On the cellular metabolism of the click chemistry probe 19-alkyne arachidonic acid

Alkyne and azide analogs of natural compounds that can be coupled to sensitive tags by click chemistry are powerful tools to study biological processes. Arachidonic acid (AA) is a FA precursor to biologically active compounds. 19-Alkyne-AA (AA-alk) is a sensitive clickable AA analog; however, its use as a surrogate to study AA metabolism requires further evaluation. In this study, AA-alk metabolism was compared with that of AA in human cells. Jurkat cell uptake of AA was 2-fold greater than that of AA-alk, but significantly more AA-Alk was elongated to 22:4. AA and AA-alk incorporation into and remodeling between phospholipid (PL) classes was identical indicating equivalent CoA-independent AA-PL remodeling. Platelets stimulated in the pre­sence of AA-alk synthesized significantly less 12-lipoxygenase (12-LOX) and cyclooxygenase products than in the presence of AA. Ionophore-stimulated neutrophils produced significantly more 5-LOX products in the presence of AA-alk than AA. Neutrophils stimulated with only exogenous AA-alk produced significantly less 5-LOX products compared with AA, and leukotriene B4 (LTB4)-alk was 12-fold less potent at stimulating neutrophil migration than LTB4, collectively indicative of weaker leukotriene B4 receptor 1 agonist activity of LTB4-alk. Overall, these results suggest that the use of AA-alk as a surrogate for the study of AA metabolism should be carried out with caution. Alkyne and azide analogs of natural compounds that can be coupled to sensitive tags by click chemistry are powerful tools to study biological processes. Arachidonic acid (AA) is a FA precursor to biologically active compounds. 19-Alkyne-AA (AA-alk) is a sensitive clickable AA analog; however, its use as a surrogate to study AA metabolism requires further evaluation. In this study, AA-alk metabolism was compared with that of AA in human cells. Jurkat cell uptake of AA was 2-fold greater than that of AA-alk, but significantly more AA-Alk was elongated to 22:4. AA and AA-alk incorporation into and remodeling between phospholipid (PL) classes was identical indicating equivalent CoA-independent AA-PL remodeling. Platelets stimulated in the pre­sence of AA-alk synthesized significantly less 12-lipoxygenase (12-LOX) and cyclooxygenase products than in the presence of AA. Ionophore-stimulated neutrophils produced significantly more 5-LOX products in the presence of AA-alk than AA. Neutrophils stimulated with only exogenous AA-alk produced significantly less 5-LOX products compared with AA, and leukotriene B4 (LTB4)-alk was 12-fold less potent at stimulating neutrophil migration than LTB4, collectively indicative of weaker leukotriene B4 receptor 1 agonist activity of LTB4-alk. Overall, these results suggest that the use of AA-alk as a surrogate for the study of AA metabolism should be carried out with caution. The click chemistry reactions that easily conjugate molecules together are now widely used to discover new drugs and inhibitor targets (1Kolb H.C. Sharpless K.B. The growing impact of click chemistry on drug discovery.Drug Discov. Today. 2003; 8: 1128-1137Crossref PubMed Scopus (2867) Google Scholar, 2Cravatt B.F. Wright A.T. Kozarich J.W. Activity-based protein profiling: from enzyme chemistry to proteomic chemistry.Annu. Rev. Biochem. 2008; 77: 383-414Crossref PubMed Scopus (879) Google Scholar, 3Niphakis M.J. Cravatt B.F. Enzyme inhibitor discovery by activity-based protein profiling.Annu. Rev. Biochem. 2014; 83: 341-377Crossref PubMed Scopus (240) Google Scholar, 4Nwe K. Brechbiel M.W. Growing applications of “click chemistry” for bioconjugation in contemporary biomedical research.Cancer Biother. Radiopharm. 2009; 24: 289-302Crossref PubMed Scopus (246) Google Scholar). 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Full Text Full Text PDF PubMed Scopus Google Scholar, K. acid remodeling in cellular glycerophospholipids the of human Lipid 54: Full Text Full Text PDF PubMed Scopus Google Scholar, remodeling and Opin. 2015; PubMed Scopus Google of cellular AA incorporation and into AA is by to the for its incorporation into phospholipids by the of The of is to the can be elongated to the of of very into AA can be between species by CoA-independent cell the of AA from can be into lipid by the of and leukotriene LTB4, leukotriene cell AA can be from by and can be by and into many lipid and remodeling and Opin. 2015; PubMed Scopus Google Scholar, B. of the activity of a enzyme in leukotriene 2010; PubMed Scopus Google Scholar, of the cyclooxygenase of Rev. 2011; PubMed Scopus Google Scholar, in and Rev. 2015; PubMed Scopus Google Scholar). can the of exogenous AA. The in cell the lipid these compounds are lipid of and have been shown to in the of including as as in in and Rev. 2015; PubMed Scopus Google Scholar, D. B. a enzyme for leukotriene in and 2015; PubMed Scopus Google Scholar, in and Med. 2008; 8: PubMed Scopus Google Scholar). The of this study is to AA-alk is a of AA for cellular and Overall, the results suggest that AA-alk be a surrogate for of cellular AA-PL metabolism but be for in lipid and in was from The was from The was from FA and from AA-alk was from Jurkat in with and 1 at in a FA incorporation Jurkat in the presence of AA AA-alk for at with and cellular lipids in using as A of lipid and Biochem. PubMed Scopus Google Scholar). Jurkat labeled in of AA-alk for at with and for cellular lipid lipids in A of lipid and Biochem. 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PubMed Scopus Google Scholar). using as in the the for to study was by the for human to in the from AA and AA-alk and by was that at a of than that of the ability of to exogenous AA-alk and AA, Jurkat with of FA for lipids and cellular In with AA-alk, a to AA-alk was on as as at on the of AA-alk, AA, and this at a the be The of the was by the of the was to be is the of the The of AA-alk and equivalent a very of AA-alk this In with exogenous AA, the cellular AA and the the in cellular AA was greater than that of the uptake of exogenous AA and AA-alk including more AA than AA-alk this this that the to AA into was greater than that of AA-alk, a greater of the AA-alk was elongated compared with AA. The uptake of exogenous AA into glycerophospholipids is to a the incorporation of AA is into by a remodeling into species D. in human of from to Biol. Chem. 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Soc. 2014; 136: PubMed Scopus Google the of the as was by A with the of for a was its products with of and as the of a with of and Serwa R. Tallman K.A. M. Marnett L.J. Porter N.A. lipid surrogates for and enzymatic Am. Chem. Soc. 2014; 136: PubMed Scopus Google Scholar, P. of PubMed Scopus Google Scholar). the of with of Serwa R. Tallman K.A. M. Marnett L.J. Porter N.A. lipid surrogates for and enzymatic Am. Chem. Soc. 2014; 136: PubMed Scopus Google Scholar, P. of PubMed Scopus Google was Platelets stimulated in the presence of exogenous AA-alk produced and from AA. Overall, the of and products was significantly in stimulated in the presence of AA-alk than in stimulated in the presence of exogenous AA The synthesized by stimulated human neutrophils are products of the 5-LOX human neutrophils products neutrophils the stimulated with PubMed Scopus (22) Google Scholar, M.J. and metabolism of acid in human Biol. Chem. Full Text PDF PubMed Google Scholar). human neutrophils stimulated with in the presence of exogenous the 5-LOX products LTB4, and and the products and by with neutrophils stimulated in the presence of exogenous AA-alk, by that to 5-LOX products with the but on than for AA with the AA-alk was the of was that was the 5-LOX from AA-alk, was a less 5-LOX synthesized by the stimulated in the presence of exogenous AA The as was by and its was compared with that of with the of for M. E. D. Brown A. structure PubMed Scopus Google Scholar, P. of leukotriene B4 and Am. Soc. PubMed Scopus (37) Google and of for and with of and for and LTB4, as be on the with the that the of the P. of leukotriene B4 and Am. Soc. PubMed Scopus (37) Google Scholar). from of the of the as from and and and and as as P. of leukotriene B4 and Am. Soc. PubMed Scopus (37) Google Scholar). with and in the of that are to from but with by with alkyne the as the and that was for Serwa R. Tallman K.A. M. Marnett L.J. Porter N.A. lipid surrogates for and enzymatic Am. Chem. Soc. 2014; 136: PubMed Scopus Google Scholar). The of 5-LOX products was in that with human 5-LOX and The and of the human from that of its 2015; PubMed Scopus Google Scholar). is to 5-LOX from exogenous substrates because release AA stimulated and the with a 5-LOX stimulated in the presence of AA AA-alk, 5-LOX products produced the stimulated in the presence of exogenous 5-LOX products synthesized in the as in with more AA-alk products produced than of AA, and with as the AA-alk Overall, the of 5-LOX products and was significantly greater in neutrophils stimulated in the presence of AA-alk than in stimulated in the presence of exogenous AA AA can human neutrophils exogenous AA is to LTB4, the leukotriene B4 receptor 1 a greater of exogenous AA the 5-LOX E. S. P. of leukotriene in human neutrophils by exogenous by receptor and of by leukotriene PubMed Scopus Google Scholar). neutrophils with exogenous AA AA-alk to the exogenous AA the of 5-LOX AA-alk a cellular that the was by of the biological of is its potent activity human the biological of and ability to neutrophil was a was more potent at stimulating neutrophil than The use of alkyne azide analogs of biological compounds that are to click chemistry reactions is to the ability to the compounds with sensitive of with the complex biological The use of these compounds can the ability to the compounds of from complex to be useful as probes is to the to a clickable its natural are for click chemistry probes because the of the is to be a biologically of the can be into a FA have proved to be useful in the of palmitoylated proteins as tubulin, and A.D. Jovanovic B. Ciepla P. Spitaler M. Lanyon-Hogg T. Tate E.W. Magee A.I. Topological analysis of Hedgehog acyltransferase, a multipalmitoylated transmembrane protein.J. Biol. Chem. 2015; 290: 3293-3307Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 12Gao X. Hannoush R.N. Method for cellular imaging of palmitoylated proteins with clickable probes and proximity ligation applied to Hedgehog, tubulin, and Ras.J. Am. Chem. Soc. 2014; 136: 4544-4550Crossref PubMed Scopus (53) Google Scholar, X. Hannoush R.N. imaging of by the Chem. Biol. 2014; PubMed Scopus Google that are to the that have been as click chemistry probes is the of AA, AA-alk K. Tallman K.A. S. Porter N.A. with to Lipid 54: Full Text Full Text PDF PubMed Scopus Google Scholar, Serwa R. Tallman K.A. M. Marnett L.J. Porter N.A. lipid surrogates for and enzymatic Am. Chem. Soc. 2014; 136: PubMed Scopus Google Scholar). AA is the precursor of biologically active lipid and as of compared with FAs, because of its in biological processes including The study compared the cellular metabolism of AA and AA-alk in the Jurkat cell that AA between as as in human that and and in human neutrophils that that the of AA into biologically active Overall, AA-alk to AA with to cellular uptake and into cellular however, its metabolism as a precursor for biologically active from its AA. have for to for cell K. acid remodeling in cellular glycerophospholipids the of human Lipid 54: Full Text Full Text PDF PubMed Scopus Google Scholar, A. in 2015; PubMed Scopus Google Scholar). with exogenous AA AA-alk, Jurkat exogenous AA. the to exogenous AA-alk was significantly with of the for AA. AA are into by that can and processes. in the uptake of FA and the FA protein of proteins A. M. S. T. K. T. and that the acid of and the metabolism of lipid in and Lipid 2014; PubMed Scopus Google Scholar, E. Biol. Med. 2008; PubMed Scopus Google Scholar, C. A. proteins in acid uptake by and PubMed Scopus Google Scholar). to in activity been shown to be for incorporation into and of human have been A. M. S. T. K. T. and that the acid of and the metabolism of lipid in and Lipid 2014; PubMed Scopus Google Scholar, M. R. acid uptake and Biochem. 2009; PubMed Scopus Google Scholar, A in Opin. 2010; 21: PubMed Scopus Google Scholar, of and 1 in the by and 290: PubMed Scopus Google with the for AA. cellular AA incorporation can the of FA proteins and the of proteins with AA uptake is and can be at in cell the of cellular uptake in been the results of the study suggest that the are as with AA-alk as a indicating that the use of AA-alk as a to study AA proteins should be with caution. into AA is by to AA can be into glycerophospholipids by reactions by to by a by to incorporation into AA-alk was as into as AA, of the AA-alk that was to its compared with only of the AA. that compared with AA, AA-alk is more as a for the in Jurkat cells. in of the these a of exogenous AA because its and is more than with of the this in these suggest that results with AA-alk as a surrogate for the study of AA be AA a of incorporation into and remodeling between classes that to be for AA compared with D. in human of from to Biol. Chem. Full Text PDF PubMed Google Scholar, K. acid remodeling in cellular glycerophospholipids the of human Lipid 54: Full Text Full Text PDF PubMed Scopus Google Scholar, T. K. of acid between and phospholipids in PubMed Scopus Google Scholar, M. of PubMed Scopus Google Scholar). remodeling is to have because AA is the precursor of very potent and have to its cellular and cellular uptake and the of incorporation of AA-alk and AA into the classes identical with between and of the incorporation occurring in to into and and less than into that the that the incorporation into classes to and in a Furthermore, the remodeling of AA from species to species was identical for AA and AA-alk to be a very surrogate of AA AA incorporation into and remodeling between cell and can exogenous AA into by reactions by and these are by exogenous AA, as as AA from by is by these into a of exogenous AA-alk as a for and of and the produced by these compared with AA that AA-alk is as by as AA. results are with a the of AA and AA-alk by human the of AA was more than that of AA-alk Serwa R. Tallman K.A. M. Marnett L.J. Porter N.A. lipid surrogates for and enzymatic Am. Chem. Soc. 2014; 136: PubMed Scopus Google Scholar). to AA-alk but the of to Serwa R. Tallman K.A. M. Marnett L.J. Porter N.A. lipid surrogates for and enzymatic Am. Chem. Soc. 2014; 136: PubMed Scopus Google is with the very of by stimulated the of that from the was in stimulated human human neutrophils AA the 5-LOX stimulated in the presence of AA-alk, alkyne of the 5-LOX products synthesized with the of the products and is because the protein for the of the of AA E. K. S. K. M. A of in human and of leukotriene B4 Biol. Chem. Full Text PDF PubMed Google the of the at the of the AA-alk are to and is a new in the of PubMed Scopus Google Scholar). the to LTB4, stimulated in the presence of AA-alk of compared with in stimulated in the presence of AA. In to neutrophils produced more 5-LOX stimulated in the presence of AA-alk than in the presence of AA, and this was to the significantly greater of compared with In was a in was the AA-alk and its the identical 5-LOX in cells. that the of AA-alk at is but that the that of a at from to the is as as with the the presence of the structure to impact the of 5-LOX for of the The is are significantly on the suggest that the use of AA-alk as a surrogate for the study of lipid metabolism be with caution. In the of exogenous AA can human neutrophils In this 5-LOX activity exogenous AA into in a the receptor a more cellular with a of 5-LOX and more of exogenous AA the 5-LOX E. S. P. of leukotriene in human neutrophils by exogenous by receptor and of by leukotriene PubMed Scopus Google Scholar). AA-alk produced a weaker of human neutrophils this than that of exogenous AA. be because AA-alk is to than LTB4, the of the that on a of that is a weaker agonist than and at be potent to the of of the for this by exogenous AA-alk, this that cellular to exogenous AA-alk are as as in to exogenous AA. In of the more of neutrophils in to AA-alk compared with AA, the biological activity of was compared with that of is as a very potent human M.J. a potent and from PubMed Scopus Google Scholar, of leukotriene neutrophil by Google Scholar, M. C.M. K.A. C.A. is a neutrophil Full Text Full Text PDF PubMed Scopus Google Scholar). human neutrophil migration was in a migration activity in the as P. L. C. M. D. M. The human of its and leukotriene B4 2011; PubMed Scopus Google Scholar). activity was less potent than that of by a of is on of the receptor of leukotriene neutrophil by Google Scholar, M. C.M. K.A. C.A. is a neutrophil Full Text Full Text PDF PubMed Scopus Google Scholar, P. L. C. M. D. M. The human of its and leukotriene B4 2011; PubMed Scopus Google this that is a weaker agonist than and that the biological activity of these the weaker ability of AA-alk and to that using should be that are to click chemistry are to be useful and discovery tools to and biological to natural analogs, and the with can be labeled and in complex biological alkyne of are these and are powerful tools that have new on the study the use of AA-alk as a powerful to AA metabolism and in biological in its metabolism and biological activity have been that should be useful to use these tools to AA in biological The for with FA analysis by with acid acid acid alkyne leukotriene B4 receptor 1 CoA-independent cyclooxygenase of very FA with 5-LOX protein leukotriene B4 phospholipid

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