FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2988692214> ?p ?o ?g. }

• W2988692214 endingPage "19423" @default.
• W2988692214 startingPage "19405" @default.
• W2988692214 abstract "Lipopolysaccharide (LPS) from the Gram-negative bacterial outer membrane potently activates the human innate immune system. LPS is recognized by the Toll-like receptor 4/myeloid differentiation factor-2 (TLR4/MD2) complex, leading to the release of pro-inflammatory cytokines. Alkaline phosphatase (AP) is currently being investigated as an anti-inflammatory agent for detoxifying LPS through dephosphorylating lipid A, thus providing a potential treatment for managing both acute (sepsis) and chronic (metabolic endotoxemia) pathologies wherein aberrant TLR4/MD2 activation has been implicated. Endogenous LPS preparations are chemically heterogeneous, and little is known regarding the LPS chemotype substrate range of AP. Here, we investigated the activity of AP on a panel of structurally defined LPS chemotypes isolated from Escherichia coli and demonstrate that calf intestinal AP (cIAP) has only minimal activity against unmodified enteric LPS chemotypes. Pi was only released from a subset of LPS chemotypes harboring spontaneously labile phosphoethanolamine (PEtN) modifications connected through phosphoanhydride bonds. We demonstrate that the spontaneously hydrolyzed O-phosphorylethanolamine is the actual substrate for AP. We found that the 1- and 4′-lipid A phosphate groups critical in TLR4/MD2 signaling become susceptible to hydrolysis only after de-O-acylation of ester linked primary acyl chains on lipid A. Furthermore, PEtN modifications on lipid A specifically enhanced hTLR4 agonist activity of underacylated LPS preparations. Computational binding models are proposed to explain the limitation of AP substrate specificity imposed by the acylation state of lipid A, and the mechanism of PEtN in enhancing hTLR4/MD2 signaling. Lipopolysaccharide (LPS) from the Gram-negative bacterial outer membrane potently activates the human innate immune system. LPS is recognized by the Toll-like receptor 4/myeloid differentiation factor-2 (TLR4/MD2) complex, leading to the release of pro-inflammatory cytokines. Alkaline phosphatase (AP) is currently being investigated as an anti-inflammatory agent for detoxifying LPS through dephosphorylating lipid A, thus providing a potential treatment for managing both acute (sepsis) and chronic (metabolic endotoxemia) pathologies wherein aberrant TLR4/MD2 activation has been implicated. Endogenous LPS preparations are chemically heterogeneous, and little is known regarding the LPS chemotype substrate range of AP. Here, we investigated the activity of AP on a panel of structurally defined LPS chemotypes isolated from Escherichia coli and demonstrate that calf intestinal AP (cIAP) has only minimal activity against unmodified enteric LPS chemotypes. Pi was only released from a subset of LPS chemotypes harboring spontaneously labile phosphoethanolamine (PEtN) modifications connected through phosphoanhydride bonds. We demonstrate that the spontaneously hydrolyzed O-phosphorylethanolamine is the actual substrate for AP. We found that the 1- and 4′-lipid A phosphate groups critical in TLR4/MD2 signaling become susceptible to hydrolysis only after de-O-acylation of ester linked primary acyl chains on lipid A. Furthermore, PEtN modifications on lipid A specifically enhanced hTLR4 agonist activity of underacylated LPS preparations. Computational binding models are proposed to explain the limitation of AP substrate specificity imposed by the acylation state of lipid A, and the mechanism of PEtN in enhancing hTLR4/MD2 signaling." @default.
• W2988692214 created "2019-11-22" @default.
• W2988692214 creator A5016781668 @default.
• W2988692214 creator A5019058431 @default.
• W2988692214 creator A5022037650 @default.
• W2988692214 creator A5034555281 @default.
• W2988692214 creator A5062535029 @default.
• W2988692214 creator A5064567113 @default.
• W2988692214 creator A5071472795 @default.
• W2988692214 creator A5082528655 @default.
• W2988692214 creator A5088043686 @default.
• W2988692214 date "2019-12-01" @default.
• W2988692214 modified "2023-09-30" @default.
• W2988692214 title "Substrate structure-activity relationship reveals a limited lipopolysaccharide chemotype range for intestinal alkaline phosphatase" @default.
• W2988692214 cites W1536714132 @default.
• W2988692214 cites W155521478 @default.
• W2988692214 cites W1555904090 @default.
• W2988692214 cites W1567737567 @default.
• W2988692214 cites W1578067645 @default.
• W2988692214 cites W1592699099 @default.
• W2988692214 cites W1603760485 @default.
• W2988692214 cites W1885710768 @default.
• W2988692214 cites W1896319706 @default.
• W2988692214 cites W1905378326 @default.
• W2988692214 cites W1915389514 @default.
• W2988692214 cites W1955383272 @default.
• W2988692214 cites W1967003457 @default.
• W2988692214 cites W1967501462 @default.
• W2988692214 cites W1972208054 @default.
• W2988692214 cites W1973399759 @default.
• W2988692214 cites W1984236474 @default.
• W2988692214 cites W1985048571 @default.
• W2988692214 cites W1995995599 @default.
• W2988692214 cites W2004927612 @default.
• W2988692214 cites W2005482276 @default.
• W2988692214 cites W2008238093 @default.
• W2988692214 cites W2008407072 @default.
• W2988692214 cites W2008487520 @default.
• W2988692214 cites W2011683499 @default.
• W2988692214 cites W2013178634 @default.
• W2988692214 cites W2014361215 @default.
• W2988692214 cites W2015642465 @default.
• W2988692214 cites W2021032925 @default.
• W2988692214 cites W2023007981 @default.
• W2988692214 cites W2025468966 @default.
• W2988692214 cites W2030002872 @default.
• W2988692214 cites W2036048288 @default.
• W2988692214 cites W2036478186 @default.
• W2988692214 cites W2036559697 @default.
• W2988692214 cites W2040898591 @default.
• W2988692214 cites W2043041439 @default.
• W2988692214 cites W2044375660 @default.
• W2988692214 cites W2049502419 @default.
• W2988692214 cites W2051101891 @default.
• W2988692214 cites W2052875305 @default.
• W2988692214 cites W2053655646 @default.
• W2988692214 cites W2053881022 @default.
• W2988692214 cites W2054317956 @default.
• W2988692214 cites W2064355487 @default.
• W2988692214 cites W2065725792 @default.
• W2988692214 cites W2066052326 @default.
• W2988692214 cites W2066063987 @default.
• W2988692214 cites W2066318573 @default.
• W2988692214 cites W2066834458 @default.
• W2988692214 cites W2071108985 @default.
• W2988692214 cites W2074044150 @default.
• W2988692214 cites W2074160421 @default.
• W2988692214 cites W2074238456 @default.
• W2988692214 cites W2079358513 @default.
• W2988692214 cites W2081652058 @default.
• W2988692214 cites W2082509173 @default.
• W2988692214 cites W2086676026 @default.
• W2988692214 cites W2087041328 @default.
• W2988692214 cites W2093738560 @default.
• W2988692214 cites W2095619327 @default.
• W2988692214 cites W2096728699 @default.
• W2988692214 cites W2098996610 @default.
• W2988692214 cites W2099156985 @default.
• W2988692214 cites W2099231162 @default.
• W2988692214 cites W2105668062 @default.
• W2988692214 cites W2110076909 @default.
• W2988692214 cites W2115893060 @default.
• W2988692214 cites W2115996594 @default.
• W2988692214 cites W2116137883 @default.
• W2988692214 cites W2116309640 @default.
• W2988692214 cites W2117204128 @default.
• W2988692214 cites W2122921940 @default.
• W2988692214 cites W2123743410 @default.
• W2988692214 cites W2125351457 @default.
• W2988692214 cites W2126279424 @default.
• W2988692214 cites W2127934565 @default.
• W2988692214 cites W2128257992 @default.
• W2988692214 cites W2130479394 @default.
• W2988692214 cites W2131536322 @default.
• W2988692214 cites W2132629607 @default.
• W2988692214 cites W2134408956 @default.
• W2988692214 cites W2146134298 @default.
• W2988692214 cites W2151387894 @default.

• next