Summary.
Numerous indolyl amino acids and their derivatives inhibited arginase activity. The inhibition was found to be non-competitive, – at least partly – allosteric, and independent on manganese ions in the active site, and it cannot be explained by the dissociation of arginase homotrimers. Indole alone is weakly inhibitory; however, the presence of three-carbon side chains and their net charges is favorable for the inhibition. The binding of the inhibitory compounds caused only minor changes in the steric structure of arginase: a slight increase in α-helix content was detected by circular dichroism together with a decrease in parallel pleated sheet and β-turn sections. A slight alteration in the tertiary structure was also found using tryptophane fluorescence studies, but buried apolar side chains were not transposed to the protein surface. Computer studies that were performed did not provide additional structural information.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- ANOVA:
-
Analysis of Variances between groups
- ANS:
-
8-anilino-1-naphthalenesulfonic acid
- DMEM:
-
Dulbecco Minimal Essential Medium
- FBS:
-
fetal bovine serum
- NOS:
-
nitric oxide synthase
- SDS:
-
sodium dodecyl sulfate
References
MM Bradford (1976) ArticleTitleA rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding Anal Biochem 72 248–254 Occurrence Handle942051 Occurrence Handle10.1016/0003-2697(76)90527-3 Occurrence Handle1:CAS:528:DyaE28XksVehtrY%3D
O Busnel F Carreaux B Carboni S Pethe SV Goff D Mansuy JL Boucher (2005) ArticleTitleSynthesis and evaluation of new omega-borono-alpha-amino acids as rat liver arginase inhibitors Bioorg Med Chem 13 2373–2379 Occurrence Handle15755639 Occurrence Handle10.1016/j.bmc.2005.01.053 Occurrence Handle1:CAS:528:DC%2BD2MXitVarsLk%3D
E Cama S Pethe JL Boucher S Han FA Emig DE Ash RE Viola D Mansuy DW Christianson (2004) ArticleTitleInhibitor coordination interactions in the binuclear manganese cluster of arginase Biochemistry 43 8987–8999 Occurrence Handle15248756 Occurrence Handle10.1021/bi0491705 Occurrence Handle1:CAS:528:DC%2BD2cXltFWjtrk%3D
AF Chaffotte C Cadieux Y Guillou ME Goldberg (1992) ArticleTitleA possible initial folding intermediate: the C-terminal proteolytic domain of tryptophane synthase β chains folds in less than 4 milliseconds into a condensed state with non-native-like secondary structure Biochemistry 31 4304–4308
DW Christianson (2005) ArticleTitleArginase: structure, mechanism, and physiological role in male and female sexual arousal Acc Chem Res 38 191–201 Occurrence Handle15766238 Occurrence Handle10.1021/ar040183k Occurrence Handle1:CAS:528:DC%2BD2MXhtF2jsL4%3D
JJ Coulombe L Favreau (1963) ArticleTitleA new simple semimicro method for colorimetric determination of urea Clin Chem 9 102–108 Occurrence Handle14023392 Occurrence Handle1:CAS:528:DyaF3sXktFKku7s%3D
GA Currie (1978) ArticleTitleActivated macrophages kill tumour cells by releasing arginase Nature 273 758–759 Occurrence Handle661984 Occurrence Handle10.1038/273758a0 Occurrence Handle1:CAS:528:DyaE1cXmtFensLY%3D
J Custot J-L Boucher S Vadon C Guedes S Dijols M Delaforge D Mansuy (1996) ArticleTitleNω-hydroxyamino-α-amino acids as a new class of very strong inhibitors of arginase J Bioinorg Chem 1 73–82 Occurrence Handle1:CAS:528:DyaK28XisVShs7g%3D
J Custot C Moali M Brollo J-L Boucher M Delaforge D Mansuy JP Tenu JL Zimmermann (1997) ArticleTitleThe new α-amino acid Nω-hydroxy-nor-L-arginine: a high-affinity inhibitor of arginase well adapted to bind to its manganese cluster J Am Chem Soc 119 4086–4087 Occurrence Handle10.1021/ja970285o Occurrence Handle1:CAS:528:DyaK2sXisVyjtrY%3D
L Di Costanzo G Sabio A Mora PC Rodriguez AC Ochoa F Centeno DW Christianson (2005) ArticleTitleCrystal structure of human arginase I at 1.29-Å resolution and exploration of inhibition in the immune response Proc Natl Acad Sci USA 102 13058–13063 Occurrence Handle16141327 Occurrence Handle10.1073/pnas.0504027102 Occurrence Handle1:CAS:528:DC%2BD2MXhtVaqu7bO
C Hey J-L Boucher S Vadon-Le Goff G Ketterer I Wessler K Racké (1997) ArticleTitleInhibition of arginase in rat and rabbit alveolar macrophages by Nω-hydroxy-D,L-indospicine, effects on L-arginine utilization by nitric oxide synthase Br J Pharmacol 121 395–400 Occurrence Handle9179379 Occurrence Handle10.1038/sj.bjp.0701143 Occurrence Handle1:CAS:528:DyaK2sXjs1KmsLo%3D
A Hrabák T Bajor Á Temesi (1994) ArticleTitleComparison of substrate and inhibitor specificity of arginase and nitric oxide (NO) synthase for arginine analogues and related compounds in murine and rat macrophages Biochem Biophys Res Commun 198 206–212 Occurrence Handle7507318 Occurrence Handle10.1006/bbrc.1994.1029
A Hrabák T Bajor Á Temesi (1996a) ArticleTitleComputer-aided comparison of the inhibition of arginase and nitric oxide synthase in macrophages by amino acids not related to arginine Comp Biochem Physiol 113B 375–381
A Hrabák T Bajor Á Temesi Gy Mészáros (1996b) ArticleTitleThe inhibitory effect of nitrite, a stable product of nitric oxide (NO) formation on arginase FEBS Lett 390 203–206 Occurrence Handle10.1016/0014-5793(96)00659-X
ZF Kanyo LR Scolnick DE Ash DW Christianson (1996) ArticleTitleStructure of a unique binuclear manganese cluster in arginase Nature 383 554–557 Occurrence Handle8849731 Occurrence Handle10.1038/383554a0 Occurrence Handle1:CAS:528:DyaK28Xmt1Gqtrg%3D
LT Lavulo TM Sossong SuffixJr MR Brigham-Burke ML Doyle JD Cox DW Christianson DE Ash (2001) ArticleTitleSubunit-subunit interactions in trimeric arginase. Generation of active monomers by mutation of a single amino acid J Biol Chem 276 14242–14248 Occurrence Handle11278703 Occurrence Handle1:CAS:528:DC%2BD3MXjt12rtr4%3D
XL Li XD Lei H Cai J Li SL Yang CC Wang CL Tsou (1998) ArticleTitleBinding of a burst-phase intermediate formed in the folding of denatured D-glyceraldehyde-3-phosphate dehydrogenase by chaperonin 60 and 8-anilino-1-naphtalenesulfonic acid Biochem J 331 505–511 Occurrence Handle9531491 Occurrence Handle1:CAS:528:DyaK1cXivV2isb0%3D
J MacMicking Q-w Xie C Nathan (1997) ArticleTitleNitric oxide and macrophage function Annu Rev Immunol 15 323–350 Occurrence Handle9143691 Occurrence Handle10.1146/annurev.immunol.15.1.323 Occurrence Handle1:CAS:528:DyaK2sXisVCmsLo%3D
M Munder K Eichmann M Modolell (1998) ArticleTitleAlternative metabolic states in murine macrophages reflected by nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotypes J Immunol 160 5347–5354 Occurrence Handle9605134 Occurrence Handle1:CAS:528:DyaK1cXjt1Gnu7s%3D
RT Schimke (1970) ArticleTitleArginase (rat liver) Methods Enzymol 17A 313–317 Occurrence Handle10.1016/0076-6879(71)17203-5
H Shin E Cama DW Christianson (2004) ArticleTitleDesign of amino acid aldehydes as transition-state analogue inhibitors of arginase J Am Chem Soc 126 10278–10284 Occurrence Handle15315440 Occurrence Handle10.1021/ja047788w Occurrence Handle1:CAS:528:DC%2BD2cXmtVOjt7w%3D
CD Tormanen (2006) ArticleTitleInhibition of rat liver and kidney arginase by cadmium ion J Enzyme Inhib Med Chem 21 119–123 Occurrence Handle16570515 Occurrence Handle10.1080/14756360500483420 Occurrence Handle1:CAS:528:DC%2BD28XjtFCitL4%3D
Q-W Xie HJ Cho J Calaycay RA Mumford KM Swiderek TD Lee A Ding T Croso CF Nathan (1992) ArticleTitleCloning and characterization of inducible nitric oxide synthase from mouse macrophages Science 256 225–228 Occurrence Handle1373522 Occurrence Handle10.1126/science.1373522 Occurrence Handle1:CAS:528:DyaK38XksVent7Y%3D
Author information
Authors and Affiliations
Additional information
Authors’ address: András Hrabák, Department of Medical Chemistry, Molecular Biology and Patho-biochemistry, Semmelweis University Medical School, Budapest, VIII. Puskin u. 9., H-1444 POB 260, Hungary
Rights and permissions
About this article
Cite this article
Hrabák, A., Bajor, T. & Mészáros, G. The inhibitory effect of various indolyl amino acid derivatives on arginase activity in macrophages. Amino Acids 34, 293–300 (2008). https://doi.org/10.1007/s00726-006-0470-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-006-0470-3