the acidic environment and promotes IAP activity [12]. Conversely, a high duodenal surface pH can augment IAP activity, thereby increasing the rate of ATP degradation, decreasing the bicarbonate release and forming a negative feedback loop [12].…”

“…Bicarbonate neutralizes the acidic environment and promotes IAP activity [12]. Conversely, a high duodenal surface pH can augment IAP activity, thereby increasing the rate of ATP degradation, decreasing the bicarbonate release and forming a negative feedback loop [12].…”